Use of risk chart algorithms for the identification of psoriatic arthritis patients at high risk for cardiovascular disease: findings derived from the project CARMA cohort after a 7.5-year follow-up period.

OBJECTIVE: To assess the predictive value of four cardiovascular (CV) risk algorithms for identifying high-risk psoriatic arthritis (PsA) patients. METHODS: Evaluation of patients with PsA enrolled in the Spanish prospective project CARdiovascular in RheuMAtology. Baseline data of 669 PsA patients with no history of CV events at the baseline visit, who were followed in rheumatology outpatient clinics at tertiary centres for 7.5 years, were retrospectively analysed to test the performance of the Systematic Coronary Risk Assessment (SCORE), the modified version (mSCORE) European Alliance of Rheumatology Associations (EULAR) 2015/2016, the SCORE2 algorithm (the updated and improved version of SCORE) and the QRESEARCH risk estimator version 3 (QRISK3). RESULTS: Over 4790 years of follow-up, there were 34 CV events, resulting in a linearised rate of 7.10 per 1000 person-years (95% CI 4.92 to 9.92). The four CV risk scales showed strong correlations and all showed significant associations with CV events (p<0.001). SCORE, mSCORE EULAR 2015/2016 and QRISK3 effectively differentiated between low and high CV risk patients, although the cumulative rate of CV events observed over 7.5 years was lower than expected based on the frequency predicted by these risk scales. Additionally, model improvement was observed when combining QRISK3 with any other scale, particularly the combination of QRISK3 and SCORE2, which yielded the lowest Akaike information criterion (411.15) and Bayesian information criterion (420.10), making it the best predictive model. CONCLUSIONS: Risk chart algorithms are very useful for discriminating PsA at low and high CV risk. An integrated model featuring QRISK3 and SCORE2 yielded the optimal synergy of QRISK3's discrimination ability and SCORE2's calibration accuracy.

Combined use of QRISK3 and SCORE2 increases identification of ankylosing spondylitis patients at high cardiovascular risk: Results from the CARMA Project cohort after 7.5 years of follow-up.

OBJECTIVE: To establish the predictive value of the QRESEARCH risk estimator version 3 (QRISK3) algorithm in identifying Spanish patients with ankylosing spondylitis (AS) at high risk of cardiovascular (CV) events and CV mortality. We also sought to determine whether to combine QRISK3 with another CV risk algorithm: the traditional SCORE, the modified SCORE (mSCORE) EULAR 2015/2016 or the SCORE2 may increase the identification of AS patients with high-risk CV disease. METHODS: Information of 684 patients with AS from the Spanish prospective CARdiovascular in ReuMAtology (CARMA) project who at the time of the initial visit had no history of CV events and were followed in rheumatology outpatient clinics of tertiary centers for 7.5 years was reviewed. The risk chart algorithms were retrospectively tested using baseline data. RESULTS: After 4,907 years of follow-up, 33 AS patients had experienced CV events. Linearized rate=6.73 per 1000 person-years (95 % CI: 4.63, 9.44). The four CV risk scales were strongly correlated. QRISK3 correctly discriminated between people with lower and higher CV risk, although the percentage of accumulated events over 7.5 years was clearly lower than expected according to the risk established by QRISK3. Also, mSCORE EULAR 2015/2016 showed the same discrimination ability as SCORE, although the percentage of predicted events was clearly higher than the percentage of actual events. SCORE2 also had a strong discrimination capacity according to CV risk. Combining QRISK3 with any other scale improved the model. This was especially true for the combination of QRISK3 and SCORE2 which achieved the lowest AIC (406.70) and BIC (415.66), so this combination would be the best predictive model. CONCLUSIONS: In patients from the Spanish CARMA project, the four algorithms tested accurately discriminated those AS patients with higher CV risk and those with lower CV risk. Moreover, a model that includes QRISK3 and SCORE2 combined the best discrimination ability of QRISK3 with the best calibration of SCORE2.

