Search Results (2,346)

It is not entirely clear how the interaction between joint inflammation and the central nervous system (CNS) response in rheumatoid arthritis (RA) works, and what pathophysiology underlies the sex differences in coexisting neuropsychiatric comorbidities. It is known that estrogen hormones reduce inflammation in RA and that this occurs mainly via the stimulation of G protein-coupled receptor-30 (GPR30), also known as G protein-coupled estrogen receptor (GPER) 1. However, changes in GPR30 expression and sex differences induced by local and systemic inflammation in RA are not yet known. Our aim was to reveal sex differences in the expression and association of joint GPR30 with local and systemic inflammation, clinical course and furthermore with hippocampal GPR30 expression during pristane-induced arthritis (PIA) in Dark Agouti (DA) rats, an animal model of RA. Furthermore, we demonstrated sex-specific differences in the association between joint and systemic inflammation and hippocampal microglia during PIA. Our results suggest sex-specific differences not only in the clinical course and serum levels of pro-inflammatory cytokines but also in the expression of GPR30. Female rats show greater synovial inflammation and greater damage to the articular cartilage compared to males during PIA attack. Male rats express higher levels of synovial and cartilaginous GPR30 than females during PIA, which correlates with a less severe clinical course. The correlation between synovial and cartilaginous GPR30 and joint inflammation scores (Krenn and Mankin) in male rats suggests that the more severe the joint inflammation, the higher the GPR30 expression. At the same time, there is no particular upregulation of hippocampal GPR30 in males. On the other hand, female rats express higher levels of neuroprotective GPR30 in the hippocampus than male rats at the basic level and during PIA attack. In addition, females have a higher number of Iba-1+ cells in the hippocampus during PIA attack that strongly correlates with the clinical score, serum levels of IL-17A, and Krenn and Mankin scores. These results suggest that male rats are better protected from inflammation in the joints and female rats are better protected from the inflammation in the hippocampus during a PIA attack, independently of microglia proliferation. However, in the remission phase, synovial GPR30 expression suddenly increases in female rats, as does hippocampal GPR30 expression in males. Further experiments with a longer remission period are needed to investigate the molecular background of these sex differences, as well as microglia phenotype profiling. Full article

Acute-phase serum amyloid A (SAA) can disrupt vascular homeostasis and is elevated in subjects with diabetes, cardiovascular disease, and rheumatoid arthritis. Cyclic nitroxides (e.g., Tempo) are a class of piperidines that inhibit oxidative stress and inflammation. This study examined whether 4-methoxy-Tempo (4-MetT) inhibits SAA-mediated vascular and renal dysfunction. Acetylcholine-mediated vascular relaxation and aortic guanosine-3′,5′-cyclic monophosphate (cGMP) levels both diminished in the presence of SAA. 4-MetT dose-dependently restored vascular function with corresponding increases in cGMP. Next, male ApoE-deficient mice were administered a vehicle (control, 100 µL PBS) or recombinant SAA (100 µL, 120 µg/mL) ± 4-MetT (at 15 mg/kg body weight via i.p. injection) with the nitroxide administered before (prophylaxis) or after (therapeutic) SAA. Kidney and hearts were harvested at 4 or 16 weeks post SAA administration. Renal inflammation increased 4 weeks after SAA treatment, as judged by the upregulation of IFN-γ and concomitant increases in iNOS, p38MAPK, and matrix metalloproteinase (MMP) activities and increased renal fibrosis (Picrosirius red staining) in the same kidneys. Aortic root lesions assessed at 16 weeks revealed that SAA enhanced lesion size (vs. control; p < 0.05), with plaque presenting with a diffuse fibrous cap (compared to the corresponding aortic root from control and 4-MetT groups). The extent of renal dysfunction and aortic lesion size was largely unchanged in 4-MetT-supplemented mice, although renal fibrosis diminished at 16 weeks, and aortic lesions presented with redistributed collagen networks. These outcomes indicate that SAA stimulates renal dysfunction through promoting the IFN-γ–iNOS–p38MAPK axis, manifesting as renal damage and enhanced atherosclerotic lesions, while supplementation with 4-MetT only affected some of these pathological changes. Full article

