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Introduction: Autoimmune CTDs like systematic lupus erythematosus (SLE), systemic sclerosis (SSc), and rheumatoid arthritis (RA)predominantly affect women during reproductive years and are linked to maternal and fetal complications. Methods: We conducted a population-based, retrospective cohort study using the national inpatient data sample to compare maternal and fetal outcomes in patients with and without CTD delivering between October 2015 and December 2020. Regression analysis was performed and adjusted for multiple patient characteristics to compare outcomes. Results: Our study comprised of 18,866,050 deliveries, of which 50,450 (0.02%) had autoimmune CTD, including 25,340 with SLE, 23,945 with RA, and 1,165 with SSc. Patients with CTDs had significantly higher odds of maternal death (aOR 3.898; 95% CI: 1.462–10.389, p = 0.007), hypertensive disorders (aOR 1.554; 95% CI: 1.456–1.659, p < 0.001), acute kidney injury (aOR 4.886; 95% CI: 3.934–6.069, p < 0.001), blood transfusions (aOR 1.853; 95% CI: 1.628–2.109, p < 0.001), peripartum cardiomyopathy (aOR 2.709; 95% CI: 1.492–4.917, p = 0.001), sepsis (aOR 2.112; 95% CI: 1.430–3.119, p < 0.001), and ARDS (aOR 1.623; 95% CI: 1.076–2.449, p = 0.021). Fetal outcomes were also worse, with higher odds of small for gestational age fetuses (aOR 1.926; 95% CI: 1.779–2.086, p < 0.001), stillbirth (aOR 1.644; 95% CI: 1.352–2.000, p < 0.001), and preterm labor (aOR 1.702; 95% CI: 1.574–1.841, p < 0.001). Patients with RA, SS, and SLE experience varying degrees of complications. Conclusion: Our study shows that pregnant patients with autoimmune CTDs have worse maternal and fetal outcomes compared to those without CTDs. The rates of adverse outcomes varies among CTD subtypes. Comprehensive preconception counseling and tailored management strategies are essential for optimizing outcomes in these patients. Key Points • Increased Maternal Complications: Patients with autoimmune CTDs had significantly higher odds of maternal death, hypertensive disorders, acute kidney injury, blood transfusions, peripartum cardiomyopathy, sepsis, and ARDS. • Adverse Fetal Outcomes: Higher odds of small for gestational age fetuses, stillbirth, and preterm labor were observed in patients with CTDs compared to those without. • CTD Subtype Variations: Complication rates varied among CTD subtypes, with SLE, RA, and SSc each presenting varying risks and outcomes. [ABSTRACT FROM AUTHOR]

Background: Rheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) are prevalent and incapacitating conditions, sharing common pathogenic pathways such as tobacco use and pulmonary inflammation. The influence of respiratory conditions including COPD on RA has been observed, meanwhile RA may constituting one of the risk factors for COPD. It unclear that whether a bidirectional associate between RA and COPD. Our study aims to explore the bidirectional relationship between RA and COPD. Methods: We systematically searched PubMed, Cochrane Library, and Embase for observational studies from the databases inception to February 20, 2024, utilizing medical subject headings (MeSH) and keywords. We included studies in which RA and COPD were studied as either exposure or outcome variables. Statistical analyses were conducted employing STATA software (version 14.0). The relationship was reported as odds ratios (OR) and corresponding 95% confidence intervals (CI). Publication bias was assessed using funnel plots and Egger's regression. Results: Nineteen studies with 1,549,181 participants were included. Risk of bias varied from low to moderate, with evidence levels rated as low or very low. Pooled analysis revealed a significant association between RA and increased COPD risk (OR=1.41, 95%CI 1.13 to 1.76, I2 = 97.8%, P =0.003). Subgroup analyses showed similar COPD risk elevations in both of genders, seropositive/seronegative RA, cohort and case control studies. Additionally, there was a significant RA risk increase among those with COPD (OR=1.36, 95%CI 1.05 to 1.76, I2 = 55.0%, P =0.022), particularly among females and seropositive RA, and cohort studies. Conclusion: The meta-analysis identifies a significant bidirectional association between RA and COPD, emphasizing mutually increased risk. Recognizing this connection may can inform proactive approaches to disease prevention and management, potentially reducing the public health burden and improving quality of life. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD42024518323. [ABSTRACT FROM AUTHOR]

Objectives CONTExT-RA is a cross-sectional, non-interventional multicentre study which enrolled patients diagnosed with RA and receiving DMARD treatment in a secondary care setting. The study evaluated disease control and associated disease burden amongst this Irish population. Methods Patients with RA attending six Irish rheumatology centres were invited to participate. Each consented patient attended a single routine study visit. Disease activity was assessed using Clinical Disease Activity Index (CDAI). The primary endpoint was EuroQol-5 dimensions (EQ-5D-5L) stratified by CDAI, compared using a non-parametric Wilcoxon Rank-Sum test. Results 130 patients were included. Using CDAI, 34 (26.2%) patients were in clinical remission (CR), 42 (32.3%) had low disease activity (LDA), 41 (31.5%) had moderate disease activity (MDA) and 13 (10.0%) had high disease activity (HDA). QoL (EQ-5D-5L index (median)) scores were significantly (P  < 0.001) greater for patients in CR or CR/LDA than for those with MDA/HDA, 0.866 (0.920), 0.777 (0.822) vs 0.578 (0.691), respectively. Patients in CR reported higher levels of work productivity, mean (s. d.) rating of 1.7 (2.52) vs those in MDA/HDA of 4.2 (3.28) (higher rating indicates greater impairment). Similar findings were observed for non-work-related activities. Conclusion Disease control for many patients with RA, treated in secondary care in Ireland, is sub-optimal with only 1 in 4 in CDAI remission. The impact of poor disease control on QoL is significant, and the superior outcomes for patients in CR provide compelling evidence that by achieving greater disease control, the burden of disease on patients can be greatly reduced. [ABSTRACT FROM AUTHOR]

Background and Objectives: Compared to the general population, rheumatoid arthritis (RA) patients have additional disease-specific risk factors for osteoporosis that include chronic exposure to systemic inflammation. The current study aimed to investigate the prevalence of osteoporosis and its associated risk factors, such as age, sex, body mass index (BMI), uric acid (UA), and vitamin D status, but also the coexistence of type 2 diabetes mellitus (DMT2) and breast cancer (Ca breast) in patients with RA in Bahrain. Material and Methods: Data from DEXA scans were collected retrospectively from the patient's electronic health records. All patients who had BMD data and at least one single comorbidity, including RA, were included in the current study. The collected data were analyzed by using SPSS, version 28. Results: A total of 4396 patients were included in the current study. The comorbidities among this cohort were as follows: 3434 patients had endocrinological diseases, among them 63.6% had DMT2; 1870 patients had rheumatological diseases, among them 15.1% had rheumatoid arthritis; and 941 patients had malignancies, among them 75.6% had breast cancer. Our results indicated that patients with RA had a high prevalence of low BMD (72.30%, p < 0.001) and low vitamin D levels (63.10%, p < 0.001) but high serum UA (20.85%). Comparing RA with non-RA patients, our results showed a statistically significant association between RA and each of BMD and UA (p = 0.017 and p = 0.004, respectively), but also between RA and each of age (p = 0.001) and Ca breast (p < 0.001). However, no association was found between RA and BMI, DMT2, or vitamin D status. Conclusions: RA patients had a high prevalence of low BMD (72.3%) and low vitamin D (63.10%) but high serum UA (20.85%). The risk of osteoporosis, hypovitaminosis, and gout must be kept in mind during the evaluation of any case with RA. [ABSTRACT FROM AUTHOR]

