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Background: Several studies have shown that patients with fibromyalgia present with neuroendocrine, inflammatory, and coagulation features linked to cardiovascular disease development. However, the exact profile of cardiovascular risk factors and events in fibromyalgia remains to be defined., Objectives: To compare the profile of cardiovascular risk factors and events between fibromyalgia outpatients and the general population in Italy., Methods: Cardiovascular risk factors and events in fibromyalgia females were collected using the criteria adopted in the CUORE Project., Results: The study comprised 62 female fibromyalgia patients and 4093 female controls from 35 to 75 years of age. The prevalence of hypertension, diabetes, atrial fibrillation, transient ischemic attack, and cardiovascular total burden was significantly higher in fibromyalgia females than in the general Italian population. No difference was found in blood fasting glucose, triglycerides, total and fractionated cholesterol levels, body mass index, and metabolic syndrome (MetS). The MetS rate was underestimated for methodological aspects., Conclusions: Fibromyalgia is associated with an increased cardiovascular burden, probably through a specific risk factor profile.

Background: Infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may cause a severe disease, termed coronavirus disease 2019 (COVID-19), with significant mortality. Host responses to this infection, mainly in terms of systemic inflammation, have emerged as key pathogenetic mechanisms and their modulation has shown a mortality benefit., Methods: In a cohort of 56 critically ill COVID-19 patients, peripheral blood transcriptomes were obtained at admission to an intensive care unit (ICU) and clustered using an unsupervised algorithm. Differences in gene expression, circulating microRNAs (c-miRNAs) and clinical data between clusters were assessed, and circulating cell populations estimated from sequencing data. A transcriptomic signature was defined and applied to an external cohort to validate the findings., Results: We identified two transcriptomic clusters characterised by expression of either interferon-related or immune checkpoint genes, respectively. Steroids have cluster-specific effects, decreasing lymphocyte activation in the former but promoting B-cell activation in the latter. These profiles have different ICU outcomes, despite no major clinical differences at ICU admission. A transcriptomic signature was used to identify these clusters in two external validation cohorts (with 50 and 60 patients), yielding similar results., Conclusions: These results reveal different underlying pathogenetic mechanisms and illustrate the potential of transcriptomics to identify patient endotypes in severe COVID-19 with the aim to ultimately personalise their therapies., Competing Interests: Conflict of interest: The authors declare no competing interests., (Copyright ©The authors 2023.)

Objectives: To update the EULAR points to consider (PtCs) on the use of immunomodulatory therapies in COVID-19., Methods: According to the EULAR standardised operating procedures, a systematic literature review up to 14 July 2021 was conducted and followed by a consensus meeting of an international multidisciplinary task force. The new statements were consolidated by formal voting., Results: We updated 2 overarching principles and 12 PtC. Evidence was only available in moderate to severe and critical patients. Glucocorticoids alone or in combination with tocilizumab are beneficial in COVID-19 cases requiring oxygen therapy and in critical COVID-19. Use of Janus kinase inhibitors (baricitinib and tofacitinib) is promising in the same populations of severe and critical COVID-19. Anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma may find application in early phases of the disease and in selected subgroups of immunosuppressed patients. There was insufficient robust evidence for the efficacy of other immunomodulators with further work being needed in relation to biomarker-based stratification for IL-1 therapy CONCLUSIONS: Growing evidence supports incremental efficacy of glucocorticoids alone or combined with tocilizumab/Janus