Search

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. [ABSTRACT FROM AUTHOR]

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. Unlabelled Image • Serum EPA level is the main factor linked to obesity, independently of gender • High EPA and Bacteroides level are good lean predictors, independently of gender • Gut Microbiota together with FFA play a gender-specific role in obesity • Fecal Faecalibacterium level is the best indicator of obese linked profile in males • Fecal Bifidobacterium complements FFA levels to predict obesity in women [ABSTRACT FROM AUTHOR]

To assess which immunosuppressive drugs have been investigated and proven efficacious in patients with cardiovascular disease (CVD) or type 2 diabetes (T2D) without preexisting immune mediated disorders to validate in vitro and animal model findings on low grade inflammation (bedside-to-bench). Clinical trials on immunosuppressive drugs in CVD or T2D were found in PubMed. Studies on patients with preexisting immune mediated inflammatory disease were excluded. A total of 19 clinical trials testing canakinumab, anakinra, methotrexate, colchicine, hydroxychloroquine, etanercept and sulfasalazine were found. Canakinumab and colchicine significantly reduced the risk of CVD, whereas methotrexate did not. Sulfasalazine showed no effect on vascular function. Anakinra and hydroxychloroquine had a positive effect on glycemic control and β-cell function in T2D. Etanercept had no effect in patients with T2D. The observed results indicate that immunosuppressive drugs specifically targeting IL-1β hold promise for dampening CVD and T2D. These findings validate in vitro and animal models showing involvement of the IL-1-axis in the pathogenesis of CVD and T2D. The use of immunosuppressive drugs targeting the chronic inflammation in these diseases could be a possible future treatment strategy as an add-on to the existing pharmacological treatment of CVD and T2D. However, potential treatment effects, adverse events and cost-effectiveness should be carefully considered with importance for drug development. [ABSTRACT FROM AUTHOR]

Abstract: 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 &y& Elsevier]

Background: Since the publication of the 2011 European Alliance of Associations for Rheumatology (EULAR) recommendations for patient research partner (PRP) involvement in rheumatology research, the role of PRPs has evolved considerably. Therefore, an update of the 2011 recommendations was deemed necessary., Methods: In accordance with the EULAR Standardised Operational Procedures, a task force comprising 13 researchers, 2 health professionals and 10 PRPs was convened. The process included an online task force meeting, a systematic literature review and an in-person second task force meeting to formulate overarching principles (OAPs) and recommendations. The level of agreement of task force members was assessed anonymously (0-10 scale)., Results: The task force developed five new OAPs, updated seven existing recommendations and formulated three new recommendations. The OAPs address the definition of a PRP, the contribution of PRPs, the role of informal caregivers, the added value of PRPs and the importance of trust and communication in collaborative research efforts. The recommendations address the research type and phases of PRP involvement, the recommended number of PRPs per project, the support necessary for PRPs, training of PRPs and acknowledgement of PRP contributions. New recommendations concern the benefits of support and guidance for researchers, the need for regular evaluation of the patient-researcher collaboration and the role of a designated coordinator to facilitate collaboration. Agreements within the task force were high and ranged between 9.16 and 9.96., Conclusion: The updated EULAR recommendations for PRP involvement are more substantially based on evidence. Together with added OAPs, they should serve as a guide for researchers and PRPs and will ultimately strengthen the involvement of PRPs in rheumatology research., Competing Interests: Competing interests: MdW: over the last 3 years, Stichting Tools has received fees for lectures or consultancy provided by Maarten de Wit from UCB, not related to this project. LG reports grants from AbbVie, Biogen, Lilly, Novartis, UCB, personal fees from AbbVie, Amgen, BMS, Celltrion, Janssen, Lilly, MSD, Novartis, Pfizer, UCB, non-financial support from AbbVie, Amgen, Galapagos, Janssen, MSD, Novartis, Pfizer, UCB, outside the submitted work. KA: funded by EULAR grant RES005 this project; research grants: UCB; consulting fees: Novartis. ME: congress travel support from Janssen and AstraZeneca outside of the submitted work. DB: Speakers bureau: AbbVie, BMS, Galapagos, Janssen, Lilly, MSD. Research grants: Novartis. Consultancy: Sandoz, UCB. Part-time work in Savana Research. EFM has received consultancy fees from Boehringer Ingelheim Portugal outside of the submitted work, LPCDR has received fees for lectures or consultancy provided by Elsa Mateus from Lilly Portugal, GSK and Novartis, outside of the submitted work. SWT has received research funding, consultancy and/ or speaker fees from: Abbvie, Arthrogen, AstraZeneca, BMS, Celgene, Galapagos, Galvani bioelectronics, GSK, Lilly, MSD, Pfizer, Roche, and Sanofi-Genzyme, all outside the submitted work. WT has received research funding, consultancy and/ or speaker fees from: AbbVie, Amgen, BMS, Celgene, Eli-Lilly, GSK, Janssen, MSD, Novartis, Ono-Pharma, Pfizer and UCB all outside of the submitted work. HB, SB, PB, JP, CD, MF, SK, UK, DPR, JR-C, JS, RS, SRS, AV, T-CW, CZ and JP report no competing interests for this project., (© European Alliance of Associations for Rheumatology, EULAR 2024. Re-use permitted under CC BY-NC-ND. No commercial re-use. No derivatives. See rights and permissions. Published by BMJ on behalf of EULAR.)