Single cell RNA sequencing (scRNA-seq) is a relatively new technology that provides an unprecedented, detailed view of cellular heterogeneity and function by delineating the transcriptomic difference among individual cells. This will allow for mapping of cell-type-specific signaling during physiological and pathological processes, to build highly specific models of cellular signaling networks between the many discrete clusters that are present. This technology therefore provides a powerful approach to dissecting the cellular and molecular mechanisms that contribute to autoimmune diseases, including rheumatoid arthritis (RA). scRNA-seq can offer valuable insights into RA unique cellular states and transitions, potentially enabling development of novel drug targets. However, some challenges that still limit its mainstream utilization and include higher costs, a lower sensitivity for low-abundance transcripts, and a relatively complex data analysis workflow relative to bulk or traditional RNA-seq. This minireview explores the emerging application of scRNA-seq in RA research, highlighting its role in producing important insights that can help pave the way for innovative and more effective therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Seropositive rheumatoid arthritis (RA) is associated with significant cardiovascular and pulmonary morbidity. However, screening for early detection of pulmonary involvement especially interstitial lung disease (ILD) is not established in RA. Methods: We propose a non-invasive radiation-free approach to screen for interstitial lung involvement (ILI) by means of pulmonary function tests (PFT) and pleuro-pulmonary transthoracic ultrasound (LUS) with additional cardiopulmonary exercise tests (CPET) with ECG, and echocardiography. We included patients with confirmed diagnosis of seropositive RA according to ACR criteria, but without symptoms for or known cardiopulmonary disease. ILD was suspected when significant LUS abnormalities and additional PFT changes were present. Results: We included 67 consecutive patients (78% female, mean age 61 ± 12 years, 48% active or previous smokers), who fulfilled the inclusion criteria and gave written informed consent. We found 48% of patients with suspected changes in PFT with a diffusion capacity (DLCOc-SB) ≤ 80%, among them 7% with forced vital capacity (FVC) ≤ 80%. In 40% of patients, we found noticeable changes in LUS, 24% with an ILD compatible pattern. In 16% of cases, LUS abnormalities and additional PFT changes were present, and ILI was suspected. Additional findings included obstructive lung disease (n = 11), subpleural consolidation (n = 6) including one confirmed lung cancer, minimal pleural effusion (n = 6), and ischemic cardiac disease (n = 2). None of the patients showed signs of pulmonary vascular involvement. Conclusions: ILI was suspected in 16% of cases using a new radiation-free screening protocol in asymptomatic RA patients. Trial registration: German Register of Clinical Studies (DRKS00028871). [ABSTRACT FROM AUTHOR]

Objectives To assess the impact of baseline RF level on drug concentrations and efficacy of certolizumab pegol [CZP; TNF inhibitor (TNFi) without a crystallizable fragment (Fc)] and adalimumab (ADA; Fc-containing TNFi) in patients with RA. Methods The phase 4 EXXELERATE study (NCT01500278) was a 104-week, randomized, single-blind (double-blind until week 12; investigator-blind thereafter), head-to-head study of CZP vs ADA in patients with RA. In this post hoc analysis, we report drug concentration and efficacy outcomes stratified by baseline RF quartile (≤Q3 or >Q3). Results Baseline data by RF quartiles were available for 453 CZP-randomized and 454 ADA-randomized patients (≤Q3: ≤204 IU/ml; >Q3: >204 IU/ml). From week 12, the area under the curve (AUC) of ADA concentration was lower in patients with RF >204 IU/ml vs patients with RF ≤204 IU/ml; the AUC of CZP concentration was similar in patients with RF ≤204 IU/ml and >204 IU/ml. For patients with RF ≤204 IU/ml, disease activity score (DAS28)-CRP was similar between CZP- and ADA-treated patients through week 104. For patients with RF >204 IU/ml, mean DAS28-CRP was lower in CZP- vs ADA-treated patients at week 104. The proportion of patients with RF >204 IU/ml achieving DAS28-CRP low disease activity at week 104 was greater in CZP- vs ADA-treated patients. Conclusion CZP was associated with maintained drug concentration and efficacy in patients with RA and high RF and may therefore be a more suitable therapeutic option than TNFis with an Fc fragment in these patients. Trial registration Clinicaltrials.gov, http://clinicaltrials.gov , NCT01500278 [ABSTRACT FROM AUTHOR]

Objectives RA patients have an increased risk for cardiovascular diseases, including atrial fibrillation (AF), but the impact of RA on ischaemic stroke risk in the context of AF remains unknown. We explored whether the risk of ischaemic stroke after diagnosis of AF is further increased among patients with RA compared with non-RA patients. Methods In the nationwide Norwegian Cardio-Rheuma Register, we evaluated cumulative incidence and hazard rate of ischaemic stroke after the first AF diagnosis (2750 individuals with RA and 158 879 without RA between 2010 and 2017) by using a competing risk model with a 3-month delayed entry. Results The 5-year unadjusted cumulative incidence of ischaemic stroke was 7.3% (95% CI: 5.9–8.7%) for patients with RA and 5.0% (95% CI: 4.9–5.2%) for patients without RA. Unadjusted univariate analyses indicated that AF patients with RA had a HR of 1.36 (95% CI: 1.13, 1.62) for ischaemic stroke compared with those without RA. Sex- and age-adjusted HR for ischaemic stroke in RA patients with AF was 1.25 (95% CI: 1.05, 1.50), and the effect size remained unchanged after adjustment for diabetes, hypertension, atherosclerotic cardiovascular disease and oral anticoagulant (OAC) treatment. RA patients were less likely to receive OAC treatment than non-RA patients (adjusted odds ratio 0.88, 95% CI: 0.80, 0.97). Conclusion RA patients diagnosed with AF are at a further increased risk for stroke compared with non-RA patients with AF, and less likely to receive OAC treatment, emphasizing the need to improve stroke prevention in AF patients with RA. [ABSTRACT FROM AUTHOR]

Silicon wafers find applications in manufacturing large-scale micro-components widely available in consumer-based electronic devices. The milling-electrochemical spark micromachining (Milling-ECSMM) process is popular nowadays as an advanced micromanufacturing process for creating microchannels and several other geometric features. This paper presents a parametric effect of voltage, tool rotation, electrolyte concentration, and duty cycle on MRR, Ra, and TWR, using a tungsten carbide (WC) two-fluted flat-end milling cutter. The experimental model was developed using response surface methodology (RSM), and parametric multi-objective optimization was carried out using desirability function analysis (DFA) and genetic algorithm (GA). SEM and optical images were taken to identify the surface quality of the machined microchannel. The optimal combination of parameters obtained from GA as 90 V, 13 rpm, 64 g/l, and 40% DC gives better convergence and multi-objective response for MRR, TWR, and Ra as 0.409 mg/min, 0.0428 mg/min, and 0.572 µm, respectively. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes extensive damage to multiple organs and tissues and has no known cure. This study introduces a microfluidic detection platform that combines a microfluidic reaction chip with a micro-spectrometer to accurately detect the anti-cyclic citrullinated peptide antibody (anti-CCP Ab) biomarker, commonly associated with arthritis. The surface of the microfluidic reaction chip is functionalized using streptavidin to enable the subsequent immobilization of biotinylated-labeled cyclic citrullinated peptide (biotin–CCP) molecules through a streptavidin–biotin reaction. The modified chip is then exposed to anti-CCP Ab, second antibody conjugated with horseradish peroxidase (HRP) (2nd Ab-HRP), 3,3′,5,5′-tetramethylbenzidine (TMB), and a stop solution. Finally, the concentration of the anti-CCP Ab biomarker is determined by analyzing the optical density (OD) of the colorimetric reaction product at 450 nm using a micro-spectrometer. The detection platform demonstrated a strong correlation (R2 = 0.9966) between OD and anti-CCP Ab concentration. This was based on seven control samples with anti-CCP Ab concentrations ranging from 0.625 to 100 ng/mL. Moreover, for 30 artificial serum samples with unknown anti-CCP Ab concentrations, the biosensor achieves a correlation coefficient of (R2 = 0.9650). The proposed microfluidic detection platform offers a fast and effective method for accurately identifying and quantifying the anti-CCP Ab biomarker. Thus, it offers a valuable tool for the early diagnosis and monitoring of RA and its progression in point-of-care settings. [ABSTRACT FROM AUTHOR]

Abstract Background High body mass index (BMI) has been shown to have an association with chronic widespread pain (CWP), both in Rheumatoid arthritis (RA) and in other pain conditions such as fibromyalgia. Research on the adipose tissue and it’s adipokines, for example the well described leptin, is emerging. The objective of this study was to determine if there is an association between leptin levels in blood and CWP in patients with RA. Methods In this cross-sectional study 334 patients with RA filled in a questionnaire including a pain mannequin and questions on weight, length and waist circumference. Data from the pain mannequin was used to calculate CWP. The subjects also submitted blood samples to a biobank that were used for this study to determine leptin levels using an ELISA-method. Results Patients fulfilling the 2019 criteria for CWP in this study had significantly higher leptin levels, waist circumferences and BMI. There was a significant association between leptin levels and CWP, odds ratio (OR) 1.014 (95% confidence interval (CI) 1.007–1.020), p