kinase inhibitors in moderate to severe and critical COVID-19. Ongoing studies may unmask the potential application of other therapeutic approaches. Involvement of rheumatologists, as systemic inflammatory diseases experts, should be encouraged in clinical trials of immunomodulatory therapy in COVID-19., Competing Interests: Competing interests: AA, AN, HB, FC, GDM, RG, CM-C and JRC have nothing to declare. PMM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Orphazyme, Pfizer, Roche and UCB, all unrelated to this manuscript. G-RRB has received consulting and/or speaker’s fees from Abbvie, Gilead, Lilly, Roche, Sanofi, Pfizer all unrelated to this manuscript. IK-P has received consulting and/or speaker’s fees from Novartis, SOBI, Amgen, CHUGAI, Pfizer, LFB, Novimmune, Abbvie and PAtent for AIDAI score AVR has received speaker fees/Honoraria from Abbvie, Lilly, Roche, UCB, SOBI and Novartis all unrelated to this manuscript. DGM has received consulting and/or speaker’s fees from Abbvie, BMS, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche and UCB, all unrelated to this manuscript. XM has received consulting and/or speaker’s fees from BMS, Eli Lilly, Galapagos, Gilead, GSK, Janssen, Novartis, Pfizer, Servier and UCB, all unrelated to this manuscript., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Chronic inflammation represents the cornerstone of the raised cardiovascular (CV) risk in patients with inflammatory rheumatic diseases (IRD). Standardized mortality ratios are increased in these patients compared to the general population, which can be explained by premature mortality associated with early atherosclerotic events. Thus, IRD patients need appropriate CV risk management in view of this CV disease (CVD) burden. Currently, optimal CV risk management is still lacking in usual care, and early diagnosis of silent and subclinical CVD involvement is mandatory to improve the long-term prognosis of those patients. Although CV involvement in such patients is highly heterogeneous and may affect various structures of the heart, it can now be diagnosed earlier and promptly treated. CV imaging provides valuable information as a reliable diagnostic tool. Currently, different techniques are employed to evaluate CV risk, including transthoracic or trans-esophageal echocardiography, magnetic resonance imaging, or computed tomography, to investigate valve abnormalities, pericardial disease, and ventricular wall motion defects. All the above methods are reliable in investigating CV involvement, but more recently, Speckle Tracking Echocardiography (STE) has been suggested to be diagnostically more accurate. In recent years, the role of left ventricular ejection fraction (LVEF) as the gold standard parameter for the evaluation of systolic function has been debated, and many efforts have been focused on the clinical validation of new non-invasive tools for the study of myocardial contractility as well as to characterize the subclinical alterations of the myocardial function. Improvement in the accuracy of STE has resulted in a large amount of research showing the ability of STE to overcome LVEF limitations in the majority of primary and secondary heart diseases. This review summarizes the additional value that STE measurement can provide in the setting of IRD, with a focus in the different clinical stages., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Familial hypercholesterolemia (FH) is characterized by increased cardiovascular risk; despite-high intensity statins, only few patients with FH achieve the recommended low-density lipoprotein cholesterol (LDL-C) targets., Objective: We aimed to evaluate the effectiveness of six-month add-on therapy with proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) or ezetimibe on lipid profile and pulse wave velocity (PWV) in patients with FH., Methods: In this observational study, we evaluated 98 genetically confirmed patients with FH with an LDL-C off-target despite high-intensity statins with or without ezetimibe; of these, 53 patients (statin plus ezetimibe) added PCSK9-i (PCSK9-i group) and 45 (statin only) added ezetimibe (EZE group) per applicable guidelines and reimbursement rules. All patients obtained biochemical analysis and PWV