Evidence that psoriatic disease is burdened by an excess cardiovascular (CV) risk has accrued, however many questions remain unanswered. Although an interplay between traditional risk factors inflammation, disease activity and pharmacological therapies, as observed in rheumatoid arthritis (RA), may account for this increased risk, metabolic comorbidities rather than inflammation seem to have a leading role in psoriatic disease. Therefore, specific approaches, risk factors targeting and the importance of traditional risk factors and inflammation management need to be considered. The purpose of this review article is to discuss current data on CV risk in psoriatic disease, and to outline similarities and differences with RA in the light of international recommendations. Arguments in favour of developing specific guidance for CV prevention in psoriatic disease are discussed., Competing Interests: Declaration of competing interest AA: Grants from UCB, Astra Zeneca, BMS outside the submitted work. LG: Research grants: AbbVie, Biogen, Lilly, Novartis, UCB; consulting fees: AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB; grants from AbbVie, Biogen, Lilly, Novartis, UCB; personal fees from AbbVie, Amgen, BMS, Celltrion, Galapagos, Janssen, Lilly, MSD, Novartis, Pfizer, Sandoz, UCB, non-financial support from AbbVie, Janssen, MSD, Novartis, Pfizer, UCB, Viatris outside the submitted work. FC, JRC, SD and CF have nothing to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: While the type I interferon (IFN-I) pathway is crucial in autoimmunity, its role in antiphospholipid antibody (aPL)-positive subjects, including aPL carriers and antiphospholipid syndrome (APS) patients, is poorly understood. This study aims at characterizing IFN-I pathway activation within the spectrum of aPL-positive subsets., Methods: A total of 112 patients [29 aPL carriers, 31 primary APS (PAPS), 25 secondary APS (SAPS), 27 systemic lupus erythematosus (SLE) patients without aPL, and 44 healthy controls (HCs)] were recruited. IFI6, IFI44, IFI44L, MX1, IFI27, OAS1, and RSAD2 gene expression was evaluated in whole blood, and a composite index (IFN score) was calculated., Results: An overall activation of the IFN-I pathway was observed across the entire APS spectrum, with differences among genes based on the specific disease subset. The composite score revealed quantitative differences across subsets, being elevated in aPL carriers and PAPS patients compared to HCs (both p < 0.050) and increasing in SAPS ( p < 0.010) and SLE patients ( p < 0.001). An unsupervised cluster analysis identified three clusters, and correspondence analyses revealed differences in clusters usage across APS subsets ( p < 0.001). A network analysis revealed different patterns characterizing different subsets. The associations between IFN-I pathway activation and clinical outcomes differed across APS subsets. Although no differences in gene expression were observed in systemic APS, the network analyses revealed specific gene-gene patterns, and a distinct distribution of the clusters previously identified was noted ( p = 0.002)., Conclusion: IFN-I pathway activation is a common hallmark among aPL-positive individuals. Qualitative and quantitative differences across the APS spectrum can be identified, leading to the identification of distinct IFN-I signatures with different clinical values beyond traditional categorization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Cecchi, Radin, Barinotti, Foddai, Menegatti, Roccatello, Suárez, Sciascia and Rodríguez-Carrio.)