Elevated levels of Inter-alpha-trypsin-inhibitor heavy chain 4 (ITIH4) have grabbed attention in rheumatoid arthritis (RA) pathogenesis, though its precise mechanisms remain unexplored. To elucidate these mechanisms, a comprehensive strategy employing network pharmacology and molecular docking was utilized. RA targets were sourced from the DisGeNET Database while interacting targets of ITIH4 were retrieved from the STRING and Literature databases. Venny 2.1 was used to identify overlapping genes, followed by Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) through Cytoscape 3.10.2 software, and molecular docking was performed in the ClusPro server. The study identified 18 interacting proteins of ITIH4 associated with RA, demonstrating their major involvement in the chemokine signaling pathway by enrichment analysis. Molecular docking of ITIH4 with the 18 proteins revealed that C-X-C chemokine-receptor type 4 (CXCR4), a major protein associated with chemokine signaling, has the highest binding affinity with ITIH4 with energy −1705.7 kcal/mol forming 3 Hydrogen bonds in the active site pocket of ITIH4 with His441, Arg288, Asp443 amino acids. The effect of ITIH4 on CXCR4 was analyzed via knockdown studies in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), demonstrating the significant downregulation of CXCR4 protein expression validated by Western blot in RA-FLS. In conclusion, it was speculated that CXCR4 might serve as a potential receptor for ITIH4 to activate the chemokine signaling, exacerbating RA pathogenesis.

Background: Individuals with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) face a heightened risk of severe coronavirus disease 2019 (COVID-19). However, the effectiveness and safety of vaccines relative to the broader population has been a subject of debate. Objective: To assess immunogenicity and to compare adverse effects following COVID-19 vaccinations in patients with SLE and RA vs matched healthy controls. Patients and methods: This work included 30 SLE, 30 RA and 30 age and sex-matched healthy controls. Assessment was done 2-6 weeks after BBIBP-CorV (Sinopharm BIBP COVID-19) vaccine including measuring serum IgG neutralizing anti-spike antibodies, a questionnaire for adverse events and assessing disease activity for patients. Results: There wasn't significant difference in the titer of neutralizing antibodies between patients and controls (p= 0.51). Fatigue, local redness, and swelling were more in control group (p< 0.0001, p=0.008 and p=0.008 respectively). Tingling sensation was higher in patients (0.006). Disease activity was significantly higher in RA and SLE patients after vaccination (p=0.001 and p=0.002 respectively). Flares occurred in 12 (40%) of SLE patients and 13 (43%) of RA patients, mainly in a mild form (58% of flares in SLE and 62% in RA). Conclusion: The BBIBP-CorV (Sinopharm BIBP) COVID-19 vaccine is immunogenic in patients and control groups. Adverse events were mainly minor with less frequent fatigue, local swelling and redness and more tingling sensation among SLE and RA than controls. In RA and SLE patients, disease flare may occur after COVID-19 vaccine mainly in a mild form. [ABSTRACT FROM AUTHOR]

• RA patients face an increased risk of CV diseases due to systemic inflammation and disease activity. • Other than traditional CV risk factors in RA patients, systemic inflammation and autoantibodies contribute to the heightened CV risk. • RA patients have low TC, LDL, and HDL but still experience high rates of CV events, known as the "lipid paradox," due to increased cholesterol breakdown and altered HDL function from inflammation. • In RA patients, inflammatory markers like CRP and cytokines promote atherosclerosis. • Early and aggressive intervention with DMARDs is crucial in achieving clinical remission, and potentially lowering the risk of CV events in RA patients. Rheumatoid arthritis (RA) is a chronic inflammatory disease mainly affecting the peripheral diarthrodial joints symmetrically and also presenting many extra-articular manifestations. Morbidity and mortality in RA patients are higher compared to the general population. Cardiovascular (CV) disease is one of the most common causes of death in these patients. Classical or traditional risk factors for atherosclerosis development occur more frequently in RA patients compared to those without this condition. Studies have showed that RA patients often present comorbidities such as hypertension, dyslipidemia, diabetes mellitus and obesity. However, the high incidence of CV events occurring in RA patients is not explained by the presence of traditional risk factors. Systemic inflammation, as it is expressed with the presence of proinflammatory cytokines and increased acute phase reactants, may contribute to the development of premature atherosclerosis in these patients. In this review, we explore the risk factors for CV disease, the generation of dyslipidemia, the lipid paradox and the role of systemic inflammation in the atherosclerotic process in RA. We discuss also the role of early therapeutic intervention that suppresses inflammation which may have beneficial effects on CV disease in RA patients. [ABSTRACT FROM AUTHOR]

Cartilage, a critical tissue for joint function, often degenerates due to osteoarthritis (OA), rheumatoid arthritis (RA), and trauma. Recent research underscores necroptosis, a regulated form of necrosis, as a key player in cartilage degradation. Unlike apoptosis, necroptosis triggers robust inflammatory responses, exacerbating tissue damage. Key mediators such as receptor-interacting serine/threonine-protein kinase-1 (RIPK1), receptor-interacting serine/threonine-protein kinase-3(RIPK3), and mixed lineage kinase domain-like (MLKL) are pivotal in this process. Studies reveal necroptosis contributes significantly to OA and RA pathophysiology, where elevated RIPK3 and associated proteins drive cartilage degradation. Targeting necroptotic pathways shows promise; inhibitors like Necrostatin-1 (Nec-1), GSK'872, and Necrosulfonamide (NSA) reduce necroptotic cell death, offering potential therapeutic avenues. Additionally, autophagy's role in mitigating necroptosis-induced damage highlights the need for comprehensive strategies addressing multiple pathways. Despite these insights, further research is essential to fully understand necroptosis' mechanisms and develop effective treatments. This review synthesizes current knowledge on necroptosis in cartilage degeneration, aiming to inform novel therapeutic approaches for OA, RA, and trauma. [ABSTRACT FROM AUTHOR]