Malondialdehyde Serum Levels in a Full Characterized Series of 430 Rheumatoid Arthritis Patients.

Background. Oxidative stress has been involved in the pathogenesis of rheumatoid arthritis (RA). The serum malondialdehyde (MDA) level is a reliable biomarker of oxidative stress status. In the present work, we aimed to analyze how a comprehensive characterization of the disease characteristics in RA, including a lipid profile, insulin resistance, and subclinical atherosclerosis, relates to serum MDA levels. Methods. In a cross-sectional study that included 430 RA patients, serum MDA levels were evaluated. Multivariable analysis was performed to examine the relationship of MDA with disease activity scores and disease characteristics, including subclinical carotid atherosclerosis, a comprehensive lipid molecule profile, and indices of insulin resistance and beta cell function indices. Results. The erythrocyte sedimentation rate (ESR) showed a significant and positive relationship with MDA. However, this did not occur for other acute phase reactants such as C-reactive protein or interleukin-6. Although the DAS28-ESR score (Disease Activity Score in 28 joints) had a positive and significant association with MDA serum levels, other disease activity scores that do not use the erythrocyte sedimentation rate in their formula did not show a significant relationship with MDA. Other disease characteristics, such as disease duration and the existence of rheumatoid factor and antibodies against citrullinated protein, were not related to serum MDA levels. This also occurred for lipid profiles, insulin resistance indices, and subclinical carotid atherosclerosis, for which no associations with circulating MDA were found. Conclusions. The disease characteristics are not related to circulating MDA levels in patients with RA.

Abatacept in usual and in non-specific interstitial pneumonia associated with rheumatoid arthritis.

OBJECTIVE: To compare the effectiveness of abatacept (ABA) in Rheumatoid Arthritis-associated Interstitial Lung Disease (RA-ILD) according to the radiological patterns of usual (UIP) or non-specific interstitial pneumonia (NSIP). METHODS: From an observational longitudinal multicentre study of 263 RA-ILD patients treated with ABA, those with UIP or NSIP were selected. Lung function, chest high resolution computerised tomography (HRCT) and dyspnoea were recorded and compared in both groups from baseline to the end of follow-up (progression definitions: improvement or worsening >10% of FVC or DLCO, changes in HRCT extension and 1-point change in the mMRC scale, respectively). Differences between final and baseline visits were calculated as the average difference (95% CI) through mixed effects models regression. RESULTS: We studied 190 patients with UIP (n=106) and NSIP (n=84). General features were similar in both groups except for older age, positive rheumatoid factor, and previous sulfasalazine therapy, which were more frequent in patients with UIP. ILD duration up to ABA initiation was relatively short: median 16 [4-50] and 11 [2-36] months (p=0.36) in UIP and NSIP, respectively. Mean baseline FVC and DLCO were 82% and 63% in UIP and 89% and 65% in NSIP, respectively. Both parameters remained stable during 24 months with ABA. HRCT lesions and dyspnoea improved/stabilized in 73.1% and 90.5% and 72.9% and 94.6% of UIP and NSIP patterns, respectively. CONCLUSION: ABA seems equally effective in stabilizing dyspnoea, lung function and radiological impairment in both UIP and NSIP patterns of RA-ILD. Early administration of ABA may prevent RA-ILD progression, regardless of the radiological pattern.

Value of inflammatory response and oxidative damage in the diagnosis of infections in severe alcoholic hepatitis.

Severe alcoholic hepatitis is the most lethal complication in alcohol dependent patients. The concurrence of infections in these patients is very frequent. Both produce a systemic inflammatory response syndrome (SIRS), secondary to intense release of inflammatory cytokines, which can complicate the diagnosis. In our study, Interleukin (IL)-6 and IL-10 levels are higher in patients with SIRS (p<0.001 and p = 0.033, respectively). IL-4, IL-6, Interferon-gamma (IFNγ), Tumor necrosis factor alpha (TNFα) and IL-17 levels correlate with liver function, as estimated by MELD-Na (p = 0.018, p = 0.008, p = 0.009, p = 0.016 and p = 0.006, respectively). Malondialdehyde (MDA), a product of lipid peroxidation and marker of cell damage, also correlates with liver function (p = 0.002), but not with SIRS or infections. Only elevated IL-6 correlates independently with the presence of infections (RR=1.023 IC 95% 1.000-1.047), so it may be useful for the correct diagnosis in these patients. Values greater than 30 pg/mL have a sensitivity: 86.7% and specificity: 94.7% for the diagnosis of infections.