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.

Objective: Chronic inflammation and immune dysregulation are crucial mechanisms for atherosclerosis in RA. Recent evidence suggests a link via humoral responses against high-density lipoproteins (HDL). This study aimed to characterize the specificity, clinical relevance and emergence of humoral responses against HDL along disease course, especially during the earliest phases of arthritis., Methods: IgG and IgM serum levels of antibodies against HDL (anti-HDL) and apolipoprotein A1 (anti-ApoA1) were measured in 82 early RA patients, 14 arthralgia individuals and 96 controls. Established RA patients (n = 42) were included for validation. Atherosclerosis and vascular stiffness were measured by Doppler ultrasound. Lipoprotein content, particle numbers and size were measured by H-NMR. Cytokines were measured by immunoassays. A cardiometabolic-related protein panel was evaluated using high-throughput targeted proteomics., Results: Anti-HDL and anti-ApoA1 responses were increased in early RA compared with controls (both P < 0.001) and were comparable to established disease. Only anti-ApoA1 antibodies were increased in arthralgia. IgG anti-HDL and anti-ApoA1 were associated with unfavourable lipoprotein traits in RA and arthralgia, respectively. A similar picture was observed for inflammatory mediators. No associations with clinical features or risk factors were found. IgG anti-HDL were independently associated with atherosclerosis occurrence in early RA, and outperformed patient stratification over conventional algorithms (mSCORE) and their anti-ApoA1 counterparts. Anti-HDL antibodies correlated with proteins involved in immune activation, remodelling and lipid metabolism pathways in early RA., Conclusion: Humoral responses against HDL particles are an early event along the arthritis course, although quantitative and qualitative differences can be noticed among stages. These differences informed distinct capacities as biomarkers and underlying pathogenic circuits., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Lifestyle factors (such as diet, physical activity or smoking habits, among others) are known to influence the progression of rheumatic and musculoskeletal diseases (RMDs). Despite contemporary improvements in RMD care, the management of lifestyle factors is suboptimal. In the context of a recent European Alliance of Associations for Rheumatology (EULAR) task force, existing informative materials regarding lifestyle factors for people with RMDs were collected from national organisations across European countries. Current materials show important limitations in terms of coverage, literature support and access, which may make the implementation of successful interventions difficult. In the present viewpoint, a roadmap to cover these gaps at the European level with the recent EULAR recommendations on lifestyle factors is discussed from an implementation perspective. This analysis may pave the ground for future implementation endeavours at the European level related to non-pharmacological interventions that may also be applicable beyond rheumatology., Competing Interests: Competing interests: JG is currently a full-time employee of IQVIA (UK)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with chronic inflammatory arthritis have a higher cardiovascular (CV) risk than the general population. Traditional CV risk factors are clearly implicated, while the impact of metabolic syndrome (MetS) is less defined. The aim of this study was to compare MetS prevalence and impact on the CV risk in psoriatic arthritis (PsA) versus rheumatoid arthritis (RA). A retrospective analysis of real-world data of PsA and RA patients referred to a rheumatology clinic was conducted. The following data were extracted and compared: demographic data; clinical data; presence of traditional CV risk factors and MetS. Univariate and multivariate models were used to compare the impact of MetS and its components in patients with PsA versus RA. Overall, 170 patients were included (PsA: 78; RA; 92). The two groups differed significantly in mean age, disease duration, and presence of MetS, while other variables were comparable. Univariate and multivariate analysis identified distinct predictors of MetS in PsA (hypertension) and RA (dyslipidemia). The history of CV events was similar in the two groups. Predictors of CV events were MetS and most of its components in PsA, while dyslipidemia was the strongest predictor in RA. These associations were stronger in PsA than in RA. In conclusion, the impact of MetS and its components is different in PsA and RA. The association of these risk factors with CV events is stronger in PsA than in RA. This suggests the implication of different mechanisms, which may require distinct strategies for the prevention of CV events in PsA and RA.