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Elevated levels of Inter-alpha-trypsin-inhibitor heavy chain 4 (ITIH4) have grabbed attention in rheumatoid arthritis (RA) pathogenesis, though its precise mechanisms remain unexplored. To elucidate these mechanisms, a comprehensive strategy employing network pharmacology and molecular docking was utilized. RA targets were sourced from the DisGeNET Database while interacting targets of ITIH4 were retrieved from the STRING and Literature databases. Venny 2.1 was used to identify overlapping genes, followed by Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) through Cytoscape 3.10.2 software, and molecular docking was performed in the ClusPro server. The study identified 18 interacting proteins of ITIH4 associated with RA, demonstrating their major involvement in the chemokine signaling pathway by enrichment analysis. Molecular docking of ITIH4 with the 18 proteins revealed that C-X-C chemokine-receptor type 4 (CXCR4), a major protein associated with chemokine signaling, has the highest binding affinity with ITIH4 with energy −1705.7 kcal/mol forming 3 Hydrogen bonds in the active site pocket of ITIH4 with His441, Arg288, Asp443 amino acids. The effect of ITIH4 on CXCR4 was analyzed via knockdown studies in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), demonstrating the significant downregulation of CXCR4 protein expression validated by Western blot in RA-FLS. In conclusion, it was speculated that CXCR4 might serve as a potential receptor for ITIH4 to activate the chemokine signaling, exacerbating RA pathogenesis. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to investigate the associations between single nucleotide polymorphisms (SNPs) of IL-6 (-174G/C), microRNA146a (rs2910164C/G) and MALAT1 (rs619586A/G) and susceptibility to rheumatoid arthritis (RA) in Egyptians. Methods: SNPs were genotyped in 101 RA patients and 104 controls. Expression levels were evaluated either by Enzyme-linked immunosorbent assay (ELISA) for IL-6 or quantitative real-time PCR (qRT-PCR) for miR-146a and MALAT1. Results:IL-6–174 GC (OR = 3.422) genotype, IL-6–174 C allele (OR = 2.565), miR-146a (rs2910164) CG (OR = 2.190) and MALAT1 (rs619586) AA (OR = 4.125) genotypes and A allele (OR = 6.122) could be considered as risk factors for RA. An increase in the expression of IL-6, miR-146a and MALAT1 was detected in RA patients, which was independent of any SNP. Conclusion: SNPs of IL-6, miR-146a and MALAT1were linked to RA predisposition in Egyptians. Plain Language Summary Rheumatoid arthritis (RA) is a chronic joint disorder with overexpression of inflammatory mediators. There is increasing evidence that epigenetic changes could play a prominent role in RA pathogenesis. This study was designated to explore the associations between genetic mutation of inflammatory cytokines (Interleukin (IL-6) and epigenetic modulators (miR-146a and MALAT1) and susceptibility to RA. Increased production of IL-6, miR-146a and MALAT1 is a remarkable event in RA patients. We provide evidence that certain genotypes could be used as risk factors for the disease. Our data suggest that detecting certain mutations is quite important in disease prediction. Special concern has to be directed to those persons harboring definite genotypes to achieve better clinical manipulation of patients at risk. Tweetable Abstract This study demonstrated an elevation in IL-6, miR-146a and MALAT1 in RA patients. Moreover, we found that susceptibility to RA is associated with IL-6 (rs1800795) GC, miR-146a (rs2910164) CG and MALAT1 (rs619586) AA genotypes. Article highlights IL-6 (-174G/C), miR-146a (rs2910164C/G) and MALAT1 (rs619586A/G) SNPs were thought to be associated with RA risk. This study aimed to investigate this association with RA in Egyptians. in 101 RA patients and 104 controls. IL-6 (-174G/C) was genotyped utilizing MS-PCR, miR-146a (rs2910164 C/G) and MALAT1 (rs619586 A/G) was genotyped using RFLP-PCR. Expression levels were evaluated either by ELISA for IL-6 or qRT-PCR for miR-146a and MALAT1. The statistical analysis showed that IL-6–174GC genotype, C allele and miR-146a (rs2910164) CG genotype were significantly increased in patients versus controls (p < 0.01, p < 0.05, p < 0.01; respectively). Patients showed a significant reduction in IL-6–174GG (p < 0.05), miR-146a (rs2910164) CC genotypes (p < 0.05) and MALAT1(rs619586) G allele (p < 0.05) compared with controls. The genotypes of IL-6–174GC, miR-146a rs2910164 CG and MALAT1 rs619586AA could all be considered risk factors for RA. CGA haplotype was significantly increased (p < 0.01) in patients than in healthy ones. A significant elevation of IL-6, miR-146a and MALAT1 expression levels was detected in RA patients (p < 0.001, p < 0.05 and p < 0.001, respectively). miR-146a was positively correlated with MALAT1 (r = 0.326, p < 0.05) in RA patients. [ABSTRACT FROM AUTHOR]

Objectives Parvovirus B19 most frequently causes epidemics of erythema infectiosum in children but also affects adults often leading to rheumatologic manifestations. While the serum profile allows the diagnosis, manifestations may mimic autoimmune conditions. The aim was to evaluate the proportion of patients with acute Parvovirus B19 infection fulfilling classification criteria for rheumatic diseases (RA and SLE). Methods We evaluated the clinical and serological features of 54 patients diagnosed with acute Parvovirus B19 infection seeking rheumatological attention between March and June 2024. Results The majority of patients were females (78%), with a mean (s. d.) age of 45 (13) years and 54% could not recall any known exposure. Fifty-one/54 (94%) had arthralgia, 27 (50%) arthritis (oligoarthritis in 67% of them), 24 (44%) fever, 19 (35%) skin rash and 7 (13%) purpura. Symptoms resolution generally occurred within 6 weeks. Complement levels were low in 14/33 (42%) tested patients, while the presence of serum ANA, anti-dsDNA, anti-phospholipids and rheumatoid factor was detected in 21/38 (55%), 10/26 (38%), 6/12 (50%) and 5/37 (13%) patients, respectively. Classification criteria for SLE were fulfilled in 93% of ANA-positive patients and RA criteria in 38% of patients with arthritis. Conclusions Parvovirus B19 infection manifestations may vary and nearly all patients with positive serum ANA fulfil the classification criteria for SLE. The risk of misclassification in patients with viral infection should not be overlooked. [ABSTRACT FROM AUTHOR]

Objectives To investigate whether circulating endothelial protein C receptor (EPCR) is associated with disease activity and inflammatory markers in rheumatoid arthritis. Methods Thirty-eight RA patients and 21 healthy controls (HC) were recruited via the A3BC biobank. Peripheral blood mononuclear cells and plasma were isolated from the blood of these participants. Plasma soluble (s)EPCR, IL-6, IL-17 and sCD14 were measured by enzyme-linked immunosorbent assay, cell membrane-associated (m)EPCR by flow cytometry; EPCR gene H3 single nucleotide polymorphism (SNP), which contributes to high plasma sEPCR levels, by PCR and DNA sequencing. Data were analysed using FlowJo10 and GraphPad Prism 10. Results RA patients had higher levels of mEPCR on T cells and plasma sEPCR compared with HC. No difference in the EPCR gene H3 SNP G genotype frequency was found between RA and HC. This SNP was significantly correlated with higher sEPCR levels in HC but not in RA patients. In RA, plasma sEPCR levels were positively correlated with IL-6, IL-17, sCD14, anti-CCP and rheumatoid factor. In contrast, mEPCR levels on T cells and natural killer cells (NK) were inversely associated with disease activity measures including 28/66 swollen joint count, 28/68 tender joint count and/or DAS28-CRP/ESR scores, and positively correlated with EPCR gene H3 SNP, which was also correlated with lower disease activity measures in RA. Conclusion Our findings suggest that EPCR may play an important role in RA, with plasma sEPCR being potentially associated with inflammatory markers and mEPCR and the EPCR gene H3 SNP possibly related to disease activity measures. [ABSTRACT FROM AUTHOR]

Introduction: Hashimoto's thyroiditis is a prevalent autoimmune disease among the population. With the progress in diagnostic and research techniques, it has come to light that Hashimoto's thyroiditis is linked to a higher likelihood of developing other disorders that impact multiple organs and systems. Throughout the course of this disease, individuals may experience an array of complications such as sexual dysfunctions, fertility problems, specific mental disorders, cardiovascular diseases and other autoimmune diseases. Aim of the Study: The primary aim of this study is to explore the potential association between Hashimoto’s thyroiditis and its consequential effects on other physiological systems and organs. Description of the State of Knowledge: Hashimoto's thyroiditis is a complex autoimmune disease characterized by chronic inflammation of the thyroid gland. The pathogenesis of the disease is not yet completely understood. Hashimoto's thyroiditis has been associated with a range of health issues, including sexual dysfunction, fertility problems, psychiatric disorders, cardiovascular diseases, and other autoimmune disorders. Materials and methods: An unsystematic scientific literature review was conducted using specific keywords such as Hashimoto's thyroiditis, fertility problems, thyroid tumor, cardiovascular diseases, and autoimmune diseases. The review was carried out on PubMed, analyzing a total of 54 sources published until 2023. Conclusions: HT's association with psychiatric disorders, fertility issues, thyroid tumors, cardiovascular dysfunction, and comorbid autoimmune conditions underscores its broad clinical impact, necessitating integrated management approaches. Effective management of HT requires collaboration among specialists to ensure early detection, proactive intervention, and patient education, ultimately improving therapeutic outcomes and quality of life. [ABSTRACT FROM AUTHOR]

