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Carriers of G6PD deficiency were at an increased risk of RA. This finding opens new windows to better understanding the RA pathogenesis.

Abstract The identification of circulating biomarkers of endothelial dysfunction (ED), a precursor to atherosclerosis, in rheumatoid arthritis (RA) would facilitate early risk stratification and prevention strategies. Ischemia-modified albumin (IMA) has emerged as a potential biomarker of oxidative stress, ischemia, and ED. However, studies examining the relationship between IMA and ED in RA patients are lacking. We measured serum IMA concentrations by using an albumin cobalt binding test and peripheral vasodilatory capacity by EndoPAT in 113 RA patients without previous cardiovascular events enrolled in the EDRA study (ClinicalTrials.gov: NCT02341066). The mean peripheral vasodilatory capacity, expressed by the log of reactive hyperemia index (logRHI), was 0.82, corresponding to 27% RA patients having ED. The mean plasma concentrations of IMA were 0.478 absorbance units. We observed a significant and inverse association between peripheral vasodilatory capacity and serum IMA concentrations (rho = − 0.22, p = 0.02). In univariate logistic regression, ED was significantly associated with serum IMA concentrations [OR 1173 (95% CI 1.3568 to 101,364), p = 0.040) and higher disease activity. In multivariate logistic regression, the independent association between ED and IMA remained significant after correction for disease activity and other RA-confounders [OR 2252 (95% CI 1.0596 to 4,787,505), p = 0.048 in Model 1; OR 7221 (95% CI 4.1539 to 12,552,859), p = 0.02 in Model 2]. Conclusions: This study suggests that IMA is a promising biomarker of ED in RA. Further research is needed to confirm our findings and determine the clinical utility of IMA in detecting and managing early atherosclerosis in RA patients.

New evidence continues to accumulate regarding a significant association between excessive inflammation and dysregulated immunity (local and systemic) and the risk of cardiovascular events in different patient cohorts. Whilst research has sought to identify novel atheroprotective therapies targeting inflammation and immunity, several marketed drugs for rheumatological conditions may serve a similar purpose. One such drug, methotrexate, has been used since 1948 for treating cancer and, more recently, for a wide range of dysimmune conditions. Over the last 30 years, epidemiological and experimental studies have shown that methotrexate is independently associated with a reduced risk of cardiovascular disease, particularly in rheumatological patients, and exerts several beneficial effects on vascular homeostasis and blood pressure control. This review article discusses the current challenges with managing cardiovascular risk and the new frontiers offered by drug discovery and drug repurposing targeting inflammation and immunity with a focus on methotrexate. Specifically, the article critically appraises the results of observational, cross-sectional and intervention studies investigating the effects of methotrexate on overall cardiovascular risk and individual risk factors. It also discusses the putative molecular mechanisms underpinning the atheroprotective effects of methotrexate and the practical advantages of using methotrexate in cardiovascular prevention, and highlights future research directions in this area.

Cardiovascular disease is the leading cause of morbidity and mortality in patients with rheumatoid arthritis and systemic lupus erythematosus. Traditional cardiovascular risk factors, although present in lupus and rheumatoid arthritis, do not explain such a high burden of early cardiovascular disease in the context of these systemic connective tissue diseases. Over the past few years, our understanding of the pathophysiology of atherosclerosis has changed from it being a lipid-centric to an inflammation-centric process. In this review, we examine the pathogenesis of atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis, the two most common systemic connective tissue diseases, and consider them as emblematic models of the effect of chronic inflammation on the human body. We explore the roles of the inflammasome, cells of the innate and acquired immune system, neutrophils, macrophages, lymphocytes, chemokines and soluble pro-inflammatory cytokines in rheumatoid arthritis and systemic lupus erythematosus, and the roles of certain autoantigens and autoantibodies, such as oxidized low-density lipoprotein and beta2-glycoprotein, which may play a pathogenetic role in atherosclerosis progression.

The aim is better to understand and critically explore and present the available data from observational studies on the pathogenetic role of the microbiome in the development of rheumatoid arthritis (RA). The electronic databases PubMed, Scopus, and Web of Science were screened for the relevant literature published in the last ten years. The primary outcomes investigated included the influence of the gut microbiome on the pathogenesis and development of rheumatoid arthritis, exploring the changes in microbiota diversity and relative abundance of microbial taxa in individuals with RA and healthy controls (HCs). The risk of bias in the included literature was assessed using the GRADE criteria. Ten observational studies were identified and included in the qualitative assessment. A total of 647 individuals with RA were represented in the literature, in addition to 16 individuals with psoriatic arthritis (PsA) and 247 HCs. The biospecimens comprised fecal samples across all the included literature, with 16S rDNA sequencing representing the primary method of biological analyses. Significant differences were observed in the RA microbiome compared to that of HCs: a decrease in Faecalibacterium, Fusicatenibacter, Enterococcus, and Megamonas and increases in Eggerthellales, Collinsella, Prevotella copri, Klebsiella, Escherichia, Eisenbergiella, and Flavobacterium. There are significant alterations in the microbiome of individuals with RA compared to HCs. This includes an increase in Prevotella copri and Lactobacillus and reductions in Collinsella. Collectively, these alterations are proposed to induce inflammatory responses and degrade the integrity of the intestinal barrier; however, further studies are needed to confirm this relationship.

