Anti-cyclic citrulline peptide (anti-CCP) antibodies are among the most critical biomarkers for the diagnosis of rheumatoid arthritis (RA), with citrullinated antigens being pivotal in triggering their production. This study aimed to explore the potential diagnostic value of multiple citrulline similar-motif antigen (MCSM) in RA.

A retrospective study was conducted on 135 patients with RA, 112 patients with other joint diseases (non-RA group), and 67 healthy controls from the Hangzhou Red Cross Hospital. The levels of MCSM in the peripheral blood were measured. The diagnostic value of MCSM in RA patients was assessed by receiver operating characteristic (ROC) curve analysis.

MCSM in serum were significantly higher in RA patients than in non-RA patients (Signal-to-Cutoff ratio (S/CO): 3.2 vs 0.5, P < 0.0001) and healthy controls (S/CO: 3.2 vs 0.4, P < 0.0001). ROC analysis showed an area under the curve (AUC) of 0.932 for MCSM. Individually, MCSM outperformed anti-CCP and rheumatoid factor (RF), achieving sensitivity of 91.1 % and specificity of 95.5 %. Notably, MCSM detection rates were significantly higher in RA patients with pain duration under one year compared to anti-CCP (89.47 % vs. 52.65 %, P < 0.05).

MCSM demonstrate high sensitivity and specificity in diagnosing RA, with significant complementary value to anti-CCP and RF, and can increase the detection rate among RA patients with a disease duration of less than one year.

To assess the comparative safety of TNF inhibitor (TNFi), non-TNFi, and Janus kinase inhibitor (JAKi) biologic or targeted synthetic DMARD (b/tsDMARD) in patients with RA for the risk of major adverse cardiovascular events (MACE) using US administrative claims data.

We performed a cohort study using Merative™ Marketscan® Research Databases (2012-2021) of individuals aged 18-64 years with RA initiating b/tsDMARD treatment. We used Cox proportional hazard models to estimate hazard ratios (HR) and 95% CI for developing MACE within 2 years of b/tsDMARD initiation, adjusting for potential confounders.

We included a total of 34 375 treatment exposures: 71% TNFi, 10% JAKi, 8% abatacept, 5% rituximab and 5% IL-6i. Most individuals were female (77-84%) with a median (interquartile range) of 50 (42, 56) years. Rituximab had the highest incidence rate of MACE (196/10 000 person-years; 95% CI 126, 291), followed by IL-6i (111/10 000 person-years; 95% CI 57, 193). Multivariable analyses showed non-statistically significantly higher MACE risk with rituximab (HR 1.5; 95% CI 0.9, 2.4) and IL-6i (HR 1.3; 95% CI 0.7, 2.4) exposures but no increased risk with JAKi relative to TNFi use.

In this large nationwide study, rituximab and IL-6i users had numerically higher, but not statistically significant, MACE risk. Our data support the safety of b/tsDMARD use for RA treatment. This study was limited by short follow-up time and confounding by indication; further studies that can overcome these limitations are needed.

Autoantibodies directed against carbamylated proteins (anti-CarP) have been recently identified as predictors for RA development. The aim of this study was to determine the positivity of anti-CarP antibodies in a real-life cohort of RA patients and their association with radiological damage, disability and disease activity. In this open-label, observational, cross-sectional study 69 RA patients and 16 healthy controls (HC) were recruited. The study was approved by institutional Ethical Committee. Circulating levels of anti-CarP antibodies were determined by commercial ELISA anti-CarP quantitative sandwich immunoassay. Articular X-rays were evaluated to define the presence of bone erosions. Disease activity (DAS28-CRP) and disability (HAQ-DI) were assessed. Pearson χ2 test, Wilcoxon test or Kruskall-Wallis test was used. Spearman rank-order correlation coefficient was applied for continuous variables. Multivariable logistic regression model was performed. Anti-CarP positivity was found in 35% of RA patients and in no HC. One quarter of seronegative RA patients were anti-CarP positive. A positive correlation between levels of anti-CarP antibodies with DAS28-CRP (p = 0.0003; Spearman r = 0.4829) and HAQ-DI (p = 0.0003; Spearman r = 0.4253) was found. 87% of anti-CarP positive patients had erosions. At multivariable logistic regression analysis, RA disease activity (OR 1.31, 95% CI [1.14, 1.63]) and circulating levels of anti-CarP antibodies (OR 1.66, 95% CI [1.28, 2.37]) were independent predictors of bone erosions. Our study confirms that anti-CarP antibodies are associated with a more aggressive RA course and are independent predictors of bone erosions.