In mammals, glial cell derived neurotrophic factor (GDNF) plays a critical role in the self-renewal and maintenance of spermatogonial stem cells (SSCs) in testis and oogenesis in ovary, whilst retinoic acid (RA), the key factor of meiosis initiation, can downregulate its expression. Unlike mammals, two Gdnf replication genes are widely present in teleost fishes, however, our understanding of them is still poor. In the present study, two paralogous gdnf from Nile tilapia (Oreochromis niloticus), namely as Ongdnfa and Ongdnfb , were characterized, and then their cellular expression profiles in testis and ovary and responsiveness to RA treatment at the tissue and cellular levels were investigated. In phylogenetic tree, the Gdnfa and Gdnfb from teleost fishes were clustered into two different subclasses, respectively, and then clustered with the homologs from cartilaginous fish and tetrapods, suggesting that OnGdnfa and OnGdnfb are orthologous to GDNF and paralogous to each other. Ongdnfa is expressed in Sertoli cells and Leydig cells in testis and oocytes in ovary. The expression pattern of Ongdnfb is similar to Ongdnfa. In the ex vivo testicular organ culture, RA down-regulated the expression of Ongdnfa , whereas up-regulated the expression of Ongdnfb (P < 0.05), suggesting that they have differential responsiveness to RA signaling. RA treatment of the cultured cells derived from adult Nile tilapia testis which have the expression of RA receptors (RAR), Ongdnfa and Ongdnfb further confirmed the above result. Collectively, our study suggests that Ongdnfa and Ongdnfb have non-germline expression patterns in testis and germline expression patterns in ovary; furthermore, they have differential responsiveness to RA signaling, implying that they might have differential biological functions. This study broadens and enriches our understanding of fish GDNF homologs and lays foundation for the study of their biological functions in the future. • Two paralogous gdnf (Ongdnfa and Ongdnfb) were characterized from Nile tilapia. • Ongdnfa and Ongdnfb had non-germline expressions in testis. • Ongdnfa and Ongdnfb had germline expressions in ovary. • Ongdnfa and Ongdnfb had differential responsiveness to RA treatment. [ABSTRACT FROM AUTHOR]

Objectives Adults with RA are being switched from etanercept originator to biosimilar in non-medical/cost-saving switching. This analysis aims to investigate outcomes in these patients, including (i) drug survival and (ii) disease activity at 6 months and 12 months, compared with those who remain on the originator. Methods Using BSRBR-RA, those who switched directly from etanercept originator to biosimilar were identified and matched to patients receiving the originator, based on gender, age, disease duration and originator start year. Drug survival was calculated; Cox-proportional hazard models assessed differences in drug persistence between those who switched vs remaining on originator. Change in DAS28 after 6 months and 12 months was compared between cohorts. Multiple imputation was used. Results A total of 1024 adults with RA switching from etanercept originator to biosimilar were included, with a matched cohort of patients remaining on the originator. Patients who switched onto a biosimilar product were no more likely to discontinue etanercept treatment vs those who remained on the originator; hazard ratio 1.06 (95%CI 0.89–1.26), with 65% of patients remaining on treatment at three years. Ninety-five (9%) patients switched back to the originator within the first year. After 6 months and 12 months, biosimilar patients were no more likely to have a worsening of DAS28 (>0.6 units) compared with those who remained on the originator. Conclusions This is the largest matched comparative effectiveness analysis showing patients switching from etanercept originator to biosimilar appearing to do just as well with regard to disease activity and drug persistence compared with those who remained on the originator. These data will be reassuring to clinicians and patients regarding non-medical switching. [ABSTRACT FROM AUTHOR]

Entre la multiplicidad de castigos en la Duat, la situación de los que aparecen en posición invertida tanto en los textos como en las representaciones es una de las más llamativas por cuanto no tiene un correlato con la realidad, como sí lo tienen la decapitación, la incineración de cuerpos o la inmovilización por sujeción. La variedad de castigos es amplia, pero por su característica, por las reiteradas menciones en los textos y por la diversidad de explicaciones que se han ensayado al respecto, la situación de estos sxd.w es particularmente interesante. Lo que este estudio se propone, además de un recorrido por los diferentes contextos funerarios en que se los cita, es explicar su significación para entender por qué era uno de los castigos más temidos por los condenados.

BackgroundRheumatoid arthritis (RA) and chronic obstructive pulmonary disease (COPD) are prevalent and incapacitating conditions, sharing common pathogenic pathways such as tobacco use and pulmonary inflammation. The influence of respiratory conditions including COPD on RA has been observed, meanwhile RA may constituting one of the risk factors for COPD. It unclear that whether a bidirectional associate between RA and COPD. Our study aims to explore the bidirectional relationship between RA and COPD.MethodsWe systematically searched PubMed, Cochrane Library, and Embase for observational studies from the databases inception to February 20, 2024, utilizing medical subject headings (MeSH) and keywords. We included studies in which RA and COPD were studied as either exposure or outcome variables. Statistical analyses were conducted employing STATA software (version 14.0). The relationship was reported as odds ratios (OR) and corresponding 95% confidence intervals (CI). Publication bias was assessed using funnel plots and Egger’s regression.ResultsNineteen studies with 1,549,181 participants were included. Risk of bias varied from low to moderate, with evidence levels rated as low or very low. Pooled analysis revealed a significant association between RA and increased COPD risk (OR=1.41, 95%CI 1.13 to 1.76, I2 = 97.8%, P=0.003). Subgroup analyses showed similar COPD risk elevations in both of genders, seropositive/seronegative RA, cohort and case control studies. Additionally, there was a significant RA risk increase among those with COPD (OR=1.36, 95%CI 1.05 to 1.76, I2 = 55.0%, P=0.022), particularly among females and seropositive RA, and cohort studies.ConclusionThe meta-analysis identifies a significant bidirectional association between RA and COPD, emphasizing mutually increased risk. Recognizing this connection may can inform proactive approaches to disease prevention and management, potentially reducing the public health burden and improving quality of life.Systematic Review Registrationhttps://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024518323.

Single cell RNA sequencing (scRNA-seq) is a relatively new technology that provides an unprecedented, detailed view of cellular heterogeneity and function by delineating the transcriptomic difference among individual cells. This will allow for mapping of cell-type-specific signaling during physiological and pathological processes, to build highly specific models of cellular signaling networks between the many discrete clusters that are present. This technology therefore provides a powerful approach to dissecting the cellular and molecular mechanisms that contribute to autoimmune diseases, including rheumatoid arthritis (RA). scRNA-seq can offer valuable insights into RA unique cellular states and transitions, potentially enabling development of novel drug targets. However, some challenges that still limit its mainstream utilization and include higher costs, a lower sensitivity for low-abundance transcripts, and a relatively complex data analysis workflow relative to bulk or traditional RNA-seq. This minireview explores the emerging application of scRNA-seq in RA research, highlighting its role in producing important insights that can help pave the way for innovative and more effective therapeutic strategies.

This study explores how ageing temperature and the volume percentage of Al2O3+B4C nanoparticles influence the machinability and hardness of stir-cast Al-7075 Metal Matrix Composite (MMC). Using liquid metallurgy techniques, hybrid materials were created by reinforcing Al7075 metal matrix with varying weight percentages of nanosized B4C (1.5%, 3%, and 4.5%) and Al2O3 (1%, 1.5%, and 2%). After fabrication, the samples were subjected to five-hour ageing process at temperatures of 100, 120, and 140 degrees Celsius, followed by cooling to ambient temperature (27 degrees Celsius). Hybrid nano composites that had been heat treated were tested for wear, tensile strength, and hardness. Results shows that, the addition of nanoparticles and heat treatment considerably improves the tensile strength, hardness, and wear resistance of hybrid composites by 3%, 17%, and 10%, respectively, for samples reinforced with 4.5% B4C + 2% Al2O3. SEM analysis was used to investigate the type of wear and the tensile fracture mode of nano composite samples by analyzing the wornout surface and the surface where tensile fracture occurred. Machinability was assessed using L27 orthogonal array tests, focusing on three key process parameters: feed rate (0.1 mm/min), depth of cut (0.2 mm/min), and spindle speed (1000 rpm). Outcomes show that, increasing the wt. % of nano-Al2O3/B4C leads to higher machining force and surface roughness (Ra) of MMCs. Conversely, higher ageing temperatures result in decreased machining force and surface roughness. Optimal surface roughness and machining force were achieved with 1% Al2O3 + 1.5% B4C and an ageing temperature of 140�C. These findings offer valuable insights into the ease of machining of composite metal alloys, emphasizing the importance of parameter selection and optimization for desired machining outcomes

Thanks to the concept of G.P. Melnikov, the technology of text’s meaning understanding is clarified. In simple cases of understanding in the linguistic consciousness of a person, a group of mental actors plays out a small drama of a sentence / utterance, the script of which is set by a predicate (Seshe - Tenier). Here, understanding is equal to seeing the situation (mise en scene) and is the initial stage. At the second stage, what is seen is equated with a life metaphor or gestalt (Lakoff and Johnson). I.A. Melchuk and his Linguistic-combinatorial dictionary (created jointly with A. Zholkovsky) made up the third part of the theory of understanding, the fourth part of which should be considered the concept of speech actions by Austin and Searle. All these linguistic concepts agree well in the spirit of G.P. Melnikov’s systemology and form a theory of understanding as a whole. The problem of the multiple layers of the text is perfectly visible in the literary texts of Ch. Aimatov, whose 95th Anniversary coincided with a similar anniversary of G.P. Melnikov.