evaluation at baseline and after six months of optimized treatment., Results: After 6 months of add-on therapy, most patients achieving LDL-C targets were in the PCSK9-i group (77.3% PCSK9-i group vs 37.8% EZE group, P < .001). The PCSK9-i group achieved both a greater LDL-C and PWV reduction than the EZE group [-51% vs -22.8%, P < .001 and -15% vs -8.5%, P < .01, respectively]. In a linear regression analysis, we showed a coefficient (r) of 0.334 for the relationship between ΔPWV and ΔLDL (P < .05); moreover, in an exploratory analysis, the relationship appeared to be stronger in patients with FH without cardiovascular events (r = 0.422, P < .01)., Conclusions: Lipid and PWV profiles in patients with FH significantly improved after addition of PCSK9-i or ezetimibe to high-intensity statin therapy; moreover, ΔPWV was associated with ΔLDL. Our results are consistent with a beneficial role of these novel therapies in FH subjects., (Copyright © 2020 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Objective: The aim was to evaluate whether T cell subsets and the lipid profile could be linked to the cardioprotective effect of IgM anti-phosphorylcholine (PC) antibodies in SLE., Methods: Anti-PC antibodies were quantified by ELISA in 197 patients and 99 controls and analysed in relationship to clinical features, treatments and serum lipids. Carotid atheromatosis was evaluated by ultrasonography; Th1, Th17, Treg and CD4+CD28null cells by flow cytometry; and cytokine serum levels by immunoassays, in a subgroup of 120 SLE patients and 33 controls., Results: IgM anti-PC serum levels were reduced in SLE patients compared with controls (P < 0.001) and were associated with age (β= -0.252; P = 0.002), high-density lipoprotein (HDL; β = 0.271; P = 0.001), low-density lipoprotein (LDL; β= -0.192; P = 0.017) and glucocorticoid treatment (β= -0.201; P = 0.012), whereas the IgG-to-IgM anti-PC ratio was increased (P = 0.007) and associated with age (β = 0.194; P = 0.028) and SLEDAI (β = 0.250; P = 0.005). Also, patients with clinical or subclinical cardiovascular disease exhibited reduced IgM anti-PC levels compared with their cardiovascular disease-free counterparts, regardless of glucocorticoid usage (P = 0.001). CD4+CD28null and Th17 cells were increased in SLE patients compared with controls (P < 0.01) and correlated inversely with IgM anti-PC levels. These associations were observed in patients displaying high triglyceride or low HDL levels, even after adjusting for clinical parameters and treatments (CD4+CD28null: β = -0.455, P = 0.001; Th17: β= -0.280, P = 0.035), but not in those with a normal lipid profile. High triglyceride and low HDL profiles were related to low IgM anti-PC and Treg levels, respectively, whereas both lipid profiles were associated with inflammatory markers and cytokines., Conclusion: The present study provides evidence for an association of IgM anti-PC antibodies with pro-atherogenic T cell subsets in SLE, with a high triglyceride/low HDL lipid profile playing a facilitating major role., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Atherosclerosis (ATH) is a chronic, dynamic, evolutive process involving morphological and structural subversion of artery walls, leading to the formation of atherosclerotic plaques. ATH generally initiates during the childhood, occurring as a result of a number of changes in the intima tunica and in the media of arteries. A key event occurring during the pathobiology of ATH is the accumulation of lipoproteins in the sub-intimal spaces mediated by extracellular matrix (ECM) molecules, especially by the chondroitin sulfate/dermatan sulfate (CS/DS) -containing proteoglycans (CS/DSPGs). Among them, the proteoglycan biglycan (BGN) is critically involved in the onset and progression of ATH and evidences show that BGN represents the missing link between the pro-atherogenic status induced by both traditional and non-traditional cardiovascular risk factors and the development and progression of vascular damage. In the light of these findings, the role of BGN in dyslipidemia, hypertension, cigarette smoking, diabetes, chronic kidney disease and inflammatory status is briefly analyzed and discussed in order to shed new light on the underlying