Subclinical Atherosclerosis Measure by Carotid Ultrasound and Inflammatory Activity in Patients with Rheumatoid Arthritis and Spondylarthritis

Objective: To compare the effect of inflammation on subclinical atherosclerosis using carotid ultrasound in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). Methods: Cross-sectional study including 347 participants (148 RA, 159 SpA, and 40 controls). We measured the carotid intima media thickness (cIMT) and detection of atheromatous plaques using carotid ultrasound. We recorded disease activity (DAS28-CRP/ASDAS-CRP) and traditional cardiovascular risk factors. We performed descriptive, bivariate, and linear multivariate analyses (dependent variable: cIMT) to evaluate the influence of diagnosis on cIMT in all patients. Two additional multivariate analyses were performed by stratifying patients according to their inflammatory activity. Results: cIMT correlated with the mean CRP during the previous 5 years in RA, but not with CRP at the cut-off date. We did not find such differences in patients with SpA. The first multivariate model revealed that increased cIMT was more common in patients with RA than in those with SpA (β coefficient, 0.045; 95% confidence interval (95% CI), 0.0002–0.09; p = 0.048) after adjusting for age, sex, disease course, and differential cardiovascular risk factors (arterial hypertension, smoking, statins, and corticosteroids). The second model revealed no differences in cIMT between the 2 groups of patients classified as remission–low activity (β coefficient, 0.020; 95% CI, −0.03 to 0.080; p = 0.500). However, when only patients with moderate–high disease activity were analysed, the cIMT was 0.112 mm greater in those with RA (95% CI, 0.013–0.212; p = 0.026) than in those with SpA after adjusting for the same variables. Conclusions: Subclinical atherosclerosis measured by carotid ultrasound in patients with RA and SpA is comparable when the disease is well controlled. However, when patients have moderate–high disease activity, cIMT is greater in patients with RA than in those with SpA after adjusting for age, sex, disease course, and cardiovascular risk factors. Our results point to greater involvement of disease activity in subclinical atherosclerosis in patients with RA than in those with SpA

Prevalence and Associated Factors of Low Bone Mineral Density in the Femoral Neck and Total Hip in Axial Spondyloarthritis: Data from the CASTRO Cohort

Studies on osteoporosis in axial spondyloarthritis (axSpA) have focused on the lumbar segment, and few studies have assessed bone mineral density (BMD) in the hip and femoral neck in these patients. The aim of this study was to evaluate the prevalence of low BMD and osteopenia in the total hip or femoral neck and the factors associated with these conditions in axSpA patients. This was a single-centre, observational, cross-sectional study among consecutive patients with axSpA according to the ASAS criteria from the CASTRO registry. All patients underwent total hip and femoral neck DXA BMD measurements. Low BMD was defined as a Z-score less than −1, and osteopenia was defined as a T-score less than −1. Multivariate logistic and generalised linear regressions were used to evaluate factors independently associated with low BMD and osteopenia in the hip or femoral neck and those associated with variability in BMD, respectively. A total of 117 patients were included, among which 30.8% were female and the mean age was 45 years. A total of 36.0% of patients had low BMD (28.1% in the total hip and 27.4% in the femoral neck), and 56.0% of patients had osteopenia (44.7% in the total hip and 53.8% in the femoral neck). A multivariate logistic regression showed that age, radiographic sacroiliitis and ASAS-HI were independently associated with low BMD in the total hip or femoral neck. Factors that were independently associated with osteopenia were Body Mass Index, disease duration, radiographic sacroiliitis and ASAS-HI. In conclusion, 36% of the patients with axSpA had low BMD in the total hip or femoral neck. A younger age and radiographic sacroiliitis were the most important factors associated with decreased BMD

The clinical and molecular cardiometabolic fingerprint of an exploratory psoriatic arthritis cohort is associated with the disease activity and differentially modulated by methotrexate and apremilast

