(A) The vasodilator response to Ach (expressed as AUC of Ach) was assessed in aortic rings from AIA and controls at day 33 post-immunization.Results are expressed as means ± SEM of 12 to 19 aortic ...rings from 19 rats/group. ** p<0.01, *** p<0.001. https://doi.org/10.1371/journal.pone.0150874.g001 1.
Active rheumatoid arthritis (RA) may damage vascular endothelial cells, thereby increasing the likelihood of adverse cardiovascular events. However, it is not yet clearly established whether RA also ...increases the risk of adverse cerebrovascular events, particularly stroke.
This study was designed to evaluate the likelihood of a causal association between RA and stroke.
A two-sample Mendelian randomization (MR) analysis was performed using the inverse variance-weighted (IVW) average, weighted median, and MR-Egger regression methods. The analysis utilized publicly available summary statistics datasets from Genome-wide association studies (GWAS) meta-analyses for RA in individuals of European descent (total n = 484,598; case = 5427, control = 479,171) as the exposure cohort, and from GWAS meta-analyses for "vascular/heart problems diagnosed by doctor: stroke" in individuals included in the UK Biobank (total n = 461,880; case = 7055, control = 454,825, MRC-IEU consortium) as the outcome cohort.
Eight single-nucleotide polymorphisms with genome-wide significance were selected from the GWASs on RA as the instrumental variables. The results of the MR-Egger and weighted median analyses showed no causal association between RA and stroke (OR = 1.081, 95 % CI 0.943–1.240, P = 0.304) vs. OR = 1.079, 95 % CI 0.988–1.179, P = 0.091), respectively. However, the inverse variance-weighted (IVW) analysis results revealed a causal association between RA and stroke (OR = 1.115, 95 % CI 1.040–1.194, P = 0.002). Cochran's Q test and MR-Egger regression revealed no evidence of heterogeneity and horizontal pleiotropy.
The MR analysis results indicated that rheumatoid arthritis (RA) may be causally associated with an increased risk of stroke.
•The exact relationship between rheumatoid arthritis and stroke is unclear.•Observational studies are biased and the results are not consistent.•Mendelian randomization(MR) avoids bias as much as possible.•This MR study suggests a potential causal relationship between rheumatoid arthritis and stroke.
Most reports of pulmonary manifestations in rheumatoid arthritis (RA) have been related to interstitial lung diseases. RA and COPD are both chronic inflammatory systemic diseases.
Does RA increase ...the risk of developing COPD? Is there a difference between seropositive and seronegative RA in the risk of COPD?
Using the Korean National Health Insurance Database, we screened individuals diagnosed with RA between 2010 and 2017. We identified 46,030 patients with RA (32,608 with seropositive RA and 13,422 with seronegative RA) and 230,150 matched control individuals; we monitored them until December 2019. We used multivariate Cox proportional hazard models to estimate the adjusted hazard ratio (aHR) of risk factors for the development of COPD.
The incidence of COPD among patients with RA was 5.04 per 1,000 person-years; it was 2.23 per 1,000 person-years in the control group. Patients with RA showed a higher risk of developing COPD (aHR, 2.11; 95% CI, 1.96-2.28) compared with the control group. Although both seropositive RA and seronegative RA were associated with an increased risk of COPD, patients with seropositive RA had a higher risk for the development of COPD (aHR, 1.26; 95% CI, 1.09-1.46) than patients with seronegative RA. In the subgroup analyses, smoking history did not demonstrate significant interactions between RA and COPD development.
RA was shown to be associated with an increased risk of COPD development, augmented by seropositivity. Physicians should monitor respiratory symptoms and pulmonary function carefully in patients with RA.
ObjectivesSince the 2007 recommendations for the management of early arthritis have been presented, considerable research has been published in the field of early arthritis, mandating an update of ...the 2007 European League Against Rheumatism (EULAR) recommendations for management of early arthritis.MethodsIn accordance with the 2014 EULAR Standardised Operating Procedures, the expert committee pursued an approach that was based on evidence in the literature and on expert opinion. The committee involved 20 rheumatologists, 2 patients and 1 healthcare professional representing 12 European countries. The group defined the focus of the expert committee and target population, formulated a definition of ‘management’ and selected the research questions. A systematic literature research (SLR) was performed by two fellows with the help of a skilled librarian. A set of draft recommendations was proposed on the basis of the research questions and the results of the SLR. For each recommendation, the categories of evidence were identified, the strength of recommendations was derived and the level of agreement was determined through a voting process.ResultsThe updated recommendations comprise 3 overarching principles and 12 recommendations for managing early arthritis. The selected statements involve the recognition of arthritis, referral, diagnosis, prognostication, treatment (information, education, pharmacological and non-pharmacological interventions), monitoring and strategy. Eighteen items were identified as relevant for future research.ConclusionsThese recommendations provide rheumatologists, general practitioners, healthcare professionals, patients and other stakeholders with an updated EULAR consensus on the entire management of early arthritis.