This article discusses the impact of nanoparticles on the mechanical properties and machining behavior of formwork grade Al7075 composites. The researchers conducted experiments to analyze the material properties and used Taguchi techniques for analysis. The results showed that the inclusion of nanoparticles significantly affected the machinability and surface quality of the composites. The study provides valuable insights for industries that utilize aluminum composites in their manufacturing processes. The addition of hard ceramic nanoparticles improves the grain refinement and mechanical strength of the composites, but decreases ductility. The wear resistance of the composites also improves with the weight percentage of hard ceramic particles. The presence of micro pits, narrow grooves, and delamination on the worn surfaces indicate the wear mechanism of delamination and plowing. The addition of ceramic nanoparticles improves wear resistance. The weight fraction of B4C content and the heat treatment temperature have significant impacts on machining force and surface roughness. The study found that the optimal results were achieved with 1.5% nano-B4C, 1% nano-Al2O3, and an ageing temperature of 140°C. The findings provide valuable insights for future studies and practical applications in the field of composite material machining. [Extracted from the article]

Pulmonary fibrosis is a progressive, irreversible, chronic interstitial lung disease associated with high morbidity and mortality rates. Current clinical drugs, while effective, do not reverse or cure pulmonary fibrosis and have major side effects, there are urgent needs to develop new anti-pulmonary fibrosis medicine, and corresponding industrially scalable process as well. Salvia castanea Diels f. tomentosa Stib., a unique herb in Nyingchi, Xizang, China, is a variant of S. castanea. and its main active ingredient is rosmarinic acid (RA), which can be used to prepare methyl rosmarinate (MR) with greater drug potential. This study presented an industrially scalable process for the preparation of MR, which includes steps such as polyamide resin chromatography, crystallization and esterification, using S. castanea Diels f. tomentosa Stib. as the starting material and the structure of the product was verified by NMR technology. The antipulmonary fibrosis effects of MR were further investigated in vivo and in vitro. Results showed that this process can easily obtain high-purity RA and MR, and MR attenuated bleomycin-induced pulmonary fibrosis in mice. In vitro, MR could effectively inhibit TGF-β1-induced proliferation and migration of mouse fibroblasts L929 cells, promote cell apoptosis, and decrease extracellular matrix accumulation thereby suppressing progressive pulmonary fibrosis. The anti-fibrosis effect of MR was stronger than that of the prodrug RA. Further study confirmed that MR could retard pulmonary fibrosis by down-regulating the phosphorylation of the TGF-β1/Smad and MAPK signaling pathways. These results suggest that MR has potential therapeutic implications for pulmonary fibrosis, and the establishment of this scalable preparation technology ensures the development of MR as a new anti-pulmonary fibrosis medicine. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic autoimmune disorder caused by inflammation of cartilaginous diarthrodial joints that destroys joints and cartilage, resulting in synovitis and pannus formation. Timely detection and effective management of RA are pivotal for mitigating inflammatory arthritis consequences, potentially influencing disease progression. Nuclear medicine using radiolabeled targeted vectors presents a promising avenue for RA diagnosis and response to treatment assessment. Radiopharmaceutical such as technetium-99m (99mTc), combined with single photon emission computed tomography (SPECT) combined with CT (SPECT/CT), introduces a more refined diagnostic approach, enhancing accuracy through precise anatomical localization, representing a notable advancement in hybrid molecular imaging for RA evaluation. This comprehensive review discusses existing research, encompassing in vitro, in vivo, and clinical studies to explore the application of 99mTc radiolabeled targeting vectors with SPECT imaging for RA diagnosis. The purpose of this review is to highlight the potential of this strategy to enhance patient outcomes by improving the early detection and management of RA. [ABSTRACT FROM AUTHOR]

Objectives Inflammatory arthritis (IA) is considered the last stage of a disease continuum, where features of systemic autoimmunity can appear years before clinical synovitis. Time to progression to IA varies considerably between at-risk individuals, therefore the identification of biomarkers predictive of progression is of major importance. We previously reported on the value of three CD4+T cell subsets as biomarkers of progression. Here, we aim to establish the value of 18 lymphocyte subsets (LS) for predicting progression to IA. Methods Participants were recruited based on a new musculoskeletal complaint and being positive for anti-citrullinated-peptide antibody. Progression (over 10 years) was defined as the development of clinical synovitis. LS analysis was performed for lymphocyte lineages, naive/memory subsets, inflammation-related cells (IRC) and regulatory cells (Treg/B-reg). Modelling used logistic/Cox regressions. Results Of 210 patients included, 93 (44%) progressed to IA, 41/93 (44%) within 12 months (rapid progressors). A total of 5/18 LS were associated with progression [Treg/CD4-naïve/IRC (adjusted P  < 0.0001), CD8 (P  = 0.021), B-reg (P  = 0.015)] and three trends (NK-cells/memory-B-cells/plasmablasts). Unsupervised hierarchical clustering using these eight subsets segregated three clusters of patients, one cluster being enriched [63/109(58%)] and one poor [10/45(22%)] in progressors. Combining all clinical and LS variables, forward logistic regression predicted progression with accuracy = 85.7% and AUC = 0.911, selecting smoking/rheumatoid-factor/HLA-shared-epitope/tender-joint-count-78 and Treg/CD4-naive/CD8/NK-cells/B-reg/plasmablasts. To predict rapid progression, a Cox regression was performed resulting in a model combining smoking/rheumatoid factor and IRC/CD4-naive/Treg/NK-cells/CD8+T cells (AUC = 0.794). Conclusion Overall, progression was predicted by specific LS, suggesting potential triggers for events leading to the development of IA, while rapid progression was associated with a different set of subsets. [ABSTRACT FROM AUTHOR]

Objectives Despite little evidence that analgesics are effective in inflammatory arthritis (IA), studies report substantial opioid prescribing. The extent this applies to other analgesics is uncertain. We undertook a comprehensive evaluation of analgesic prescribing in patients with IA in the Clinical Practice Research Datalink Aurum to evaluate this. Methods From 2004 to 2020, cross-sectional analyses evaluated analgesic prescription annual prevalence in RA, PsA and axial spondyloarthritis (axSpA), stratified by age, sex, ethnicity, deprivation and geography. Joinpoint regression evaluated temporal prescribing trends. Cohort studies determined prognostic factors at diagnosis for chronic analgesic prescriptions using Cox proportional hazards models. Results Analgesic prescribing declined over time but remained common: 2004 and 2020 IA prescription prevalence was 84.2/100 person-years (PY) (95% CI 83.9, 84.5) and 64.5/100 PY (64.2, 64.8), respectively. In 2004, NSAIDs were most prescribed (56.1/100 PY; 55.8, 56.5), falling over time. Opioids were most prescribed in 2020 (39.0/100 PY; 38.7, 39.2). Gabapentinoid prescribing increased: 2004 prevalence 1.1/100 PY (1.0, 1.2); 2020 prevalence 9.9/100 PY (9.7, 10.0). Most opioid prescriptions were chronic (2020 prevalence 23.4/100 PY [23.2, 23.6]). Non-NSAID analgesic prescribing was commoner in RA, older people, females and deprived areas/northern England. Conversely, NSAID prescribing was commoner in axSpA/males, varying little by deprivation/geography. Peri-diagnosis was high-risk for starting chronic opioid/NSAID prescriptions. Prognostic factors for chronic opioid/gabapentinoid and NSAID prescriptions differed, with NSAIDs having no consistently significant association with deprivation (unlike opioids/gabapentinoids). Conclusion IA analgesic prescribing of all classes is widespread. This is neither evidence-based nor in line with guidelines. Peri-diagnosis is an opportune moment to reduce chronic analgesic prescribing. [ABSTRACT FROM AUTHOR]