Objectives: (1) To evaluate clinical and molecular cardiovascular disease (CVD) signs and their relationship with psoriatic arthritis (PsA) features and (2) to identify a clinical patient profile susceptible to benefit from methotrexate (MTX) and/or apremilast regarding CVD risk. Methods: This cross-sectional study included 100 patients with PsA and 100 age-matched healthy donors. In addition, an exploratory cohort of 45 biologically naïve patients treated for 6 months with apremilast, MTX or combined therapy according to routine clinical practice was recruited. Extensive clinical and metabolic profiles were obtained. Ninety-nine surrogate CVD-related molecules were analysed in plasma and peripheral blood mononuclear cells (PBMCs). Hard cluster analysis was performed to identify the clinical and molecular phenotypes. Mechanistic studies were performed on adipocytes. Results: Cardiometabolic comorbidities were associated with disease activity and long-term inflammatory status. Thirty-five CVD-related proteins were altered in the plasma and PBMCs of PsA patients and were associated with the key clinical features of the disease. Plasma levels of some of the CVD-related molecules might distinguish insulin-resistant patients (MMP-3, CD163, FABP-4), high disease activity (GAL-3 and FABP-4) and poor therapy outcomes (CD-163, LTBR and CNTN-1). Hard cluster analysis identified two phenotypes of patients according to the rates of cardiometabolic comorbidities with distinctive clinical and molecular responses to each treatment. Conclusions: (1) Novel CVD-related proteins associated with clinical features could be emerging therapeutic targets in the context of PsA and (2) the pleiotropic action of apremilast could make it an excellent choice for the management of PsA patients with high CVD risk, targeting metabolic alterations and CVD-related molecules

Subclinical cardiovascular risk signs in adults with juvenile idiopathic arthritis in sustained remission.

Juvenile Idiopathic Arthritis (JIA) is one of the most common chronic diseases of childhood that often persists into adulthood and can result in significant long-term morbidity. As a long lasting chronic inflammatory disease, concern has been raised regarding the risk of premature development of cardiovascular disease (CVD) in JIA. This study aims to determine whether adults with JIA in clinical remission display clinical and subclinical signs of CVD risk: inflammatory mediators, adipokines, endothelial dysfunction and oxidative stress markers. This is a cross-sectional study including 25 patients diagnosed with JIA according to the International League of Associations for Rheumatology criteria (ILAR 2001) and 25 age- and sex-matched controls. Remission was determined by JADAS10  Mean duration of the disease was 13.47 ± 5.47 years. Mean age was 25.11 ± 7.21. Time in remission was 3.52 ± 3.33 years. Patients were in remission with no treatment (40%) and with treatments (60%). CVD risk factors and CIMT were similar in JIA patients and controls. However, cholesterol levels were significantly elevated in JIA patients. Levels of adipocytokines, oxidative stress and endothelial activation markers were elevated in serum and PBMCs from JIA patients. Serum of those JIA patients induced the activation of adipocytes, endothelial cells and healthy PBMCs. JIA adult patients in remission have subclinical signs of inflammation and CVD risk, showed by an increase in the levels of inflammatory cytokines, endothelial activation and oxidative stress markers and adipokines, molecules closely involved in the alteration of the vascular system

Association between Carotid Intima-Media Thickness and the Use of Biological or Small Molecule Therapies in Patients with Rheumatoid Arthritis