Analyze the correlation between the DNA methylation levels of Protocadherin 17 (PCDH17) cg03865667 and rheumatoid arthritis (RA), and evaluate its potential as a biomarker for diagnosing RA. Peripheral blood samples were collected from a cohort of 370 individuals, comprising patients diagnosed with RA, ankylosing spondylitis (AS), psoriatic arthritis (PsA), gout, systemic lupus erythematosus (SLE), dermatomyositis (DM), primary Sjögren's syndrome (SS), and healthy controls (HC), for subsequent analysis.DNA methylation sequencing techniques were employed to evaluate the methylation levels of the PCDH17 cg03865667 locus. Relative to the HC, AS, and SS groups, PCDH17 cg03865667 was significantly downregulated in RA patients (P = 0.0403; p = 0.0290; p = 0.044). Compared to the HC group, the methylation levels at CpG sites 57,631,544, 57,631,571, and 57,631,581 were significantly downregulated in RA patients (p = 0.0078; p = 0.0123; p = 0.0309). For the TTCCTT and TTTCTT haplotypes, methylation levels were significantly lower in RA patients than in HC (p = 0.0188; p = 0.0053), particularly for the TTTCTT haplotype. Significant differences were observed between the CCP(-) RF(-) group, the CCP(+) / RF(+) group, and the HC group among the RA subgroups. No significant differences were found within the double-positive subgroup.The average methylation level of PCDH17 was negatively correlated with C-reactive protein (CRP) (r=-0.28, p = 6.9e-4). This study indicates that PCDH17 cg03865667 methylation may function as a potential biomarker for RA diagnosis. The subgroup analysis suggests that it may serve as a potential biomarker for diagnosing RA, indicating a capacity to enhance the diagnostic accuracy for seronegative RA and reduce the likelihood of missed and incorrect diagnoses.

Abatacept, a biological disease-modifying antirheumatic drug(bDMARD), has demonstrated unique and effective therapeutic properties for rheumatoid arthritis (RA).

This review offers an in-depth examination of the mechanism by which abatacept exerts its effects in RA treatment and assesses its efficacy and safety based on a range of studies. We conducted a comprehensive search of PubMed, Embase databases, Web of Science, the Cochrane Library, MEDLINE, Wanfang Data, and CNKI from the time the databases were created until 30 July 2024.

By modulating the CD28 and CD80/CD86 costimulatory signaling pathways, abatacept is instrumental in regulating immune cells and cytokines implicated in the pathogenesis RA. Longitudinal studies have highlighted its capacity to mitigate disease advancement and maintain joint functionality. The most frequently reported adverse effects associated with abatacept are headache, nausea, and upper respiratory tract infections, which are typically self-resolving. The incidence of serious infections was not high, mainly various types of bacterial pneumonia. Comparative safety analyses of abatacept with other DMARDs yield encouraging results. As our understanding of the mechanism of action of abatacept improves, we may be able to better identify appropriate biologic therapies and advanced combination therapies for RA patients and ultimately improve patient outcomes.

More than 500 million people worldwide suffer from arthritis, experiencing daily pain and inflammation. Current treatments for osteoarthritis (OA) and rheumatoid arthritis (RA) are palliative, offering only symptom relief. No disease-modifying OA drugs (DMOADs) capable of restoring joint functionality and regenerating the cartilage matrix have yet been approved by the FDA or EMA.

This review highlights recent advances in nanocrystals for arthritis drug delivery, including conventional nanosuspensions and novel transdermal microneedles. Special attention is given to intra-articular DMOADs formulated as nanocrystal-in-microparticles, designed to extend drug release over months. Papers and reviews with the mentioned contents and published over the last 5 years were included in the review process.

New DMOADs and disease-modifying antirheumatic drugs (DMARDs) are often poorly water-soluble, limiting their clinical progress. The versatility of nanocrystals and nanosuspensions offers a potential advantage over other types of nanoparticles, as they can be adapted to various delivery systems, administration routes, and types of arthritis. Due to the avascular nature of cartilage, exploring the intra-articular route for OA management is essential. Implementing cartilage-targeted strategies or using stimuli-responsive hydrogels can further enhance their therapeutic potential.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by the presence of autoantibodies against modified proteins, known as anti-modified protein autoantibodies (AMPAs). While the relationship between different AMPA isotypes and various risk factors remains poorly understood, investigating this association is important for a deeper understanding of RA pathophysiology. Smoking, has its primary effects in the lungs, and it remains unclear whether smoking is preferentially linked to specific AMPA isotypes, such as IgA, which could suggest a mucosal origin. Therefore, we set out to investigate the association between smoking, genetic risk factors for RA, and the presence of specific AMPA isotypes, particular IgA.

In 618 RA patients, anti-citrullinated protein antibodies (ACPA-) and anti-acetylated protein antibodies (AAPA-) IgA, -IgG and -IgM and RF-IgA and -IgM were measured by ELISA. Associations with genetic risk factors, smoking and autoantibodies were assessed with logistic regression analysis. For replication, a comprehensive meta-analysis incorporating 3309 RA patients was performed.