Objectives Multimorbidity is burdensome for people with RA. We investigated differences in multimorbidity and comorbidities by sex and age in the RA population. Methods This cross-sectional analysis used national administrative claims (OptumLabs ® Data Warehouse) from people with RA and non-RA comparators (matched on age, sex, race, census region, index year and length of baseline insurance coverage) from 2010–2019. RA was determined using a validated algorithm. Multimorbidity was defined as ≥2 (MM2+) or ≥5 (MM5+) comorbidities from a validated set of 44 chronic conditions. We used logistic regression to assess associations between characteristics and multimorbidity. Results The sample included 154 391 RA patients and 154 391 non-RA comparators. For people aged 18–50 years, RA women (vs RA men) had 7.5 and 4.4 (vs 3.2 and 0.9 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. For people aged 51+ years, RA women (vs RA men) had 2.1 and 2.5 (vs 1.2 and 0.3 in non-RA women vs non-RA men) percentage point increases for MM2+ and MM5+, respectively. Interactions revealed that differences in multimorbidity between women and men were exacerbated by RA (vs non-RA) (P  < 0.05), with more pronounced effects in people aged 18–50. Men had more cardiovascular-related conditions, whereas RA women had more psychological, neurological and general musculoskeletal conditions. Other comorbidities varied by sex and age. Conclusion Multimorbidity disproportionately impacts women with RA. Research, clinical and policy agendas for rheumatic diseases should acknowledge and support the variation in care needs by sex and gender across the lifespan. [ABSTRACT FROM AUTHOR]

Objectives The severity of fatigue in RA has improved very little in recent decades, leaving a large unmet need. Fortunately, not all RA patients suffer from persistent fatigue, but the subgroup of patients who suffer the most is insufficiently recognizable at diagnosis. As disease activity is partly coupled to fatigue, DAS components may associate with the course of fatigue. We aimed to identify those RA patients who remain fatigued by studying DAS components at diagnosis in relation to the course of fatigue over a 5-year follow-up period in two independent early RA cohorts. Methods In all, 1560 consecutive RA patients included in the Leiden Early Arthritis Cohort and 415 RA patients included in the tREACH trial were studied. Swollen joint count, tender joint count, ESR and Patient Global Assessment (PGA) [on a Visual Analogue Scale (VAS)] were studied in relation to fatigue (VAS, 0–100 mm) over a period of 5 years, using linear mixed models. Results Higher tender joint count and higher PGA at diagnosis were associated with a more severe course of fatigue. Furthermore, patients with mono- or oligo-arthritis at diagnosis remained more fatigued. The swollen joint count, in contrast, showed an inverse association. An investigation of combinations of the aforementioned characteristics revealed that patients presenting with mono- or oligo-arthritis and PGA ≥ 50 remained the most fatigued over time (+20 mm vs polyarthritis with PGA < 50), while the DAS course over time did not differ. This subgroup comprised 14% of the early RA population. Data from the tREACH trial showed similar findings. Conclusion The RA patients who remain the most fatigued were those characterized by mono- or oligo-arthritis and high PGA (VAS ≥ 50) at diagnosis. This understanding may enable early-intervention with non-pharmacological approaches in dedicated patient groups. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by progressive joint destruction. Early diagnosis and treatment, before joint deformation or destruction occurs, are crucial. Identifying novel biomarkers for RA in saliva could potentially enable early detection of the disease, prior to its onset. We conducted a comprehensive proteomic analysis of salivary proteins in a mouse model of RA. Proteins were identified using western blotting and enzyme-linked immunosorbent assay in the serum, saliva, and ankle joints of DBA/1JJmsSlc mice, a model of RA. Ankle joints and submandibular glands were stained with hematoxylin and eosin and immunostained, and the results were compared with those of control mice. Citrullinated alpha-1 antitrypsin (A1AT, 46 kDa) was commonly detected in the saliva, serum, and ankle joints of mice with severe RA and was confirmed through proteomic analysis. Western blotting showed a band corresponding to 46 kDa in the serum, saliva, and ankle joints. Immunostaining of the ankle joints with the A1AT antibody showed a strong positive signal in the synovium. In DBA/1JJmsSlc mice, cyclic citrullinated peptide antibodies and A1AT may be involved in citrullination and contribute to the development and severity of RA, making them valuable treatment targets requiring further study. • New biomarkers are needed for early diagnosis of rheumatoid arthritis (RA). • We analyzed serum, saliva, and ankle joint proteins from mice with rheumatoid arthritis (DBA mice) to find diagnostic markers for RA. • Citrullinated A1AT was commonly detected in serum, saliva and ankle joints of mice with RA severe group. • Suggesting that A1AT may be involved in the pathogenesis and severity of RA. [ABSTRACT FROM AUTHOR]

Objective Anti-TNF biologics have been widely used to ameliorate disease activity in patients with RA. However, a large fraction of patients show a poor response to these agents. Moreover, no clinically applicable predictive biomarkers have been established. This study aimed to identify response-associated biomarkers using longitudinal transcriptomic data in two independent RA cohorts. Methods RNA sequencing data from peripheral blood cell samples of Korean and Caucasian RA cohorts before and after initial treatment with anti-TNF biologics were analysed to assess treatment-induced expression changes that differed between highly reliable excellent responders and null responders. Weighted correlation network, immune cell composition, and key driver analyses were performed to understand response-associated transcriptomic networks and cell types and their correlation with disease activity indices. Results In total, 305 response-associated genes showed significantly different treatment-induced expression changes between excellent and null responders. Co-expression network construction and subsequent key driver analysis revealed that 41 response-associated genes played a crucial role as key drivers of transcriptomic alteration in four response-associated networks involved in various immune pathways: type I IFN signalling, myeloid leucocyte activation, B cell activation, and NK cell/lymphocyte–mediated cytotoxicity. Transcriptomic response scores that we developed to estimate the individual-level degree of expression changes in the response-associated key driver genes were significantly correlated with the changes in clinical indices in independent patients with moderate or ambiguous response outcomes. Conclusion This study provides response-specific treatment-induced transcriptomic signatures by comparing the transcriptomic landscape between patients with excellent and null responses to anti-TNF drugs at both gene and network levels. [ABSTRACT FROM AUTHOR]

Objective The objective of this study was to assess differentially expressed blood proteins between patients with active RA and patients in remission after MTX treatment, with the aim of identifying a biomarker of MTX resistance (MTXR). Methods Two populations of RA patients treated with a stable dose of s.c. MTX for at least 3 months were constituted according to the DAS28: remission (DAS28 < 2.6; n  = 24) and active disease (DAS28 > 3.2; n  = 32). The two groups of RA patients were homogeneous regarding their epidemiological characteristics, except for the duration of treatment, which was longer in the remission group. After collection of a blood sample, plasma protein digestion was performed, followed by untargeted proteomics analysis. Then, a targeted analysis was performed to confirm the results of the untargeted approach. Results Untargeted proteomics analysis revealed eight plasma proteins that were differentially expressed between the two groups of patients. Among them, triosephosphate isomerase (TPI-1) and glucose-6-phosphate isomerase (GPI), which are main actors in glycolysis, were found down-regulated in the active group. This result was confirmed for TPI-1 in the targeted proteomics analysis. Conclusion A first step was achieved in the search for biomarkers of MTXR, with the identification of two actors in glycolysis (TPI-1 and GPI). The next step will be to confirm these results in a larger cohort, including samples from treatment-naive patients, to assess the predictive potential of these protein markers. [ABSTRACT FROM AUTHOR]

Objectives Rituximab (RTX) is a safe and effective treatment for RA. However, there are some concerns about infection risk and preliminary data suggest dose and time dependency. This study aims to determine the infection incidence in a large real-life population of RA patients using RTX, with special focus on (ultra-)low dosing and time since last infusion. Methods RA patients treated with 1000, 500 or 200 mg RTX per cycle between 2012 and 2021 at the Sint Maartenskliniek were included in a retrospective cohort study. Patient-, disease-, treatment- and infection characteristics were retrieved from electronic health records. Infection incidence rates, dose and time relations with RTX infusion were analysed using mixed-effects Poisson regression. Results Among 490 patients, we identified 819 infections in 1254 patient years. Most infections were mild and respiratory tract infections were most common. Infection incidence rates were 41, 54 and 71 per 100 patient years for doses of 200, 500 and 1000 mg. Incidence rate ratio (IRR) was significantly lower for 200 mg compared with 1000 mg (adjusted IRR 0.35, 95% CI 0.17, 0.72, P  = 0.004). In patients receiving 1000 or 500 mg RTX, infections seemed to occur more frequently within the first two months after infusion compared with later on in the treatment cycle, suggesting an association with peak concentration. Conclusion Ultra-low dosing (200 mg) of RTX is associated with a lower risk of infections in RA. Future interventions focusing on ultra-low dosing and slow release of RTX (e.g. by subcutaneous administration) may lower infection risk. [ABSTRACT FROM AUTHOR]