Background and Objectives: Anti-tumor necrosis factor-alpha (TNF-α) agents are effective in treating rheumatoid arthritis (RA) but may entail a risk of lymphoma due to TNF-α’s role in immune surveillance. This systematic review and meta-analysis assesses the risk of lymphoma in patients with RA treated with anti-TNF agents versus patients treated with methotrexate and/or a placebo. Materials and Methods: The Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Embase, PubMed, and Google Scholar were systematically searched for relevant literature. Data were extracted and analyzed to determine risk ratios (RRs) and 95% confidence intervals (CIs), with heterogeneity assessed using I² statistics. Methodological quality and risk of bias were assessed using the Cochrane Risk of Bias tool for randomized controlled trials (RCTs) and the Newcastle–Ottawa Scale for observational studies. Results: The search yielded 932 articles, 13 of which were retained for qualitative review and 12 for quantitative synthesis. Overall, the studies reviewed included 181,735 participants: 3772 from six RCTs and 177,963 from seven observational studies. The meta-analysis of RCTs revealed no significant difference in the risk of lymphoma between patients receiving anti-TNF-α therapy and patients on conventional treatments, with an overall RR of 1.43 (95% CI: 0.32–5.16) and I² of 0%. Conversely, observational studies showed some variability, with an overall RR of 1.43 (95% CI: 0.59–3.47) and significant heterogeneity (I² = 95%), whereas others indicated a potentially elevated risk of lymphoma in specific subgroups but had inconsistent results. Conclusions: The systematic and meta-analysis revealed no significant difference in the risk of lymphoma for patients with RA treated with anti-TNF-α agents versus conventional therapies. However, given the limitations of the studies included, additional research is needed to validate the results and explore potential risk factors contributing to the development of lymphoma in patients with RA. Full article

Aggregatibacter actinomycetemcomitans (A. actinomycetecomitans) is a Gram-negative bacterial species that is an essential component of the oral microbiota. Due to its aggregative properties, it plays a role in the pathogenesis of human diseases. The presence of the surface proteins Fim, Briae, and microvesicles enables the bacterium to adhere to the epithelial surface and the tooth’s surface. The presence of leukotoxin A (LtxA), which plays an important role in the pathogenicity of the bacterium, has been associated with both periodontitis and the etiology of rheumatoid arthritis (RA). A. actinomycetecomitans is also associated with several other systemic diseases and complications, such as endocarditis and different abscesses. In addition to leukotoxin A, A. actinomycetecomitans possesses several different virulence factors, including bacteriocins, chemotaxis inhibitory factors, cytotoxic factors, Fc-binding proteins, immunosuppressive factors, lipopolysaccharide collagenase, fibroblast inhibitory factors, antibiotic resistance determinants, adhesins, invasive factors and factors that inhibit the function of polymorphonuclear leukocytes. The ability of A. actinomycetemcomitans lipopolysaccharide to induce macrophages to secrete the interleukins IL-1, IL-1β, and tumor necrosis factor (TNF) is of considerable importance. The primary etiologic factor in the pathogenesis of periodontal disease is the oral biofilm colonized by anaerobic bacteria. Among these, A. actinomycetemcomitans occupies an important place as a facultative anaerobic bacterium. In addition, A. actinomycetemcomitans possesses many virulence factors that contribute to its potential to cause cancer. This article provides an overview of the virulence factors of A. actinomycetecomitans and its association with various systemic diseases, its oncogenic potential, and the treatment options for infections caused by A. actinomycetecomitans. Full article