The complement system is linked to insulin resistance in patients with systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients more commonly have insulin resistance (IR) than control subjects. Recent studies have revealed that the complement (C) system is not only a mediator of the immune system but is also related to the pathogenesis of atherosclerosis in the general population. Given that the C alteration is a characteristic of SLE, in the present work we set out to analyse if there is a relationship between the C system and IR in patients with SLE. METHODS: New generation functional assays of the three pathways of the C system were performed in 225 non-diabetic patients with SLE. In addition, the serum levels of inactive (C1q, C2, C3, C4, factor D), activated (C3a) and regulators (C1 inhibitor and factor H) molecules of the C system were evaluated. Insulin and C-peptide serum levels were measured, and insulin resistance and indices of beta cell function were calculated using the homeostatic model assessment (HOMA). Metabolic syndrome criteria fulfillments were applied. Multivariable linear regression analysis was performed to assess the relationship between C system and IR indices and the presence of metabolic syndrome. RESULTS: After adjusting for covariates that included traditional cardiovascular risk factors associated with IR and prednisone, serum C3a and factor H levels were positively related to higher levels of the HOMA2-IR index. Besides, in the multivariable analysis, after adjustment for covariates, serum levels of C1q and C3 associated with a higher odds ratio for the presence of metabolic syndrome. CONCLUSIONS: IR and metabolic syndrome are positively and independently related to higher serum levels of some serum C elements in patients with SLE with a predominant role of the alternative pathway elements.

Hematological Composite Scores in Patients with Inflammatory Bowel Disease.

The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and the systemic immune-inflammatory index (SIRI, neutrophils × monocytes/lymphocytes) have been identified as potential inflammatory biomarkers. In this work we aimed to analyze whether the hematological composite scores differ between inflammatory bowel disease (IBD) patients and healthy controls, and if they are related to disease activity. A total of 197 IBD patients-130 Crohn's (CD) disease and 67 ulcerative colitis (UC)-and 208 age- and sex-matched healthy controls were enrolled. C-reactive protein and fecal calprotectin were assessed. Multivariable linear regression analysis was executed. After adjustment, NLR and PLR, but not SIRI and MLR, were significantly higher in IBD patients compared to controls. C-reactive protein and SIRI and NLR were correlated in IBD patients. However, fecal calprotectin was not related to any of these blood scores. Furthermore, disease activity parameters were not associated with any of the blood composite scores in both CD and UC patients. In conclusion, NLR and PLR, but not SIRI and MLR, are independently higher in IBD patients compared to controls. However, the four hematological scores are not related to disease activity in either CD or UC patients. Based on these results, blood-based inflammatory scores may not serve as subrogated biomarkers of disease activity in IBD.

Interleukin-6 serum levels are associated with disease features and cardiovascular risk in patients with systemic sclerosis.

OBJECTIVES: Systemic sclerosis (SSc) is a chronic multisystem disease characterised by microcirculatory vascular dysfunction and progressive fibrosis of the skin and internal organs. Interleukin-6 (IL-6) is a proinflammatory cytokine that has been implicated in the pathogenesis of several autoimmune diseases and in the initiation and progression of the cardiovascular disease. In the present work we aimed to study the relationship of IL-6 with clinical manifestations and the cardiovascular risk in patients with SSc. METHODS: Cross-sectional study that included 53 individuals with SSc. A multivariate analysis was performed to study the relationship between IL-6 and disease characteristics and cardiovascular risk assessed by Systematic Coronary Risk Estimation (SCORE2) in SSc. RESULTS: The presence of digital ulcers, calcinosis, and anti-Scl70 antibody was associated with higher levels of IL-6. This was also the case for functional respiratory parameters where this association was found to be significant and negative after correction for covariates. In addition, the SCORE2 cardiovascular risk algorithm showed a positive and significant association with circulating IL-6. CONCLUSIONS: IL-6 levels are associated with disease manifestations and cardiovascular risk in patients with SSc.