Background: Type I interferons (IFN-Is) play a role in a broad range of rheumatic and musculoskeletal diseases (RMDs), and compelling evidence suggests that their measurement could have clinical value, although testing has not progressed into clinical settings., Objective: To develop evidence-based points to consider (PtC) for the measurement and reporting of IFN-I assays in clinical research and to determine their potential clinical utility., Methods: EULAR standardised operating procedures were followed. A task force including rheumatologists, immunologists, translational scientists and a patient partner was formed. Two systematic reviews were conducted to address methodological and clinical questions. PtC were formulated based on the retrieved evidence and expert opinion. Level of evidence and agreement was determined., Results: Two overarching principles and 11 PtC were defined. The first set (PtC 1-4) concerned terminology, assay characteristics and reporting practices to enable more consistent reporting and facilitate translation and collaborations. The second set (PtC 5-11) addressed clinical applications for diagnosis and outcome assessments, including disease activity, prognosis and prediction of treatment response. The mean level of agreement was generally high, mainly in the first PtC set and for clinical applications in systemic lupus erythematosus. Harmonisation of assay methodology and clinical validation were key points for the research agenda., Conclusions: IFN-I assays have a high potential for implementation in the clinical management of RMDs. Uptake of these PtC will facilitate the progress of IFN-I assays into clinical practice and may be also of interest beyond rheumatology., Competing Interests: Competing interests: MKC has received consulting fees from AstraZeneca, Bristol Meyers Squibb, Lilly, and Shannon Pharmaceuticals, as well as grant/research support from Gilead. LR has received consulting fees from AstraZeneca. EMV served in the speakers’ bureau of GSK, received consulting fees from AURINIA, SANDOZ, GSK, AstraZeneca, Roche, and Modus, as well as grant/research support from AstraZeneca. PGC has received consultancies or speaker fees from AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, Galapagos, GSK, Merck, Pfizer, Novartis and UCB., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: In-stent restenosis (ISR) is a major challenge in interventional cardiology. Both ISR and excessive skin healing are aberrant hyperplasic responses, which may be functionally related. However, the cellular component underlying ISR remains unclear, especially regarding vascular homeostasis. Recent evidence suggest that novel immune cell populations may be involved in vascular repair and damage, but their role in ISR has not been explored. The aims of this study is to analyze (i) the association between ISR and skin healing outcomes, and (ii) the alterations in vascular homeostasis mediators in ISR in univariate and integrative analyses., Methods: 30 patients with ≥1 previous stent implantation with restenosis and 30 patients with ≥1 stent without restenosis both confirmed in a second angiogram were recruited. Cellular mediators were quantified in peripheral blood by flow cytometry. Skin healing outcomes were analyzed after two consecutive biopsies., Results: Hypertrophic skin healing was more frequent in ISR patients (36.7%) compared to those ISR-free (16.7%). Patients with ISR were more likely to develop hypertrophic skin healing patterns (OR 4.334 [95% CI 1.044-18.073], p=0.033), even after correcting for confounders. ISR was associated with decreased circulating angiogenic T-cells (p=0.005) and endothelial progenitor cells (p<0.001), whereas CD4 + CD28 null and detached endothelial cells counts were higher (p<0.0001 and p=0.006, respectively) compared to their ISR-free counterparts. No differences in the frequency of monocyte subsets were found, although Angiotensin-Converting Enzyme expression was increased (non-classical: p<0.001; and intermediate: p<0.0001) in ISR. Despite no differences were noted in Low-Density Granulocytes, a relative increase in the CD16 - compartment was observed in ISR (p=0.004). An unsupervised cluster analysis revealed the presence of three profiles with different clinical severity, unrelated to stent types or traditional risk factors., Conclusion: ISR is linked to excessive skin healing and profound alterations in cellular populations related to vascular repair and endothelial damage. Distinct cellular profiles can be distinguished within ISR, suggesting that different alterations may uncover different ISR clinical phenotypes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lozano, Bangueses, Rodríguez, Pevida, Rodríguez-Aguilar, Rodríguez, Espasandín-Arias, Llames, Meana, Suárez and Rodríguez-Carrio.)