Rheumatoid arthritis (RA) is a chronic autoimmune disease that primarily affects the small joints of the hands and feet, characterized by pain, inflammation, and joint damage. In this context, magnetic resonance imaging (MRI) is useful to identify and monitor joint/tendon inflammation and the evolution of joint damage, playing a key role in treatment response evaluation, in addition to clinical measurements. Various methods to quantify joint inflammation and damage with MRI in RA have been developed, such as RA-MRI Score (RAMRIS), Early RA-MRI Score (ERAMRS), and Simplified RA-MRI Score (SAMIS). RAMRIS, introduced in 2002, offers an objective means to assess inflammation and damage via MRI in RA trials, encompassing findings such as synovitis, bone erosion, and edema/osteitis. Recently, an updated RAMRIS version was developed, which also includes the evaluation of joint space narrowing and tenosynovitis. The RAMRIS-5, which is a condensed RAMSIS version focusing on five hand joints only, has been proven to be a valuable resource for the semi-quantitative evaluation of RA joint damage, both in early and established disease. This narrative literature review will provide an overview of the MRI scoring systems that have been developed for the assessment of joint inflammation and structural damage in RA patients. Full article

Auranofin (AF) is a gold-based compound with a well-known pharmacological and toxicological profile, currently used in the treatment of some severe forms of rheumatoid arthritis. Over the last twenty years, AF has also been repurposed as antiviral, antitumor, and antibacterial drug. In this review we focused on the antibacterial properties of AF, specifically researching the minimal inhibitory concentrations (MIC) of AF in both mono- and diderm bacteria reported so far in literature. AF proves to be highly effective against monoderm bacteria, while diderm are far less susceptible, probably due to the outer membrane barrier. We also reported the current mechanistic hypotheses concerning the antimicrobial properties of AF, although a conclusive description of its antibacterial mode of action is not yet available. Even if its mechanism of action has not been fully elucidated yet and further studies are required to optimize its delivery strategy, AF deserves additional investigation because of its unique mode of action and high efficacy against a wide range of pathogens, which could lead to potential applications in fighting antimicrobial resistance and improving therapeutic outcomes in infectious diseases. Full article

In recent years, several changes have occurred in the management of chronic immunological conditions with the emerging use of targeted therapies. This two-phase cross-sectional study was conducted through structured in-person interviews in 2018–2019 and 2022. Additional data sources included ambulatory medical records and the itemized reimbursement reporting interface of the National Health Insurance Fund. Drug interactions were analyzed using the UpToDate Lexicomp, Medscape drug interaction checker, and Drugs.com databases. The chi-square test was used, and odds ratios (ORs) were calculated. In total, 185 patients participated. In 53% of patients (n = 53), a serious drug–drug interaction (DDI) was identified (mean number: 1.07 ± 1.43, 0–7), whereas this value was 38% (n = 38) for potential drug–supplement interactions (mean number: 0.58 ± 0.85, 0–3) and 47% (n = 47) for potential targeted drug interactions (0.72 ± 0.97, 0–5) in 2018. In 2022, 78% of patients (n = 66) were identified as having a serious DDI (mean number: 2.27 ± 2.69, 0–19), 66% (n = 56) had a potential drug–supplement interaction (mean number: 2.33 ± 2.69, 0–13), and 79% (n = 67) had a potential targeted drug interactions (1.35 ± 1.04, 0–5). Older age (>60 years; OR: 2.062), female sex (OR: 3.387), and polypharmacy (OR: 5.276) were identified as the main risk factors. Screening methods and drug interaction databases do not keep pace with the emergence of new therapeutics. Full article