Mean Platelet Volume in a Series of 315 Patients with Rheumatoid Arthritis: Relationship with Disease Characteristics, including Subclinical Atherosclerosis and Cardiovascular Comorbidity.

Mean platelet volume (MPV) refers to the average platelet size in femtoliters. Increased or decreased MPV has been associated with several disorders, including inflammatory and cardiovascular diseases. In the present study, our objective was to analyze the relationship of MPV with disease activity in a large and well-characterized series of patients with rheumatoid arthritis (RA). This is a cross-sectional study that included 315 patients with RA and 208 controls matched by sex and age. Complete blood count, including MPV, was assessed. Multivariable analysis was performed to examine the relationship of MPV with RA disease characteristics, carotid atherosclerosis, and traditional cardiovascular factors, including a comprehensive profile of lipid molecules and insulin resistance or beta cell function indices. The multivariable analysis, which includes other hematological modifications produced by the disease and platelet values, showed that MPV levels were significantly lower in RA patients than in controls. Erythrocyte sedimentation rate and interleukin-6, but not C-reactive protein, were negatively correlated with MPV after adjustment for covariates. Similarly, disease activity and MPV had a significant and independent negative correlation. No relationships were found between MPV and cardiovascular risk factors, lipid profile or insulin resistance indices or subclinical atherosclerosis. In conclusion, patients with RA have lower levels of MPV than controls. MPV is negatively related to acute phase reactants and disease activity in RA.

Red Cell Distribution Width Association with Subclinical Cardiovascular Disease in Patients with Rheumatoid Arthritis.

Red cell distribution width (RDW) is a measure of the variation in mean corpuscular volume that reflects the degree of anisocytosis on the peripheral blood smear. RDW value variation has been implicated in several disorders including chronic inflammatory processes and cardiovascular (CV) diseases. In the present work, our objective was to study the relationship that RDW has with the characteristics of the disease in patients with rheumatoid arthritis (RA), focusing on CV risk factors and subclinical atherosclerosis. A cross-sectional study was conducted that included 430 patients with RA and 208 controls matched by sex and age. Complete blood count, including RDW, was assessed. Multivariable analysis was performed to analyze the relationship of RDW with RA disease characteristics, subclinical carotid atherosclerosis, and traditional CV factors, including a comprehensive profile of lipid molecules and insulin resistance and beta cell function indices. After multivariable adjustment, the RDW was significantly higher in RA patients compared with controls (beta coefficient 1.0 [95% confidence interval 0.2 to 1.8] %, p = 0.020). Furthermore, although the erythrocyte sedimentation rate showed a positive and significant relationship with RDW, this association was not found with C-reactive protein and interleukin-6. A positive and independent relationship was observed between DAS28-ESR disease activity score and RDW. However, no association was found between the RDW and other disease activity scores that do not include erythrocyte sedimentation rate in their formula. The SCORE2 CV risk algorithm was positively and significantly associated with higher RDW values. Likewise, a negative relationship was found between RDW with total cholesterol and low-density lipoprotein cholesterol, and a positive relationship was found between RDW and insulin resistance indices. In conclusion, RDW values are higher in RA patients compared to matched controls. Although the relationship of RDW with disease activity was not consistent, RDW shows associations with subclinical CV disease risk factors, including dyslipidemia and insulin resistance, and with the SCORE2 CV disease-risk prediction algorithm.

Blood Composite Scores in Patients with Systemic Lupus Erythematosus.