Background: Type I interferons (IFN-I) contribute to a broad range of rheumatic and musculoskeletal diseases (RMDs). Compelling evidence suggests that the measurement of IFN-I pathway activation may have clinical value. Although several IFN-I pathway assays have been proposed, the exact clinical applications are unclear. We summarise the evidence on the potential clinical utility of assays measuring IFN-I pathway activation., Methods: A systematic literature review was conducted across three databases to evaluate the use of IFN-I assays in diagnosis and monitor disease activity, prognosis, response to treatment and responsiveness to change in several RMDs., Results: Of 366 screened, 276 studies were selected that reported the use of assays reflecting IFN-I pathway activation for disease diagnosis (n=188), assessment of disease activity (n=122), prognosis (n=20), response to treatment (n=23) and assay responsiveness (n=59). Immunoassays, quantitative PCR (qPCR) and microarrays were reported most frequently, while systemic lupus erythematosus (SLE), rheumatoid arthritis, myositis, systemic sclerosis and primary Sjögren's syndrome were the most studied RMDs. The literature demonstrated significant heterogeneity in techniques, analytical conditions, risk of bias and application in diseases. Inadequate study designs and technical heterogeneity were the main limitations. IFN-I pathway activation was associated with disease activity and flare occurrence in SLE, but their incremental value was uncertain. IFN-I pathway activation may predict response to IFN-I targeting therapies and may predict response to different treatments., Conclusions: Evidence indicates potential clinical value of assays measuring IFN-I pathway activation in several RMDs, but assay harmonisation and clinical validation are urged. This review informs the EULAR points to consider for the measurement and reporting of IFN-I pathway assays., Competing Interests: Competing interests: MKC has received consulting fees from AstraZeneca, Bristol Meyers Squibb, Lilly and Shannon Pharmaceuticals, as well as grant/research support from Gilead. LR has received consulting fees from AstraZeneca. EV served in the speakers’ bureau of GSK, received consulting fees from AURINIA, SANDOZ, GSK, AstraZeneca, Roche and Modus, as well as grant/research support from AstraZeneca. PGC has received consultancies or speaker fees from AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, Galapagos, GSK, Merck, Pfizer, Novartis and UCB., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To systematically review the literature for assay methods that aim to evaluate type I interferon (IFN-I) pathway activation and to harmonise-related terminology., Methods: Three databases were searched for reports of IFN-I and rheumatic musculoskeletal diseases. Information about the performance metrics of assays measuring IFN-I and measures of truth were extracted and summarised. A EULAR task force panel assessed feasibility and developed consensus terminology., Results: Of 10 037 abstracts, 276 fulfilled eligibility criteria for data extraction. Some reported more than one technique to measure IFN-I pathway activation. Hence, 276 papers generated data on 412 methods. IFN-I pathway activation was measured using: qPCR (n=121), immunoassays (n=101), microarray (n=69), reporter cell assay (n=38), DNA methylation (n=14), flow cytometry (n=14), cytopathic effect assay (n=11), RNA sequencing (n=9), plaque reduction assay (n=8), Nanostring (n=5), bisulphite sequencing (n=3). Principles of each assay are summarised for content validity. Concurrent validity (correlation with other IFN assays) was presented for n=150/412 assays. Reliability data were variable and provided for 13 assays. Gene expression and immunoassays were considered most feasible. Consensus terminology to define different aspects of IFN-I research and practice was produced., Conclusions: Diverse methods have been reported as IFN-I assays and these differ in what elements or aspects of IFN-I pathway activation they measure and how. No 'gold standard' represents the entirety of the IFN pathway, some may not be specific for IFN-I. Data on reliability or comparing assays were limited, and feasibility is a challenge for many assays. Consensus terminology should improve consistency of reporting., Competing Interests: Competing interests: MKC has received consulting fees from AstraZeneca, Bristol Meyers Squibb, Lilly and Shannon Pharmaceuticals, as well as grant/research support from Gilead. LR has received consulting fees from AstraZeneca. EV served in the speakers’ bureau of GSK, received consulting fees from AURINIA, SANDOZ, GSK, AstraZeneca, Roche, and Modus, as well as grant/research support from AstraZeneca. PGC has received consultancies or speaker fees from AbbVie, Amgen, AstraZeneca, BMS, Eli Lilly, Galapagos, GSK, Merck, Pfizer, Novartis and UCB. The rest of the authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Introduction: Rheumatoid arthritis (RA) exhibit a cardiovascular (CV) risk that is 1.5-2.0 times higher compared to the general population. This CV risk excess is likely caused by the involvement of chronic inflammation and immune dysregulation. Therefore, conventional algorithms and imaging techniques fail to fully account for this risk excess and provide a suboptimal risk stratification, hence limiting clinical management in this setting., Areas Covered: Compelling evidence has suggested a role for adaptations of conventional algorithms (Framingham, SCORE, AHA, etc) or the development of RA-specific algorithms, as well as the use of a number of several, noninvasive imaging techniques to improve CV risk assessment in RA populations. Similarly, in-depth analyses of atherosclerosis pathogenesis in RA patients have shed new light into a plethora of soluble biomarkers (such as inflammatory cytokines, vascular remodeling mediators or autoantibodies) that may provide incremental value for CV risk stratification., Expert Opinion: Extensive research has demonstrated a lack of performance of chart adaptations in capturing real CV risk in RA population, as well as for RA-specific algorithms. Similarly, limitations have been detected in the use of soluble mediators. The development of a novel, RA-specific algorithm including classical and non-traditional risk factors may be advisable.