Background: The relationship between serum glycoprotein syndecan-1 and disease activity in rheumatoid arthritis (RA) is still unknown. This study aimed to evaluate whether serum syndecan-1 concentrations are associated with moderate/severe disease activity. Methods: Study Design: This was a cross-sectional study. Seventy-five adult women with RA were classified into (a) moderate/severe RA based on the disease activity score, using the erythrocyte sedimentation rate (DAS28-ESR ≥ 3.2, n = 50), and (b) RA in remission (DAS28-ESR < 2.6, n = 25). Twenty-five healthy women were taken as the reference group. Syndecan-1 levels were determined using enzyme-linked immunosorbent assay (ELISA). High values of serum syndecan-1 levels (≥24 ng/mL) were used to identify the utility values of this biomarker. Results: The patients with RA had higher levels of syndecan-1 than the controls (p < 0.001). RA patients with active disease had higher syndecan-1 levels than RA patients in remission (57.6 vs. 23.5 ng/mL, respectively; p = 0.002). High syndecan-1 concentrations demonstrated the following utility values for identifying disease activity: sensitivity, 84% (95%CI: 71–93); specificity, 52% (95%CI: 31–72); positive predictive value, 78% (95%CI: 70–84); and negative predictive value, 62% (95%CI: 44–77). Conclusions: High syndecan-1 levels have good sensitivity and positive predictive value for identifying disease activity; however, their specificity is limited. Future prospective studies are needed to assess whether syndecan-1 levels can predict treatment failure in RA. Full article

Aim of the study was to investigate the demographic data and disease course characteristics of patients with Sjögren’s syndrome (SS) and inflammatory joint pain of various origins and to search for factors that might help with the distinction of polyarthritis as an extraglandular manifestation and rheumatoid arthritis as an associated systemic autoimmune disorder. A total of 355 patients were retrospectively analyzed, 128 of whom served as controls (SS-C), while 159 had polyarthritis as an extraglandular symptom of Sjögren’s syndrome (SS-pa) and 68 were diagnosed as having associated rheumatoid arthritis (SS-RA). The patients without any inflammatory joint manifestations were significantly older than the SS-pa patients, while, for the SS-RA group, the difference was not significant. The onset of joint pain appeared significantly earlier in the SS-RA patients. Regarding either extraglandular manifestations or associated autoimmune disorders, there were significant differences between the controls and both SS-pa and SS-RA groups, while no significant difference was found between the SS-pa and SS-RA groups. Thus, laboratory and imaging methods should be used to differentiate between the two conditions, but laboratory biomarkers are even more important for early diagnosis. A ROC curve analysis showed an acceptable diagnostic accuracy in differentiating between SS-pa and SS-RA patients using a binary logistic regression model, where highly positive rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) values, kidney involvement, and anti-Ro/SS-A positivity were shown to significantly raise the odds of having RA, whereas anti-La/SS-B positivity seemed to have a protective role, since it significantly decreased the odds of having it. Further biomarkers are needed to better classify SS patient cohorts with inflammatory joint pain of different origins and, consequently, different management requirements. Full article

The Receptor Activator Nuclear of κB Ligand (RANKL) plays an important function in immune responses, activating osteoclast cells and unchanged bone resorption, which in turn leads to bone erosion and inflammation. Genetic variants in the promoter region of the RANKL gene could lead to a higher risk of rheumatoid arthritis (RA). Objective: To assess the association of rs9533155 (-693C>G) and rs9533156 (-643T>C) genetic variants with RA risk. Methods: A case–control study was carried out. A total of 94 patients with RA (RA group) and 134 subjects without any rheumatologic disease (control group) were included. Genetic DNA was extracted from peripheral white blood cells (leukocytes). Genetic variant rs9533155 (-693C>G) was screened by an approach based on Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP), while rs9533156 (-643T>C) was screened using quantitative polymerase chain reaction (qPCR) with TaqMan probes. RANKL serum levels were measured by ELISA. Results: For rs9533155 (-693C>G), the polymorphic homozygous genotype frequencies (CC) were higher in the RA group (p = 0.006). Individuals carrying the risk genotype presented higher levels of serum RANKL. Carriers of the polymorphic homozygous genotype in the dominant model (CC vs. CG + GG) had an increased risk of developing RA (OR: 1.8, 95% CI 1.04 to 3.1). No association between rs9533156 (-643T>C) and the haplotypes with RA risk was observed. Conclusion: The rs9533155 (-693C>G) genetic variant exhibits a potential role in RA risk. The studied population had no association with the rs9533156 (-643T>C) genetic variant. Full article