Complete blood count-derived ratios have been described as inflammatory biomarkers in several diseases. These hematological scores include the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammatory index ([SIRI]; neutrophils × monocytes/lymphocytes). Our aim was to study how these biomarkers are related to disease expression in a large and well-characterized series of patients with systemic lupus erythematosus (SLE). A total of 284 SLE patients and 181 age- and sex-matched healthy controls were recruited. The NLR, MLR, PLR, and SIRI were calculated, and activity (SLEDAI-2K), severity (Katz), and damage index (SLICC-DI) scores were assessed in patients with SLE. Multivariable linear regression analysis was performed to study whether these scores differ between patients and controls and how they are related to clinical and laboratory features of the disease. Crude cell counts of neutrophils, monocytes, lymphocytes, and platelets were lower in SLE patients compared to controls. Despite this, NLR, MLR, and PRL, but not SIRI, were higher in SLE patients than in controls after multivariable analysis. However, the relationship between the different scores and disease characteristics was limited. Only the Katz severity index revealed a significant positive relationship with SIRI, NLR, and MLR after adjustment for covariates. Similarly, alternative complement cascade activation and low C3 were significantly associated with higher NLR, MLR, and PLR. In conclusion, although cytopenias are a common feature of patients with SLE, hematologic composite scores are independently higher in this population compared to controls. However, the relationship of these scores with the characteristics of the disease is scarce, with the relationship with the complement system being the most consistent.

Identification of novel biomarkers for the prediction of subclinical coronary artery atherosclerosis in patients with rheumatoid arthritis: an exploratory analysis.

BACKGROUND: Cardiovascular (CV) risk estimation calculators for the general population underperform in patients with rheumatoid arthritis (RA). The purpose of this study was to identify relevant protein biomarkers that could be added to traditional CV risk calculators to improve the capacity of coronary artery calcification (CAC) prediction in individuals with RA. In a second step, we quantify the improvement of this prediction of CAC when these circulating biomarkers are added to standard risk scores. METHODS: A panel of 141 serum and plasma proteins, which represent a broad base of both CV and RA biology, were evaluated and prioritized as candidate biomarkers. Of these, 39 proteins were selected and measured by commercial ELISA or quantitative mass spectroscopy in 561 individuals with RA in whom a measure of CAC and frozen sera were available. The patients were randomly split 50:50 into a training/validation cohort. Discrimination (using area under the receiver operator characteristic curves) and re-classification (through net reclassification improvement and integrated discrimination improvement calculation) analyses were performed first in the training cohort and replicated in the validation cohort, to estimate the increase in prediction accuracy for CAC using the ACA/AHA (American College of Cardiology and the American Heart Association) score with, compared to without, addition of these circulating biomarkers. RESULTS: The model containing ACC/AHA score plus cytokines (osteopontin, cartilage glycoprotein-39, cystatin C, and chemokine (C-C motif) ligand 18) and plus quantitative mass spectroscopy biomarkers (serpin D1, paraoxonase, and clusterin) had a statistically significant positive net reclassifications index and integrated discrimination improvement for the prediction of CAC, using ACC/AHA score without any biomarkers as the reference category. These results were confirmed in the validation cohort. CONCLUSION: In this exploratory analysis, the addition of several circulating CV and RA biomarkers to a standard CV risk calculator yielded significant improvements in discrimination and reclassification for the presence of CAC in individuals with RA.

The Ratio of Monocytes to HDL-Cholesterol Is Associated with Cardiovascular Risk and Insulin Resistance in Patients with Rheumatoid Arthritis.