mechanisms governing the association between BGN and ATH., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In chronic kidney disease (CKD), hyperphosphatemia-induced inflammation aggravates vascular calcification (VC) by increasing vascular smooth muscle cell (VSMC) osteogenic differentiation, ADAM17-induced renal and vascular injury, and TNFα-induction of neutral-sphingomyelinase2 (nSMase2) to release pro-calcifying exosomes. This study examined anti-inflammatory β-glucans efficacy at attenuating systemic inflammation in health, and renal and vascular injury favoring VC in hyperphosphatemic CKD. In healthy adults, dietary barley β-glucans (Bβglucans) reduced leukocyte superoxide production, inflammatory ADAM17, TNFα, nSMase2, and pro-aging/pro-inflammatory STING (Stimulator of interferon genes) gene expression without decreasing circulating inflammatory cytokines, except for γ-interferon. In hyperphosphatemic rat CKD, dietary Bβglucans reduced renal and aortic ADAM17-driven inflammation attenuating CKD-progression (higher GFR and lower serum creatinine, proteinuria, kidney inflammatory infiltration and nSMase2), and TNFα-driven increases in aortic nSMase2 and calcium deposition without improving mineral homeostasis. In VSMC, Bβglucans prevented LPS- or uremic serum-induced rapid increases in ADAM17, TNFα and nSMase2, and reduced the 13-fold higher calcium deposition induced by prolonged calcifying conditions by inhibiting osteogenic differentiation and increases in nSMase2 through Dectin1-independent actions involving Bβglucans internalization. Thus, dietary Bβglucans inhibit leukocyte superoxide production and leukocyte, renal and aortic ADAM17- and nSMase2 gene expression attenuating systemic inflammation in health, and renal injury and aortic calcification despite hyperphosphatemia in CKD.

Inflammation is central to chronic kidney disease (CKD) pathogenesis and vascular outcomes, but the exact players remain unidentified. Since low density granulocytes (LDGs) are emerging mediators in inflammatory conditions, we aimed to evaluate whether LDGs may be altered in CKD and related to clinical outcomes as biomarkers. To his end, LDGs subsets were measured in peripheral blood by flow cytometry and confocal microscopy in 33 CKD patients undergoing peritoneal dialysis and 15 healthy controls (HC). Analyses were replicated in an additional cohort. DEF3 (marker of early granulopoiesis) gene expression on PBMCs was quantified by qPCR. Total CD15 + LDGs and both CD14 low CD16 + and CD14 - CD16 - subsets were expanded in CKD. The relative frequency of the CD14 - CD16 - subpopulation was higher among the CD15 + pool in CKD. This alteration was stable over-time. The increased CD14 - CD16 - CD15 + paralleled Kauppila scores and DEF3 expression, whereas no association was found with CD14 low CD16 + CD15 + . Both subsets differed in their CD11b, CD10, CD35, CD31, CD62L, IFNAR1 and CD68 expression, FSC/SSC features and nuclear morphology, pointing to different origins and maturation status. In conclusion, LDGs were expanded in CKD showing a skewed distribution towards a CD14 - CD16 - CD15 + enrichment, in association with vascular calcification. DEF3 expression in PBMC can be a marker of LDG expansion.

Serum free fatty acids (FFA) are generally elevated in obesity. The gut microbiota is involved in the host energy metabolism through the regulation of body fat storage, and a link between diet, FFA and the intestinal microbiota seems to exist. Our aim was to explore the interaction among serum FFA levels, gut microbiota, diet and obesity through a model regression tree in 66 subjects (age 52.7 ± 11.2 y) classified according to Body Mass Index (BMI). Total and individual FFA were analyzed by colorimetric enzymatic assay and methyl-tert-butylether-based extraction protocol (MTBE), respectively. Microbiota was determined by qPCR and diet through a food frequency questionnaire. Statistical analyses were performed, and predictive factors for obesity were obtained via classification by decision trees using machine learning methods. An obese-linked FFA profile was characterized by decreased eicosapentaenoic (EPA) and increased linoleic, gamma-linolenic and palmitic acids levels simultaneously. Serum EPA and