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder primarily targeting joints, significantly impacting patients’ quality of life. The introduction of tumor necrosis factor-alpha (TNF-α) inhibitors has markedly improved RA management by reducing inflammation. However, these medications are associated with adverse skin reactions, which can vary greatly among patients due to genetic differences. Objectives: This study aimed to identify risk factors associated with skin adverse events by TNF-α in RA patients. Methods: A cohort study was conducted, encompassing patients with RA who were prescribed TNF-α inhibitors. This study utilized machine learning algorithms to analyze genetic data and identify markers associated with skin-related adverse events. Various machine learning algorithms were employed to predict skin and subcutaneous tissue-related outcomes, leading to the development of a risk-scoring system. Multivariable logistic regression analysis identified independent risk factors for skin and subcutaneous tissue-related complications. Results: After adjusting for covariates, individuals with the TT genotype of rs12551103, A allele carriers of rs13265933, and C allele carriers of rs73210737 exhibited approximately 20-, 14-, and 10-fold higher incidences of skin adverse events, respectively, compared to those with the C allele, GG genotype, and TT genotype. The machine learning algorithms used for risk prediction showed excellent performance. The risk of skin adverse events among patients receiving TNF-α inhibitors varied based on the risk score: 0 points, 0.6%; 2 points, 3.6%; 3 points, 8.5%; 4 points, 18.9%; 5 points, 36.7%; 6 points, 59.2%; 8 points, 90.0%; 9 points, 95.7%; and 10 points, 98.2%. Conclusions: These findings, emerging from this preliminary study, lay the groundwork for personalized intervention strategies to prevent TNF-α inhibitor-associated skin adverse events. This approach has the potential to improve patient outcomes by minimizing the risk of adverse effects while optimizing therapeutic efficacy. Full article

Harlequin glory bower (Clerodendrum trichotomum) is a shrub or small tree belonging to the Lamiaceae family, native to Japan, Korea, and eastern China. It has esthetic value and in Europe, it is cultivated as an ornamental plant. Its sweet-smelling flowers have a white or pink crown. The calyx turns from green to pink–purple over time, providing an especially decorative touch around surrounding the ripe deep-blue fruits that persist until winter. In the areas of its natural occurrence, the leaves and young shoots of C. trichotomum, and sometimes the roots, flowers and fruits, are used in folk medicine due to its anti-inflammatory, analgesic, anticancer, sedative, and hypotensive effects. Products based on Harlequin glory are also used in the treatment of rheumatoid arthritis, joint pain, skin inflammation, or asthma. Preliminary research on the composition of raw material suggests that its health-promoting effect is associated with the presence of numerous secondary metabolites, including phenylpropanoids, flavonoids, lignans, terpenoids, steroids, alkaloids, and anthraquinones. This work reviews the current state of knowledge about the phytochemistry and in vitro and in vivo pharmacological properties of the extracts and main active components isolated from C. trichotomum. It also indicates that before it can be used in modern medicine, further research is necessary regarding the safety and efficacy of the raw material, its mechanisms of action, and dosage. Full article