The monocytes to high-density lipoprotein (HDL)-cholesterol ratio (MHR) indicates inflammation based on the anti-inflammatory properties of HDL-cholesterol as well as the pro-inflammatory effect of monocytes. Several studies have investigated MHR in various disorders, specifically in cardiovascular diseases. Consequently, MHR has been significantly associated with cardiovascular and all-cause mortality in the general population, regardless of established risk factors. However, its role in the augmented risk of cardiovascular disease found in rheumatoid arthritis (RA) has not been studied to date. This is a cross-sectional study that encompassed 430 patients with RA and 208 controls matched by sex and age. Complete blood cell count and complete lipid profile were evaluated. Multivariable analysis was made to analyze the relationship between MHR and RA disease and features subclinical carotid atherosclerosis, and traditional CV factors including insulin resistance and beta cell function indices. MHR values did not differ between controls and patients after multivariable adjustment (12 ± 6 vs. 11 ± 6, p = 0.18). No relationship between this ratio and the characteristics of the disease was found excluding ESR, which showed a significant and positive association with MHR after adjustment for covariates. MHR significantly correlated with Systematic Coronary Risk Evaluation-2 (SCORE2) cardiovascular risk algorithm, and insulin resistance and beta cell function parameters after adjustment. In conclusion, MHR does not differ between patients with RA and controls. The relationship of this biomarker with disease-related data is poor. However, MHR is highly and positively related to cardiovascular risk and insulin resistance in RA.

Positron Emission Computed Tomography Spectrum of Large Vessel Vasculitis in a Tertiary Center: Differences in 18F-fluorodeoxyglucose Uptake between Large Vessel Vasculitis with Predominant Cranial and Extracranial Giant Cell Arteritis Phenotypes.

(1) Objective:To assess the spectrum of PET-CT-related large vessel vasculitis (LVV) in a Spanish tertiary center and to determine whether FDG uptake by PET-CT differs between giant cell arteritis (GCA) with predominant cranial or extracranial phenotypes. (2) Methods: The spectrum of patients diagnosed with LVV by PET-CT in a tertiary referral hospital that cares for 450,000 people over a period of two years was reviewed. Moreover, differences in FDG uptake between LVV-GCA with predominantly cranial and extracranial phenotype were analyzed. (3) Results: Eighty patients were diagnosed with LVV by PET-CT. Most were due to systemic vasculitis (n = 64; 80%), especially GCA (n = 54; 67.5%). Other conditions included the presence of rheumatic diseases (n = 4; 3.2%), tumors (n = 9; 7.2%) and infections (n = 3; 2.4%). LVV-GCA patients with predominant extracranial GCA phenotype were younger (mean ± SD: 68.07 ± 9.91 vs. 75.46 ± 7.64 years; p = 0.017) and had a longer delay to the diagnosis (median [interquartile range] 12 [4-18] vs. 4 [3-8]; p = 0.006), but had polymyalgia rheumatica symptoms more frequently than those with predominantly cranial GCA phenotype (46.3% vs. 15.4%, p = 0.057). When FDG uptake was compared according to the two different disease patterns, no statistically significant differences were observed. However, patients with extracranial LVV-GCA showed a non-significantly higher frequency of vasculitic involvement of lower-extremity arteries. (4) Conclusions: Regardless of the predominant phenotype, LVV identified by PET-CT is more commonly due to GCA in the Spanish population. In these GCA patients, younger age, PMR, and a higher frequency of lower-extremity artery vasculitis suggest the presence of LVV.

Malondialdehyde Serum Levels in Patients with Systemic Sclerosis Relate to Dyslipidemia and Low Ventricular Ejection Fraction.