gender were identified as the most significant variables with 100% and 80% of importance, respectively. Palmitic acid, Bifidobacterium and Faecalibacterium explained >30%, followed by Bacteroides group with 20% and docosahexaenoic acid (DHA) almost with 15% of importance. Also, the regression tree model obtained for predicting obesity, showed a non-obese-linked profile, independently of gender, with serum EPA > 0.235 μg/mL and Bacteroides > 9.055 log n° cells per g of feces. Moreover, Faecalibacterium and Bifidobacterium seemed to play an important role by complementing the levels of FFA in predicting obesity in males and females, respectively., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Emerging evidence suggests a role for 7-dehydrocholesterol reductase (DHCR7) in the crosstalk between cholesterol and vitamin D. Our aim was to evaluate the impact of vitamin D-related polymorphisms and DHCR7 levels in the association between vitamin D deficiency and altered lipid profile in rheumatoid arthritis (RA). Serum 25(OH)-vitamin D, DHCR7 levels and vitamin D-related polymorphisms (VDR-rs2228570, CYP27A1-rs933994, CYP2R1-rs10741657 and DHCR7-rs12785878) were analyzed in 211 RA patients,94 controls and in a prospective cohort of 13 RA patients undergoing TNFα-blockade. Vitamin D was decreased in RA (p < 0.001), correlated to HDL-cholesterol (r = 0.217, p < 0.001) and total-/HDL-cholesterol ratio (r = -0.227, p = 0.004). These correlations were restricted to the VDR-rs2228570 status. Vitamin D deficiency was associated with lower HDL-cholesterol (p = 0.028), higher tender (p = 0.005) and swollen (p = 0.002) joint counts, higher DAS28 (p = 0.018) and HAQ (p = 0.024) in AG/AA-patients but not in their GG-counterparts. The associations among DHCR7, vitamin D and lipid profile followed a seasonal pattern, decreased DHCR7 (p = 0.008) and vitamin D (p < 0.001) and increased total-cholesterol (p = 0.025) being found in winter/spring. Increasing vitamin D upon TNFα-blockade paralleled RA clinical improvement (r = -0.610, p = 0.027) and DHCR7 elevation (r = 0.766, p = 0.002). In conclusion, vitamin D-related polymorphisms and DHCR7 are pivotal to understand the complex, seasonal associations between vitamin D and lipid profile in RA.

Background and Aims: Cardiovascular (CV) morbidity is increased in inflammatory joint diseases (IJD), as rheumatoid (RA) and psoriatic arthritis (PsA). Whereas increased prevalence of subclinical atherosclerosis has been reported in these conditions, whether an early myocardial functionality is also impaired remains unknown. The aim of this study was to evaluate the myocardial functionality by speckle-tracking echocardiography (STE) in recent onset RA and PsA patients and its potential associations with the levels of circulating CD34  +  cells, vitamin D, and with disease activity., Methods: STE was used to assess the myocardial functionality in patients with very early RA (n = 41) and PsA (n = 35) without traditional CV risk factors, and 58 matched healthy controls (HC). Global longitudinal and circumferential strain (GLS and GCS) was estimated. Pulse wave velocity (PWV) and carotid intima-media thickness (cIMT) were measured as surrogate markers of atherosclerosis. Circulating CD34  +  counts were evaluated by flow cytometry and vitamin D levels were quantified by HPLC. Disease activity was assessed by Disease Activity Score-28 (DAS28)., Results: RA patients exhibited impaired GLS and GCS (both p < 0.001) as compared to HC, GLS being also altered in PsA (p = 0.020 vs. HC). DAS28 was correlated to GLS (r = 0.908, p < 0.001) and GCS (r = 0.868, p < 0.001) in RA, these findings being confirmed by multivariate regression analyses adjusted for confounders and Principal Component Analyses. GLS and GCS were impaired in PsA patients with high disease activity as compared to HC, and GLS was found to be a predictor of cIMT in this condition. On the other hand, vitamin D was negatively associated with cIMT in HC (r = -0.308, p = 0.026) but not in PsA or RA, although decreased levels were observed (both p < 0.001). Vitamin D was an independent predictor of decreased CD34  +  levels in PsA and RA. CD34  +  counts negatively correlated DAS28, GLS and GCS in RA., Conclusions: Subclinical myocardial dysfunction is observed in IJD patients with preserved left-ventricular function and without traditional CV risk factors. Subclinical myocardial dysfunction was found to be a very early event in IJD. Disease activity was the main predictor of myocardial strain impairment. Interestingly, myocardial function was altered and associated with cIMT also in PsA patients with high disease activity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: The interactions between inflammation and lipid profile in rheumatoid arthritis (RA) are poorly understood. The lipid profile study in RA has been biased toward lipoprotein levels, whereas those of triglycerides (TGs) and lipoprotein functionality have been underestimated., Objectives: Since recent findings suggest a role for TG and TG-rich lipoproteins (TRL) on inflammation, we aimed to evaluate a combined lipid profile characterized by high TG and low high-density lipoprotein cholesterol levels (TG high HDL low ) in RA., Methods: Lipid profiles were analyzed in 113 RA patients, 113 healthy controls, and 27 dyslipemic subjects. Levels of inflammatory mediators, paraoxonase-1 (PON1) activity, and total antioxidant capacity were quantified in serum. PON1-rs662 status was evaluated by real-time polymerase chain reaction., Results: The TG high HDL low profile was detected in 29/113 RA patients. Although no differences in prevalence compared with healthy controls or dyslipemic subjects were observed, this profile was associated with increased tumor necrosis factor α (P = .004), monocyte chemotactic protein (P = .004), interferon-gamma-inducible protein-10 (P = .018), and leptin (P < .001) serum levels in RA, where decreased PON1 activity and total antioxidant capacity were found. TG high HDL low prevalence was lower among anti-TNFα-treated patients (P = .004). When RA patients were stratified by PON1-rs662 status, these associations remained in the low-activity genotype (QQ). Finally, a poor clinical response on TNFα blockade was related to an increasing prevalence of the TG high HDL low profile over treatment (P = .021) and higher TRL levels at baseline (P = .042)., Conclusions: The TG high HDL low profile is associated with systemic inflammation, decreased PON1 activity, and poor clinical outcome on TNFα blockade in RA, suggesting a role of TRL and HDL dysfunction as the missing link between inflammation and lipid profile., (Copyright © 2017 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Background: Immune cells under chronic inflammation shed microparticles (MPs) that could fuel the inflammatory responses and atherosclerosis typically presented in systemic lupus erythematosus (SLE). This study analyzes total and subset-specific MPs from SLE patients and their possible influence on clinical features, leukocyte activation and serum cytokines., Methods: Total MPs and those derived from platelets, endothelial cells, monocytes, granulocytes and T-cells were quantified in plasma of 106 SLE patients and 33 healthy controls by flow cytometry. MP amounts were analyzed according to clinical manifestations, blood leukocyte populations and circulating cytokines (IFNα, TNFα, IL-10, BLyS, IL-17, IL-1β, CXCL10, CCL-2, CCL3, leptin). Finally, the in vitro effect of SLE-isolated MPs on the leukocyte activation status was analyzed., Results: Total circulating MPs in SLE patients were related to increased disease duration and the presence of cardiovascular disease. Furthermore, patients displayed increased counts of MPs from platelets, monocytes and T-lymphocytes, especially in SLE patients with disease activity or with TNFα high -profile. Accordingly, MPs were associated with increased expression of activation markers in blood T-cells and monocytes. Finally, analyses propose a role of glucocorticoids in MPs generation and leukocyte activation since both fresh and cultured T-cells under this treatment presented higher IL-10 and CD25 production., Conclusions: The altered profile of subset-specific SLE-MPs was influenced by the disease activity and altered status of leukocyte native cells, also associated with a TNFα high -profile., Translational Results: SLE patients, especially those with disease activity, displayed increased counts of MPs derived