Objective: A EULAR taskforce was convened to develop recommendations for lifestyle behaviours amongst people with rheumatic and musculoskeletal diseases (RMDs). This paper reviews the literature on work-related factors and disease-specific outcomes for people with osteoarthritis, rheumatoid arthritis (RA), systemic lupus erythematosus, axial spondyloarthritis (axSpA), psoriatic arthritis, systemic sclerosis (SSc) and gout., Methods: Two separate systematic literature reviews (SLRs) were conducted. The first identified SLRs, published between 01/2013 and 09/2018. The second identified original observational and intervention studies published before 05/2019. Manuscripts were included if they assessed the effects of vocational interventions on disease-specific outcomes (i.e. clinical outcomes, patient-reported outcomes, and work outcomes) or if they assessed the association between work-related factors and these outcomes. Medline, Embase, Cochrane Library of systematic reviews and CENTRAL databases were searched., Results: Two SLRs were identified including individuals with SSc and inflammatory arthritis. Subsequently, 23 original manuscripts were identified, with most of them (43.5%) including people with RA and no manuscripts on gout. Most observational studies evaluated the association between work-related factors and work outcomes while limited information was available on the impact of work on clinical outcomes. A few studies suggested that physically demanding jobs have a small detrimental effect on radiographic progression in axSpA and PsA. Intervention studies showed beneficial effects of vocational interventions for disease-specific outcomes, but with small effect sizes., Conclusion: Many studies indicated that work participation is not likely to be detrimental and, in some cases, may be beneficial for RMD-specific outcomes and should therefore receive attention within healthcare consultations., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022. Published by Elsevier Inc.)

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.)