Objectives To investigate the influence of genetic factors on persistence with treatment of early RA with MTX monotherapy. Methods We conducted a genome-wide association study (GWAS) in a sample of 3902 Swedish early-RA patients initiating MTX in DMARD monotherapy as their first-ever DMARD. The outcome, short- and long-term MTX treatment persistence, was defined as remaining on MTX at 1 and at 3 years, respectively, with no additional DMARDs added. As genetic predictors, we investigated individual SNPs, and then calculated a polygenic risk score (PRS) based on SNPs associated with RA risk. The SNP-based heritability of persistence was estimated overall and by RA serostatus. Results No individual SNP reached genome-wide significance (P  < 5 × 10−8), either for persistence at 1 year or at 3 years. The RA PRS was not significantly associated with MTX treatment persistence at 1 year [relative risk (RR) = 0.98 (0.96–1.01)] or at 3 years [RR = 0.96 (0.93–1.00)]. The heritability of MTX treatment persistence was estimated to be 0.45 (0.15–0.75) at 1 year and 0.14 (0–0.40) at 3 years. The results in seropositive RA were comparable with those in the analysis of RA overall, while heritability estimates and PRS RRs were attenuated towards the null in seronegative RA. Conclusion Despite being the largest GWAS on an MTX treatment outcome to date, no genome-wide significant associations were detected. The modest heritability observed, coupled with the broad spread of suggestively associated loci, indicate that genetic influence is of polygenic nature. Nevertheless, MTX monotherapy persistence was lower in patients with a greater genetic disposition, per the PRS, towards RA. [ABSTRACT FROM AUTHOR]

Lihua Zhu,1,&ast; Lingling Zhou,2,3,&ast; Liang Wang,4,&ast; Cunte Chen,2 Jie Qiao,1 Xinran Huang,1 Xiaoyan Su,1 Shaohua Chen,2 Bo Li,2 Xiuli Wu,2 Yangqiu Li2 1Department of Rheumatology and Immunology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China; 2Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, People’s Republic of China; 3Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, 510632, People’s Republic of China; 4Department of Oncology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yangqiu Li, Institute of Hematology, School of Medicine, Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, 510632, People’s Republic of China, Tel +86 20 85226877, Fax +86 20 85226877, Email yangqiuli@hotmail.com Lihua Zhu, Department of Rheumatology and Immunology, First Affiliated Hospital, Jinan University, Guangzhou, 510632, People’s Republic of China, Email zhulihua20121113@163.comBackground: There have been several studies regarding the susceptibility of A20 gene SNPs (rs2230926 and rs5029937) in rheumatoid arthritis (RA). However, little is known about the association between polymorphisms in the A20 promoter and RA. The aim of this study was to investigate the characteristics of A20 promoter polymorphisms and the association between these polymorphisms and clinical significance in Chinese RA patients.Methods: PCR and sequencing were used to identify A20 gene polymorphisms in peripheral blood mononuclear cells (PBMCs) from 123 RA cases and 31 healthy individuals.Results: Only one SNP (rs5029924) in the A20 gene promoter was identified in RA patients and healthy individuals. 6 patients who carried heterozygous rs5029924 (3918C>T) together with heterozygous rs5029937 (11,571 G>T) and rs2230926 (12,486 T>G, Phe127Cys) suffered from joints deformity or refractory RA.Conclusion: We reported the A20 promoter polymorphism rs5029924 in RA patients for the first time. rs5029924 concomitant with rs2230926 and rs5029937 may be a prognostic predictor for joint deformity or refractory RA.Keywords: A20, promoter, polymorphism, RA, deformity, refractory, predictor

Background and Objectives: Compared to the general population, rheumatoid arthritis (RA) patients have additional disease-specific risk factors for osteoporosis that include chronic exposure to systemic inflammation. The current study aimed to investigate the prevalence of osteoporosis and its associated risk factors, such as age, sex, body mass index (BMI), uric acid (UA), and vitamin D status, but also the coexistence of type 2 diabetes mellitus (DMT2) and breast cancer (Ca breast) in patients with RA in Bahrain. Material and Methods: Data from DEXA scans were collected retrospectively from the patient’s electronic health records. All patients who had BMD data and at least one single comorbidity, including RA, were included in the current study. The collected data were analyzed by using SPSS, version 28. Results: A total of 4396 patients were included in the current study. The comorbidities among this cohort were as follows: 3434 patients had endocrinological diseases, among them 63.6% had DMT2; 1870 patients had rheumatological diseases, among them 15.1% had rheumatoid arthritis; and 941 patients had malignancies, among them 75.6% had breast cancer. Our results indicated that patients with RA had a high prevalence of low BMD (72.30%, p < 0.001) and low vitamin D levels (63.10%, p < 0.001) but high serum UA (20.85%). Comparing RA with non-RA patients, our results showed a statistically significant association between RA and each of BMD and UA (p = 0.017 and p = 0.004, respectively), but also between RA and each of age (p = 0.001) and Ca breast (p < 0.001). However, no association was found between RA and BMI, DMT2, or vitamin D status. Conclusions: RA patients had a high prevalence of low BMD (72.3%) and low vitamin D (63.10%) but high serum UA (20.85%). The risk of osteoporosis, hypovitaminosis, and gout must be kept in mind during the evaluation of any case with RA.

In this study, the effects of cutting speed and feed rate on the roughness parameters Ra, Rz, Rsk, Rku, Rpk, Rvk, and A2 were examined during machining with coated carbide tools in a dry environment. The authors introduced the Rvk/Rpk ratio, a coefficient that facilitates a simpler evaluation of surface wear resistance. Specifically, if this ratio is greater than 1, the surface is more wear-resistant, while values less than 1 indicate a higher tendency for surface wear. The Taguchi OA method was used to analyze and identify the significance of technological parameters on output characteristics. Based on the results, it was established that feed rate has the greatest impact on all output characteristics. The highest cutting force was measured at a cutting speed of 60 m/min and a feed rate of 0.15 mm/rev, attributed to the fact that at lower cutting speeds, the base material does not soften while the cross-sectional area of the chip increases. To achieve the lowest Ra and Rz surface roughness, a cutting speed of 100 m/min and a feed rate of 0.05 mm/rev are recommended. If the goal is to enhance surface wear resistance and improve oil retention capability, machining with a cutting speed of 80–100 m/min and a feed rate of 0.15 mm/rev is advisable, as the coarser machining increases both the Rvk/Rpk ratio and the oil-retaining pocket size, which together improve the wear resistance of the machined surface.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that causes extensive damage to multiple organs and tissues and has no known cure. This study introduces a microfluidic detection platform that combines a microfluidic reaction chip with a micro-spectrometer to accurately detect the anti-cyclic citrullinated peptide antibody (anti-CCP Ab) biomarker, commonly associated with arthritis. The surface of the microfluidic reaction chip is functionalized using streptavidin to enable the subsequent immobilization of biotinylated-labeled cyclic citrullinated peptide (biotin–CCP) molecules through a streptavidin–biotin reaction. The modified chip is then exposed to anti-CCP Ab, second antibody conjugated with horseradish peroxidase (HRP) (2nd Ab-HRP), 3,3′,5,5′-tetramethylbenzidine (TMB), and a stop solution. Finally, the concentration of the anti-CCP Ab biomarker is determined by analyzing the optical density (OD) of the colorimetric reaction product at 450 nm using a micro-spectrometer. The detection platform demonstrated a strong correlation (R2 = 0.9966) between OD and anti-CCP Ab concentration. This was based on seven control samples with anti-CCP Ab concentrations ranging from 0.625 to 100 ng/mL. Moreover, for 30 artificial serum samples with unknown anti-CCP Ab concentrations, the biosensor achieves a correlation coefficient of (R2 = 0.9650). The proposed microfluidic detection platform offers a fast and effective method for accurately identifying and quantifying the anti-CCP Ab biomarker. Thus, it offers a valuable tool for the early diagnosis and monitoring of RA and its progression in point-of-care settings.