from platelets, monocytes and T-lymphocytes, which were more frequently found in TNFα high -type patients. The origin of such SLE-MP subsets seems to be related to the over-activated status of T-cells and monocytes characteristic of these patients. Ex vivo and in vitro analyses propose a role of glucocorticoids in the generation of circulating MPs and leukocyte activation in SLE patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: Innate lymphoid cells (ILCs) are emerging mediators of immunity, and accumulation of inflammatory ILC populations can occur in inflammatory-mediated conditions. Since early lymph node (LN) activation has been shown in rheumatoid arthritis (RA), we aimed to investigate the frequency and distribution of ILCs in LN biopsy specimens obtained during the earliest phases of RA., Methods: Twelve patients with early RA, 12 individuals with IgM rheumatoid factor and/or anti-citrullinated protein antibodies without arthritis (RA risk group), and 7 healthy controls underwent ultrasound-guided inguinal LN biopsy. ILC subsets and the expression of vascular cell adhesion molecule (VCAM) and intercellular adhesion molecule (ICAM) by LN endothelial cells and fibroblasts were analyzed by flow cytometry., Results: Although no differences in the frequencies of total ILCs (Lin-CD45 +/low CD127+) were found, the distribution of the ILC subpopulations differed among groups. RA patients showed lower numbers of lymphoid tissue-inducer (LTi) cells (c-Kit+NKp44- ILCs) and increased ILC1 (c-Kit-NKp44- ILCs) and ILC3 (c-Kit+NKp44+ ILCs) numbers compared with controls (P < 0.001, P < 0.050, and P < 0.050, respectively). Individuals at risk of RA exhibited an increased frequency of ILC1 compared with controls (P < 0.01). LTi cells paralleled the expression of adhesion molecules on endothelial cells and fibroblasts., Conclusion: Our findings indicate that during the at-risk and earliest phases of RA, the ILC distribution in LN changes from a homeostatic profile toward a more inflammatory profile, thereby providing evidence of a role for ILCs in RA pathogenesis., (© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.)

Several lines of evidence suggest that chronic inflammation and immune dysregulation are related to altered lipid profiles in rheumatoid arthritis (RA), but the actual mechanisms are still unclear. We wondered whether the development of antibodies against high-density lipoprotein (HDL) can be found in RA patients linked to clinical and cardiovascular (CV) risk factors. To this end, immunoglobulin G (IgG) anti-HDL antibodies and total IgG serum levels were quantified in 212 RA patients, 131 sex- and age-matched healthy controls (HC), and 52 subjects with traditional CV risk factors (tCVRs). A subgroup of 13 RA patients was prospectively followed on TNFα-blockade. TNFα, interferon (IFN)α, MIP1α, IFNγ, IL-8, VEGF, GM-CSF, IL-17, MCP-1, SDF-1α, resistin, and leptin serum levels were quantified by immunoassays. IgG anti-HDL levels were higher in RA patients compared with HC (P < 0.0001) and tCVR subjects (P = 0.015). Differences with HC remained after correction for total IgG levels (P < 0.003). Anti-HDL/IgG were negatively associated with HDL levels in RA (-1.182 [-1.823 to -0.541], P = 0.0003) after adjusting for demographical, clinical, inflammatory parameters, and treatments. RA patients with high levels of anti-HDL/IgG (n = 40, 18.8%) were more likely to have experienced a CV event (P < 0.0001) and exhibited increased levels of several proinflammatory mediators (C-reactive protein, IFNα, MIP1α, IFNγ, IL-8, GM-CSF, IL-17 and MCP-1). Finally, change in anti-HDL antibodies on TNFα-blockade was independently associated with increasing HDL levels. Overall, IgG anti-HDL antibodies are increased in RA independently of tCVRs and associated with a proinflammatory milieu and impaired lipid blood profile, which may contribute to the increased rate of CV events in these patients., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: The role of Red Cell Distribution Width (RDW) as a predictor of cardiovascular (CV) events has been proposed in a variety of conditions, including Rheumatoid Arthritis (RA). However, the mechanisms underlying this effect are still unknown. Since