Clematis Florida (CF) is a folk medicinal herb in the southeast of China, which is traditionally used for treating osteoarticular diseases. However, the mechanism of its action remains unclear. The present study used network pharmacology and experimental validation to explore the mechanism of CF in the treatment of rheumatoid arthritis (RA). Liquid chromatography–mass spectrometry (LC-MS/MS) identified 50 main compounds of CF; then, their targets were obtained from TCMSP, ETCM, ITCM, and SwissTargetPrediction databases. RA disease-related targets were obtained from DisGeNET, OMIM, and GeneCards databases, and 99 overlapped targets were obtained using a Venn diagram. The protein–protein interaction network (PPI), the compound–target network (CT), and the compound–potential target genes–signaling pathways network (CPS) were constructed and analyzed. The results showed that the core compounds were screened as oleanolic acid, oleic acid, ferulic acid, caffeic acid, and syringic acid. The core therapeutic targets were predicted via network pharmacology analysis as PTGS2 (COX-2), MAPK1, NF-κB1, TNF, and RELA, which belong to the MAPK signaling pathway and NF-κB signaling pathway. The animal experiments indicated that topical application of CF showed significant anti-inflammatory activity in a mouse model of xylene-induced ear edema and had strong analgesic effect on acetic acid-induced writhing. Furthermore, in the rat model of adjuvant arthritis (AA), topical administration of CF was able to alleviate toe swelling and ameliorate joint damage. The elevated serum content levels of IL-6, COX-2, TNF-α, IL-1β, and RF caused by adjuvant arthritis were reduced by CF treatment. Western blotting tests showed that CF may regulate the ERK and NF-κB pathway. The results provide a new perspective for the topical application of CF for treatment of RA. Full article

Rheumatoid arthritis (RA) is a chronic, autoimmune rheumatic disease characterized by synovial joint inflammation with subsequent destruction as well as systemic manifestation, leading to impaired mobility and impaired quality of life. The etiopathogenesis of RA is still unknown, with genetic, epigenetic and environmental factors (incl. tobacco smoking) contributing to disease susceptibility. The link between genetic factors like “shared epitope alleles” and the development of RA is well known. However, why only some carriers have a break in self-tolerance and develop autoimmunity still needs to be clarified. The presence of autoantibodies in patients’ serum months to years prior to the onset of clinical manifestations of RA has moved the focus to possible epigenetic factors, including environmental triggers that could contribute to the initiation and perpetuation of the inflammatory reaction in RA. Over the past several years, the role of microorganisms at mucosal sites (i.e., microbiome) has emerged as an essential mediator of inflammation in RA. An increasing number of studies have revealed the microbial role in the immunopathogenesis of autoimmune rheumatic diseases. Interaction between the host immune system and microbiota initiates loss of immunological tolerance and autoimmunity. The alteration in microbiome composition, the so-called dysbiosis, is associated with an increasing number of diseases. Immune dysfunction caused by dysbiosis triggers and sustains chronic inflammation. This review aims to provide a critical summary of the literature findings related to the hypothesis of a reciprocal relation between the microbiome and the immune system. Available data from studies reveal the pivotal role of the microbiome in RA pathogenesis. Full article

Objective: To elucidate the chemical profile of Xanthocerais lignum’s extracts of different polarities and their impact on rheumatoid arthritis (RA), we identified anti-RA markers and predicted their action mechanisms. Methods: A collagen-induced arthritis rat model was established, and UPLC-Q-Exactive Orbitrap MS technology was employed to analyze and identify the chemical constituents within the alcohol extract of Xanthocerais lignum and its various extraction fractions, as well as their translocation into the bloodstream. Serum spectrum–effect correlation analysis was utilized to elucidate the pharmacodynamic material basis of Xanthocerais lignum against RA and to screen for Q-Markers. Finally, the potential anti-RA mechanisms of the Q-Markers were predicted through compound-target interaction data and validated using molecular docking techniques. Results: We identified 71 compounds, with flavan-3-ols and flavanones as key components. Of these, 36 were detected in the bloodstream, including 17 original and 19 metabolized forms. Proanthocyanidin A2, dihydroquercetin, catechin, and epicatechin (plus glucuronides) showed potential anti-RA activity. These compounds, acting as Q-Markers, may modulate ERK, NF-κB, HIF-1α, and VEGF in the HIF-1 pathway. Conclusions: This research clarifies Xanthocerais lignum’s pharmacodynamic material basis against RA, identifies 4 Q-Markers, and offers insights into their mechanisms, aiding quality assessment and lead compound development for RA treatment. Full article