Systemic sclerosis (SSc) is a chronic disease characterized by vasculopathy with the involvement of dysfunctional microcirculatory vessels. Features of the disease include progressive fibrosis of the skin and internal organs and systemic inflammation characterized by the presence of circulating autoantibodies and proinflammatory cytokines. Furthermore, macrovascular disease and atherosclerosis are more common in patients with SSc than in the general population. Oxidative stress plays a crucial role in the development of several processes, including endothelial dysfunction, cancer, inflammation, and atherogenesis. Malondialdehyde (MDA) is a well-established marker of oxidative stress. In this work, we have analyzed the relationship between serum MDA levels and clinical, laboratory, and vascular characteristics in a well-characterized cohort of 53 patients with SSc. A multivariable analysis was performed to study the relationship between circulating MDA and disease characteristics in patients with SSc. Cardiovascular assessment was also performed, including ultrasonography of the carotid and aorta, and echocardiography. MDA showed a significant and positive relationship with the serum levels of lipid profile molecules such as total cholesterol (ß coefficient = 0.006 (95% CI: 0.0004 to 0.01), nmol/mL, p = 0.037) and LDL cholesterol (ß coefficient = 0.008 (95% CI: 0.001 to 0.01) nmol/mL, p = 0.017). On the contrary, most manifestations of the disease, including skin, lung, and joint involvement, as well as the presence of digital ulcers, were not related to MDA. However, high MDA levels were significantly and independently associated with lower ventricular ejection fraction after adjustment for covariates (ß coefficient = -0.04 (95% CI: -0.06 to -0.02), nmol/mL, p = 0.001). In conclusion, serum MDA levels were related to higher levels of total and LDL cholesterol and a lower left ventricular ejection fraction in patients with SSc. MDA could serve as a potential biomarker of dyslipidemia and heart failure in SSc.

Relationship between Disease Characteristics and Circulating Interleukin 6 in a Well-Characterized Cohort of Patients with Systemic Lupus Erythematosus.

Interleukin-6 (IL-6) is a proinflammatory cytokine that mediates pleiotropic functions in immune responses and inflammatory diseases. The literature lacks studies, with a clinical perspective, on the relationship between IL-6 serum levels and the characteristics of the disease in patients with systemic lupus erythematosus (SLE). In the present work, we aimed to analyze the association between circulating IL-6 and disease manifestations in a well-characterized series of patients with SLE. Serum IL-6 levels and disease activity (SLEDAI-2K), severity (Katz) and damage index (SLICC-DI), complete lipid profile, and subclinical carotid atherosclerosis were evaluated in 284 patients with SLE. In addition, a complete characterization of the complement system was performed in samples from patients with SLE. A multivariate linear regression analysis was carried out to study the relationship between clinical and laboratory characteristics of the disease and IL-6 levels. Age (beta coef. 0.07 [95%CI 0.01-0.1] pg/mL, p = 0.014), C-reactive protein (beta coef. 0.21 [95%CI 0.16-0.25] pg/mL, p < 0.01), and male gender (beta coef. 2 [95%CI 0.3-0.5] pg/mL, p = 0.024), were positively associated with higher IL-6 levels in SLE patients. Most disease characteristics and damage and activity indices did not show significant relationships with IL-6. However, after multivariate analysis, IL-6 was associated with lower serum levels of HDL cholesterol (beta coef. -0.04 [95%CI -0.08-(-0.1)] pg/mL, p = 0.011), and apolipoprotein A1 (beta coef. -0.02 [95%CI -0.04-(-0.001)] pg/mL, p = 0.035). In contrast, the alternative complement cascade, C1inh, and C3a were all positively and independently associated with higher serum levels of IL-6. Moreover, stratification of the Systematic Coronary Risk Assessment 2 (SCORE2) results according to different categories of cardiovascular risk was associated with higher circulating serum IL-6 levels (beta coef. 0.2 [95%CI 0.02-0.4], pg/mL, p = 0.028). In conclusion, in a large series of SLE patients, IL-6 was not associated with disease-related features of SLE, including damage, severity, or activity indices. However, an association was found between serum IL-6 levels and circulating C3a and cardiovascular risk. Our study emphasizes the importance that IL-6 could have in cardiovascular disease and complement system disruption of SLE patients. Therapies targeting IL-6 could have a role in these two clinical manifestations of patients with SLE.

Relationship of Fibroblast Growth Factor 23 Serum Levels with Disease Characteristics in Systemic Lupus Erythematosus Patients.