Objective: The objective of this study was to assess the association of carotid intima-media thickness (CIMT), and also the presence of atheromatous plaque, with biological and targeted synthetic disease-modifying antirheumatic drugs, in an established cohort of patients with rheumatoid arthritis (RA). Patients and Methods: We conducted a cross-sectional observational study based on a cohort of patients with RA and a registry of healthy controls, in whom the CIMT and presence of atheromatous plaque were assessed by ultrasound. Data were collected on disease activity, lab results and treatments. Descriptive and bivariate analyses were performed and two multivariate linear regression models (with CIMT as the dependent variable) were constructed to identify variables independently associated with CIMT in our sample of patients with RA. Results: A total of 176 individuals (146 patients with RA and 30 controls) were included. A higher percentage of patients than controls had atheromatous plaque (33.8% vs. 12.5%, p = 0.036), but no differences were found in terms of CIMT (0.64 vs. 0.61, p = 0.444). Compared to values in patients on other therapies, the CIMT was smaller among patients on tumour necrosis factor alpha (TNFα) inhibitors (mean [SD]: 0.58 [0.10] vs. 0.65 [0.19]; p = 0.013) and among those on Janus kinase inhibitors (mean [SD]: 0.52 [0.02] vs. 0.64 [0.18]; p < 0.001), while no differences were found as a function of the use of the other therapies considered. The multivariate linear regression analysis to identify factors associated with CIMT in our patients, adjusting for traditional cardiovascular risk factors such as hypertension, high levels of low-density lipoproteins, diabetes mellitus and smoking, showed that male sex, older age and having a greater cumulative erythrocyte sedimentation rate were independently associated with a larger CIMT, while patients on TNFα inhibitors had a CIMT 0.075 mm smaller than those on other treatments. Conclusions: The use of TNFα inhibitors may protect against subclinical atherosclerosis in patients with RA, patients on this biologic having smaller CIMTs than patients on other disease-modifying antirheumatic drugs. Nonetheless, these results should be confirmed in prospective studies with larger sample sizes

Assessment of the relationship between estimated cardiovascular risk and structural damage in patients with axial spondyloarthritis.

To evaluate the association of estimated cardiovascular (CV) risk and subclinical atherosclerosis with radiographic structural damage in patients with axial spondyloarthritis (axSpA). Cross-sectional study including 114 patients axSpA from the SpA registry of Córdoba (CASTRO) and 132 age- and sex-matched healthy controls (HCs). Disease activity and the presence of traditional CV risk factors were recorded. The presence of atherosclerotic plaques and carotid intima media thickness (cIMT) were evaluated through carotid ultrasound and the SCORE index was calculated. Radiographic damage was measured though modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The association between mSASSS and SCORE was tested using generalized linear models (GLM), and an age-adjusted cluster analysis was performed to identify different phenotypes dependent on the subclinical CV risk. Increased traditional CV risk factors, SCORE, and the presence of carotid plaques were found in axSpA patients compared with HCs. The presence of atherosclerotic plaques and SCORE were associated with radiographic structural damage. The GLM showed that the total mSASSS was associated independently with the SCORE [β coefficient 0.24; 95% confidence interval (CI) 0.10-0.38] adjusted for disease duration, age, tobacco, C-reactive protein, and non-steroidal anti-inflammatory drugs (NSAID) intake. Hard cluster analysis identified two phenotypes of patients. Patients from cluster 1, characterized by the presence of plaques and increased cIMT, had a higher prevalence of CV risk factors and SCORE, and more structural damage than cluster two patients. Radiographic structural damage is associated closely with increased estimated CV risk: higher SCORE levels in axSpA patients were found to be associated independently with mSASSS after adjusting for age, disease duration, CRP, tobacco and NSAID intake

Subclinical Atherosclerosis Measure by Carotid Ultrasound and Inflammatory Activity in Patients with Rheumatoid Arthritis and Spondylarthritis.