Rheumatoid arthritis (RA) has unclear pathogenesis, but the molecules that feed its inflammatory state are known. Small interfering RNAs (siRNAs) are useful to identify molecular targets and evaluate ...the efficacy of specific drugs, and can themselves be used for therapeutic purposes.
A systematic search of different databases to March 2022 was performed to define the role of siRNAs in RA therapy. Twenty suitable studies were identified.
Small interfering RNAs can be useful in the study of inflammatory processes in RA, and identify possible therapeutic targets and drug therapies.
Many genes and cytokines participate in the inflammatory process of RA and can be regulated with siRNA. However, it is difficult to determine whether the responses to siRNAs and other drugs studied in human cells in vitro are similar to the responses in vivo.
Inflammatory processes can be affected by the gene dysregulation of siRNAs on inflammatory cytokines.
To date, it is not possible to determine whether the pharmacological response of siRNAs on cells in vitro would be similar to what takes place in vivo for the diseases studied so far.
Ferroptosis is an emerging target in rheumatoid arthritis (RA). We previously reported that transient receptor potential melastatin 7 (TRPM7) expression is correlated with RA cartilage destruction ...and demonstrated that TRPM7 mediates ferroptosis in chondrocytes. Here, we further determined the role and mechanism of (R)-N-(Benzimidazol-2-yl)-1,2,3,4-tetrahydro-1-naphthylamine (NS8593), a TRPM7 inhibitor, in chondrocyte ferroptosis of RA. We established in vitro models of ferroptosis in human chondrocytes (C28/I2 cells) by using ferroptosis inducer Erastin. The results showed that NS8593 could protect C28/I2 cells from ferroptosis by inhibiting TRPM7 channel, which was manifested by restoring cell viability, reducing cytotoxicity, affecting the expression of ferroptosis marker protein, and restoring redox balance to alleviate Erastin-induced oxidative stress injury. Mechanistically, the Heme oxygenase-1 (HO-1) axis responded to Erastin stimulation, which resulted in TRPM7-mediated chondrocyte ferroptosis，NS8593 could reduce the expression of HO-1 by inhibiting TRPM7 channel. Moreover, NS8593 alleviated articular cartilage destruction and inhibited chondrocyte ferroptosis in AA rats. In conclusion, NS8593 mitigated articular cartilage damage and chondrocyte ferroptosis through the TRPM7/HO-1 pathway, suggesting that NS8593 may be a potential novel drug for the treatment of RA.
Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease; the clinical manifestations are correlated with continuum multiarticular synovitis, cartilage and bone damage, and defeat of ...joint function, that causes disability. Involvement of internal organs is also frequent. Between the inflammatory cells involved in RA, macrophages play a key role. These cells can polarize in different phenotype and mediate the immune/inflammatory reaction as well as the reparatory phase when possible. The properties of these cells are mediate by the body's environmental factors.
In this systematic review, all English-speaking articles concerning the role of M1 (pro-inflammatory) or M2 (anti-inflammatory) macrophages in RA were systematically reviewed and categorized according to their polarized-function in RA, especially in the synovial tissue. Analyses of the endogenous molecules and the drugs that could modulate M1 and M2 activity in RA were achieved.
A sensitive search was developed in Pubmed, Web of Science, Ovid Med-Line, Embase Database and Science Direct Database (la both from Elsevier) to identify articles to increase the highlighting on the role of macrophages M1 and M2 in RA using the following terms: ((M1 AND M2) AND Rheumatoid Arthritis). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Relevant data were extracted and analyzed using a standardized template designed for this review.
In total 39 resulting articles were selected and categorized according to description of M1/M2's role in RA. Data from humans, mice and rats were subcategorized, thus in every section were highlighted the contribute, in peripheral blood and synovial tissue, of both polarized macrophages; section for endogenous molecules and drugs that favor the switch from M1 to M2 macrophages were carried out. The most evinced relevant results, were that in RA blood and in the synovial tissue, there isn't a clear distinction phase with M1 or M2 macrophages (by membrane marker analysis); rather there is M1 and M2 subset disequilibrium and by deeply analyses of mRNA gene and cytokine produced, it emerged that a non-coherent expression inner marker match with membrane molecules, and also the tissue section can define the marker expressed.
This systematic review emphasizes that the rigid classical subdivision of M1 and M2 macrophages, as well as the different samples' results comparison, might be questionable. In addition, it is suggested, when taking samples from RA patients, to carefully consider their therapies in order to analyze the M1 and M2 macrophages behavior without drug influence.
In line with the advances in M1 and M2 knowledge, and the progression in the single-cell methodologies by identification of individual cell molecular markers, therapeutic approaches seem possible to favor the anti-inflammatory macrophage response in RA (e.g. M2 polarization).
•There are no differences in the circulating monocyte populations among RA and HD.•M1/M2 polarization changes through the disease activity phases.•In RA synovial tissue there are both mature macrophages and mixed M1/M2 phenotypes.•Molecular milieu modulates M1/M2 polarization in animal models and humans.•Animal RA models are still unable to reproduce the human disease comparably.
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