Fibroblast growth factor 23 (FGF23), a hormone secreted by osteocytes and osteoblasts, is a major regulator of vitamin D and phosphate homeostasis. FGF23 has been associated with the disturbance of mineral homeostasis, and with kidney and cardiovascular diseases. Systemic lupus erythematosus (SLE) is an autoimmune disorder that can affect virtually any organ. In the present work, we set out to analyze the relationship of FGF23 with the expression of SLE, including patterns of activity, damage, and severity. A total of 284 well-characterized patients with SLE were recruited. Activity (SLEDAI), severity (Katz), and damage index (SLICC-DI) scores were determined. The serum levels of FGF23 were also assessed. Multivariable linear regression analysis was performed to study the relationship between disease characteristics and FGF23. FGF23 and 25(OH) vitamin D were negatively correlated. Furthermore, prednisone use was associated with higher circulating FGF23 after an adjustment for confounding factors. SLICC-DI was related to higher serum levels of FGF23 after a multivariable analysis. However, when the SLICC-DI index items and domains were analyzed separately, apart from proteinuria ≥3.5 gm/24 h, only the musculoskeletal domain, encompassing arthritis and osteoporosis, was significantly associated with higher serum levels of FGF23. In conclusion, an association is observed between elevated serum FGF23 levels and disease damage, particularly related to musculoskeletal complications and proteinuria, in patients with SLE.

Relationship between Malondialdehyde Serum Levels and Disease Features in a Full Characterized Series of 284 Patients with Systemic Lupus Erythematosus.

Malondialdehyde (MDA) is a marker of oxidative stress and antioxidant status. Oxidative stress has been observed to be increased in systemic lupus erythematosus (SLE). Some studies have shown that MDA is upregulated in SLE compared to controls. However, the literature lacks reports regarding the relationship of MDA to disease manifestations. This is relevant since SLE is a multisystemic disease which may affect virtually any organ in the body. In this study, we set out to analyze how MDA serum levels are associated with disease expression in a large series of SLE patients who were fully characterized in clinical and laboratory terms. A total of 284 patients with SLE were recruited. Serum levels of MDA, and the activity (SLEDAI), severity (Katz) and damage index (SLICC-DI) scores, full lipid profile, and carotid subclinical atherosclerosis were assessed. In addition, a full characterization of the complement system was performed in SLE patients' samples. Multivariable linear regression analysis was executed to study the relationship between clinical and laboratory disease characteristics and MDA. A statistically significant negative relationship was found between disease duration and MDA. In contrast, the presence of anti-nucleosome antibodies was positively associated with MDA. Regarding the SLICC-DI areas, both the musculoskeletal domain and the cutaneous domain were significantly related to higher serum MDA values. Furthermore, after adjustment for confounding factors, lower levels of the classical complement pathway, which denotes activation, were associated with higher serum levels of MDA. In conclusion, cumulative musculoskeletal and skin damage in SLE patients is associated with superior serum levels of MDA. In addition, activation of the complement system is also related to higher circulating MDA levels.

HDL Cholesterol Efflux and the Complement System Are Linked in Systemic Lupus Erythematosus.

Cholesterol efflux capacity (CEC), the ability of high-density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages, has been linked to cardiovascular events. Systemic lupus erythematosus (SLE) is characterized by the consumption of complement (C) proteins and has been associated with an increased risk of cardiovascular disease. CEC is reduced in SLE patients compared to controls. In the present work, our objective was to analyze whether the disruption of C influences CEC in patients with SLE. New-generation functional assays of the three pathways of the C system were performed in 207 patients with SLE. Additionally, serum levels of inactive (C1q, C2, C3, C4, and factor D) and activated (C3a) molecules, and regulators (C1-inhibitor and factor H) of C system were measured. CEC, using an in vitro assay, and lipoprotein serum concentrations were assessed. Multivariable linear regression analysis was performed to assess the relationship between C system and CEC. After full multivariable analysis, the alternative C cascade functional test showed a significant and negative relationship with CEC. This was also the case for C2 and C3, in which the associations were found to be positive and statistically significant, after adjustment for covariates. In conclusion, C system and CEC are interconnected in patients with SLE.