inflammation and Endothelial Progenitor Cells (EPCs) imbalance have been reported in RA patients to be related to CV disease, we wondered whether RDW could be linked to endothelial repair failure in RA., Methods: EPCs (CD34+VEGFR2+CD133+) were quantified by flow cytometry in peripheral blood samples from 194 RA patients. IFNα, TNFα, IFNγ, IL-8, VEGF, GM-CSF, MCP-1, ICAM-1, EGF, Leptin and Resistin serum levels were quantified by immunoassays. Clinical and immunological parameters as well as history of traditional CV risk factors and CV events were registered from medical records. RDW was measured in complete blood cell count analyses., Results: RDW was negatively related to EPC counts in patients with established disease (>1 year, n=125) (r=-0.306, p<0.001). Moreover, RDW was independently associated to an EPC depletion in the whole group (β [95% CI]: -3.537 [-6.162, -0.911], p=0.009) after adjusting for clinical parameters, disease duration, treatments and traditional CV risk factors. Additionally, RDW was positively correlated with IFNα serum levels, a cytokine related to endothelial damage, and with IL-8, VEGF and neutrophil to lymphocyte ratio, thus supporting the association with inflammation and vascular remodelling., Conclusions: RDW was associated to EPC depletion and increased levels of different mediators linked to endothelial damage and vascular repair failure, thereby shedding new light on the nature of RDW as CV-predictor., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objectives: To analyse the influence of IFNα on TNFα production by human peripheral blood mononuclear cells (PBMCs), as well as the possible interference of this cytokine on the effect of antimalarial drugs, TNFα regulators widely used in the treatment of systemic lupus erythematosus (SLE)., Methods: PBMCs, monocytes or T cells were treated with IFNα alone or simultaneously to cellular stimuli as well as in the presence or absence of chloroquine. Supernatants from such cultures were collected to quantify TNFα by ELISA. TNFα and STAT4 expression in cultured cells were analysed by intracellular flow cytometry. In addition, STAT4 gene expression and serum levels of TNFα and IFNα were quantified in 53 SLE patients and 45 controls., Results: IFNα alone did not modify significantly TNFα production, but an increase was observed in stimulated PBMC. Further analyses showed that monocytes were the cellular population responsible for this effect. In addition, IFNα treatment increased STAT4 in stimulated monocytes, suggesting that TNFα upregulation could be mediated by STAT4. On the other hand, the analysis of the antimalarial effect showed that chloroquine was able to inhibit in vitro the expression of TNFα and STAT4 enhanced by IFNα. In antimalarial-treated SLE patients, however, only those with high IFNα serum levels presented lower expression of STAT4., Conclusions: IFNα treatment enhances the induction of TNFα and STAT4 in stimulated monocytes, an effect inhibited in vitro by chloroquine treatment. However, the consequence of antimalarial treatment on SLE patients could be different depending on their IFNα serum levels., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In this work we studied CD4+FOXP3+ populations in systemic lupus erythematosus (SLE) and the relationship with Th cytokine production. We found an increment in CD25-FOXP3+ population in SLE associated with CD4+ downregulation and disease progression. CD25low cells were also upregulated and showed increased percentages of FOXP3+ and CD127-/low cells, supporting the activated status of SLE lymphocytes. Despite the normal levels of CD25highFOXP3+ cells, the negative correlations observed in controls with the frequency of IFNγ, TNFα and IL-10 secreting cells were disrupted in patients, supporting a defective Treg function. Also, CD25high cells showed an altered balance in the production of these cytokines. In addition, CD25highFOXP3+ cells correlated directly with IL-17A and IL-8 but not with TGFβ in SLE. The increased proportion of IL-17+ cells among the CD25high subset and the positive correlation between IL-17 levels and Treg cells suggest a trans-differentiation of Treg into Th17 cells in SLE., (Copyright © 2012 Elsevier Ltd. All rights reserved.)