There have been significant advances, particularly over the last 20 years, in the identification of non-coding RNAs (ncRNAs) and their pathophysiological role in a wide range of disease states, particularly cancer and other chronic conditions characterized by excess inflammation and oxidative stress such as atherosclerosis, diabetes, obesity, multiple sclerosis, osteoporosis, liver and lung fibrosis. Such discoveries have potential therapeutic implications as a better understanding of the molecular mechanisms underpinning the effects of ncRNAs on critical homeostatic control mechanisms and biochemical pathways might lead to the identification of novel druggable targets. In this context, increasing evidence suggests that several natural compounds can target ncRNAs at different levels and, consequently, influence processes involved in the onset and progression of disease states. The natural phenol resveratrol has been extensively studied for therapeutic purposes in view of its established anti-inflammatory and antioxidant effects, particularly in disease states such as cancer and cardiovascular disease that are associated with human aging. However, increasing in vitro and in vivo evidence also suggests that resveratrol can directly target various ncRNAs and that this mediates, at least in part, its potential therapeutic effects. This review critically appraises the available evidence regarding the resveratrol-mediated modulation of different ncRNAs in a wide range of disease states characterized by a pro-inflammatory state and oxidative stress, the potential therapeutic applications, and future research directions.

Spondyloarthritis are chronic inflammatory diseases affecting spine, peripheral joints and enthesis, as well as extra-articular sites (bowel, eyes, skin). Diagnosis of spondyloarthritis often is slow and requires a multidisciplinary approach. The “Early SpA Clinic” project aimed at improving the patient care and journeys, by solving some organizational issues existing in Rheumatology Clinics. The “Early SpA Clinic” involved 19 Italian Rheumatology Centers using in-depth organizational analyses to identify areas for improvement. From the results of the analyses, some organizational solutions were suggested, and their impact measured at the end of the project through specific KPI. With the implementation of the suggested organizational solutions, Centers achieved relevant results, positively impacting on all the phases of the patient journey: decrease in waiting lists (−23%) and in the time length to transit the Center (−22%), increase in the percentage of new diagnoses (+20%), in the saturation of outpatient clinic capacity (+16%), and in the patient satisfaction (+4%). Centers involved in the “Early SpA Clinic” implemented several organizational actions based on an overall assessment of their activities and on solutions that required no additional resources. Overall, the Centers achieved the “Early SpA Clinic” objectives in terms of better management of resources, personnel, spaces, equipment, in relation to the volumes of patients.

Background: A decrease in serum paraoxonase (PON-1) and arylesterase (ARE) activity has been reported in rheumatoid arthritis (RA) patients and linked to chronic inflammation and impaired antioxidant defense. Methods: A systematic review and meta-analysis were performed to critically appraise the current evidence on plasma/serum concentrations of PON-1 and ARE activity in RA patients and healthy controls. The Web of Science, PubMed, Scopus, and Google Scholar databases were searched from inception to November 2021. We used random-effects meta-analysis. The risk of bias was estimated using the Joanna Briggs Institute Critical Appraisal Checklist tool. The certainty of the evidence was assessed with GRADE. The study complied with the PRISMA statements and was registered in PROSPERO (CRD42022345380). Results: Seventeen studies reported PON-1 activity (1144 RA patients, 797 controls) and ten reported ARE activity (1367 RA patients, 1037 controls). RA patients had significantly lower PON-1 (SMD = −1.32, 95% CI −1.94 to −0.70; p < 0.001) and ARE activity (SMD = −0.91, 95% CI −1.37 to −0.46; p < 0.001). There was substantial heterogeneity (PON, I2 97%; ARE, 95.7%, p < 0.001 for both). There was no publication bias. The pooled SMD values did not significantly change after sensitivity analysis. The certainty of the evidence was very low due to the observational nature of the studies and the large heterogeneity. Conclusion: Our meta-analysis has shown that both serum PON-1 and ARE activity are significantly lower in RA patients, suggesting a deficit in antioxidant defense mechanisms in this disease.

A capillary electrophoresis method was developed to detect and measure hydroxychloroquine (HCQ) and its active metabolite desethyl hydroxychloroquine (DHCQ) in whole blood in patients with rheumatoid arthritis. The best separation in terms of peak area reproducibility, migration time, peak shape, and resolution of adjacent peaks was obtained in a 60 cm, 75 µm i.d. uncoated fused-silica capillary using a background electrolyte mixture of an aqueous 55 mmol/L TRIS solution brought to pH 2.6 with phosphoric acid and methanol (85:15) and a voltage and a temperature of separation of 20 kV and 30 °C, respectively. Analytes were separated in less than 12 min, with excellent linearity (R2 ≥ 0.999) in the concentration range of 0.5–8 µmol/L. The recovery of analytes spiked in whole blood was 99–101% for HCQ and 98–99% for DHCQ. Analysis of five samples from patients with rheumatoid arthritis receiving HCQ 400 mg daily yielded mean steady-state concentrations of 2.27 ± 1.61 and 1.54 ± 0.55 μmol/L for HCQ and DHCQ, respectively, with a HCQ to DHCQ ratio of 1.40 ± 0.77.