To compare the effect of inflammation on subclinical atherosclerosis using carotid ultrasound in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). Cross-sectional study including 347 participants (148 RA, 159 SpA, and 40 controls). We measured the carotid intima media thickness (cIMT) and detection of atheromatous plaques using carotid ultrasound. We recorded disease activity (DAS28-CRP/ASDAS-CRP) and traditional cardiovascular risk factors. We performed descriptive, bivariate, and linear multivariate analyses (dependent variable: cIMT) to evaluate the influence of diagnosis on cIMT in all patients. Two additional multivariate analyses were performed by stratifying patients according to their inflammatory activity. cIMT correlated with the mean CRP during the previous 5 years in RA, but not with CRP at the cut-off date. We did not find such differences in patients with SpA. The first multivariate model revealed that increased cIMT was more common in patients with RA than in those with SpA (β coefficient, 0.045; 95% confidence interval (95% CI), 0.0002-0.09; p = 0.048) after adjusting for age, sex, disease course, and differential cardiovascular risk factors (arterial hypertension, smoking, statins, and corticosteroids). The second model revealed no differences in cIMT between the 2 groups of patients classified as remission-low activity (β coefficient, 0.020; 95% CI, -0.03 to 0.080; p = 0.500). However, when only patients with moderate-high disease activity were analysed, the cIMT was 0.112 mm greater in those with RA (95% CI, 0.013-0.212; p = 0.026) than in those with SpA after adjusting for the same variables. Subclinical atherosclerosis measured by carotid ultrasound in patients with RA and SpA is comparable when the disease is well controlled. However, when patients have moderate-high disease activity, cIMT is greater in patients with RA than in those with SpA after adjusting for age, sex, disease course, and cardiovascular risk factors. Our results point to greater involvement of disease activity in subclinical atherosclerosis in patients with RA than in those with SpA

Ubiquinol Effects on Antiphospholipid Syndrome Prothrombotic Profile: A Randomized, Placebo-Controlled Trial.

Antiphospholipid syndrome (APS) leukocytes exhibit an oxidative perturbation, directly linked to alterations in mitochondrial dynamics and metabolism. This disturbance is related to the patients' prothrombotic status and can be prevented by in vitro treatment with coenzyme Q10. Our aim was to investigate short-term effects of in vivo ubiquinol (reduced coenzyme Q10 [Qred]) supplementation on markers related to inflammation and thrombosis in APS through a prospective, randomized, crossover, placebo-controlled trial. Thirty-six patients with APS were randomized to receive Qred (200 mg/d) or placebo for 1 month. Thirty-three patients with APS completed the intervention, which increased plasma coenzyme Q10. Qred improved endothelial function and decreased monocyte expression of prothrombotic and proinflammatory mediators, inhibited phosphorylation of thrombosis-related protein kinases, and decreased peroxides and percentage of monocytes with depolarized mitochondria; mitochondrial size was increased, and mitochondrial biogenesis-related genes were upregulated. Qred ameliorated extruded neutrophil extracellular traps in neutrophils and downregulated peroxides, intracellular elastase, and myeloperoxidase. Nanostring microRNA profiling revealed 20 microRNAs reduced in APS monocytes, and 16 of them, with a preponderance of cardiovascular disease-related target mRNAs, were upregulated. Monocytes gene profiling showed differential expression of 29 atherosclerosis-related genes, 23 of them changed by Qred. Interaction networks of genes and microRNAs were identified. Correlation studies demonstrated co-ordinated effects of Qred on thrombosis and endothelial function-associated molecules. Our results highlight the potential of Qred to modulate the overexpression of inflammatory and thrombotic risk markers in APS. Because of the absence of clinically significant side effects and its potential therapeutic benefits, Qred might act as safe adjunct to standard therapies in APS. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02218476

Molecular Changes in the Adipose Tissue Induced by Rheumatoid Arthritis: Effects of Disease-Modifying Anti-Rheumatic Drugs

Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.This research was funded by grants from the Instituto de Salud Carlos III (PI17/01316 and PI18/00837), co-financed by the European Regional Development Fund (ERDF), a way to make Europe, Spain, MINECO (RyC-2017-23437), and the Spanish Inflammatory and Rheumatic diseases Network (RIER, RD16/0012/0015). CL-P was supported by a contract from the Junta de Andalucia (Nicolas Monardes programme).Ye