High Density Lipoprotein (HDL) plays a protective role in abdominal aortic aneurysm (AAA); however, recent findings suggest that oxidative modifications could lead to dysfunctional HDL in AAA. This study aimed at testing the effect of oxidized HDL on aortic lesions and humoral immune responses in a mouse model of AAA induced by elastase, and evaluating whether antibodies against modified HDL can be found in AAA patients. HDL particles were oxidized with malondialdehyde (HDL-MDA) and the changes were studied by biochemical and proteomics approaches. Experimental AAA was induced in mice by elastase perfusion and then mice were treated with HDL-MDA, HDL or vehicle for 14 days. Aortic lesions were studied by histomorphometric analysis. Levels of anti-HDL-MDA IgG antibodies were measured by an in-house immunoassay in the mouse model, in human tissue-supernatants and in plasma samples from the VIVA cohort. HDL oxidation with MDA was confirmed by enhanced susceptibility to diene formation. Proteomics demonstrated the presence of MDA adducts on Lysine residues of HDL proteins, mainly ApoA-I. MDA-modification of HDL abrogated the protective effect of HDL on cultured endothelial cells as well as on AAA dilation in mice. Exposure to HDL-MDA elicited an anti-HDL-MDA IgG response in mice. Anti-HDL-MDA were also detected in tissue-conditioned media from AAA patients, mainly in intraluminal thrombus. Higher plasma levels of anti-HDL-MDA IgG antibodies were found in AAA patients compared to controls. Anti-HDL-MDA levels were associated with smoking and were independent predictors of overall mortality in AAA patients. Overall, MDA-oxidized HDL trigger a specific humoral immune response in mice. Besides, antibodies against HDL-MDA can be detected in tissue and plasma of AAA patients, suggesting its potential use as surrogate stable biomarkers of oxidative stress in AAA., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The risk of cardiovascular disease is increased in patients with rheumatoid arthritis compared with the general population owing to the influence of traditional and non-traditional risk factors. Inflammation has a pivotal contribution and can accelerate the atherosclerotic process. Although dampening inflammation with DMARDs should theoretically abrogate this process, evidence suggests that these drugs can also promote atherosclerosis directly and indirectly, hence adding to an increased cardiovascular burden. However, the extent and direction of the effects largely differ across drugs. Understanding how these drugs influence endothelial damage and vascular repair mechanisms is key to understanding these outcomes. NSAIDs and glucocorticoids can increase the cardiovascular risk. Conversely, conventional, biologic and targeted DMARDs control inflammation and reduce this risk, although some of these drugs can also aggravate traditional factors or thrombotic events. Given these data, the fundamental objective for clinicians should be disease control, in an individualized approach that considers the most appropriate drug for each patient, taking into account joint and cardiovascular outcomes. This Review provides a comprehensive analysis of the effects of DMARDs and other approved drugs on cardiovascular involvement in rheumatoid arthritis, from a clinical and mechanistic perspective, with a roadmap to inform the research agenda.

Objective: Eicosanoids modulate inflammation via complex networks involving different pathways and downstream mediators, including oxylipins. Although altered eicosanoids are linked to rheumatoid arthritis (RA), suggesting that metabolization is enhanced, the role of oxylipins in disease stratification remains unexplored. This study was undertaken to characterize oxylipin networks during the earliest stages of RA and evaluate their associations with clinical features and treatment outcomes., Methods: In total, 60 patients with early RA (according to the American College of Rheumatology/European League Against Rheumatism 2010 criteria), 11 individuals with clinically suspect arthralgia (CSA), and 28 healthy control subjects were recruited. Serum samples were collected at the time of onset. In the early RA group, 50 patients who had not been exposed to disease-modifying antirheumatic drug (DMARD) or glucocorticoid treatment at the time of recruitment were prospectively followed up at 6 and 12 months after having received conventional synthetic DMARDs. A total of 75 oxylipins, mostly derived from arachidonic, eicosapentanoic, and linoleic acids, were identified in the serum by liquid chromatography tandem mass spectrometry., Results: Univariate analyses demonstrated differences in expression patterns of 14 oxylipins across the RA, CSA, and healthy control groups, with each exhibiting a different trajectory. Network analyses revealed a strong grouping pattern of oxylipins in RA patients, whereas in individuals with CSA, a fuzzy network of oxylipins with higher degree and closeness was found. Partial least-squares discriminant analyses yielded variable important projection scores of >1 for 22 oxylipins, which allowed the identification of 2 clusters. Cluster usage differed among the groups (P = 0.003), and showed associations with disease severity and low rates of remission at 6 and 12 months in RA patients who were initially treatment-naive. Pathway enrichment analyses revealed different precursors and pathways between the groups, highlighting the relevance of the arachidonic acid pathway in individuals with CSA and the lipooxygenase pathway in patients with early RA. In applying distinct oxylipin signatures, subsets of seropositive and seronegative RA could be identified., Conclusion: Oxylipin networks differ across stages during the earliest phases of RA. These distinct oxylipin networks could potentially elucidate pathways with clinical relevance for disease progression, clinical heterogeneity, and treatment response., (© 2020, American College of Rheumatology.)

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.)

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.

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.)

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.)