Smoking was primarily associated with IgA AMPA, with associations that prevailed after correcting for the concurrent presence of AMPA IgG (ACPA-IgA OR 1.89 [1.14-3.12], AAPA-IgA 2.30 [1.35-3.94]). To further substantiate these results, we performed a meta-analysis of 3309 RA patients and observed that smoking was again predominantly associated with the combined presence of ACPA-IgA in addition to ACPA-IgG (OR 2.05 [1.69-2.49], p < 0.001) versus the single presence of ACPA-IgG (OR 1.18 [0.97-1.44], p = 0.11). A gene-environment interaction between the most important genetic risk factor for RA (the HLA shared epitope alleles) and smoking was only seen in patients that were both ACPA-IgG and ACPA-IgA positive, but not in patients who were only positive for ACPA-IgG.

These data provide a pivotal refinement of existing knowledge regarding risk factor associations for RA and lend novel support to the hypothesis that smoking may exert its effect on RA by the induction of local (auto)immune responses at mucosal sites.

This study aimed to investigate the associations of multi-omics polygenic risk score (PRS) and rheumatoid arthritis (RA) to identify potential genes/proteins and biological pathways.

Based on multi-omics data from 48,813 participants in the INTERVAL cohort, we calculated multi-omics PRS for 13,646 mRNAs (RNASeq), 308 proteins (Olink), 2380 proteins (SomaScan), 726 metabolites (Metabolon), and 141 metabolites (Nightingale). Using the generalized linear model, we first evaluated the associations between multi-omics PRS and RA in 58,813 UK Biobank participants. The Gene Ontology (GO) project and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed to identify the functional pathways in RA. Furthermore, differential gene expression profile datasets were used to validate the identified genes/proteins in our study.

We identified 59 transcriptomics PRS and 29 proteomics PRS significantly associated with RA. Both proteomics and transcriptomic PRS identified HLA-DQA2 (RNASeq: OR=1.19, P=1.18×10-24; SomaScan: OR=1.24, P=4.43×10-27) and AGER (RNASeq: OR=0.91, P=4.18×10-4; SomaScan: OR=0.93, P=3.97×10-3) were significantly associated with RA. Proteomic PRS from different profiling platforms (SomaScan and Olink) identified a consistent association between TFF3 (SomaScan: OR=0.90, P=4.08×10-6; Olink: OR=0.93, P=4.87×10-3) and RA. The identified gene/proteins were mainly enriched in the NF-kappa B signaling pathway (hsa04064, P=5.06×10-5) and Cytokine-cytokine receptor interaction (hsa04060, P=2.49×10-4). In addition, a total of 12 candidate genes in our study were verified in two independent GEO datasets, such as FLOT1 and ABCF1.

Our findings provide novel insights into the involvement of identified genes/proteins and pathways in the pathogenesis of RA from multi-omics levels.

Rheumatoid arthritis (RA) is a global health problem with a heavy disease burden on both individuals and society. However, there is a lack of comprehensive nationwide data on RA prevalence, incidence, and associated economic burdens based on large-scale population studies in China.

A population-based study was conducted based on data from the Urban Employee Basic Medical Insurance and Urban Resident Basic Medical Insurance claims covering 380 million residents from 23 provinces in China, from 2013 to 2017. The prevalence and incidence rates of RA stratified by sex, age, and region were estimated by a two-stage approach with Poisson regression models. The rates were age- and sex-standardized. The associated annual costs and hospital visit times were estimated.

789 583 patients were identified with a mean age of 54.74 ± 14.72 years, of whom 61.25% were female. The standardized prevalence rate of RA in China in 2017 was 334.35 (95% CI 288.20-383.92) per 100 000 people with 443.97 (95% CI 368.23-526.76) and 242.25 (95% CI 188.87-302.24) per 100 000 people in females and males. The prevalence increased at an average annual rate of 21.79%. The incidence rate in 2017 was 128.71 (95% CI, 101.69-158.91) per 100 000 person-years. The prevalence and incidence rates peaked at 65-74 years old in both sexes. The prevalence and incidence rates were lower in Southern China compared to other regions. The average annual cost per capita for RA patients was estimated to be US$907.78.

The high and rising prevalence, incidence, and medical costs of RA impose a substantial societal burden. Distinct patterns in prevalence across geographic regions require further research for underlying causes.

In rheumatoid arthritis (RA), excessive reactive oxygen species (ROS) and chronic inflammation drive damage to the synovium, cartilage, and bone. Developing precise and synergistic therapy for RA is crucial for improving remission rates. Here, carbon dots (CDs) with multienzyme activity and inflammation-targeting capabilities are designed to deliver methotrexate (MTX) for synergistic RA treatment. Specifically, positively charged CDs with porphyrin iron cores and amino-functionalized surfaces are synthesized to simultaneously scavenge hydrogen peroxide, superoxide anions, and hydroxyl radicals. Conjugation of MTX-loaded CDs with polyethylene glycol (CDs2-P@M) via Schiff base reaction significantly prolongs in vivo circulation time. In collagen-induced arthritis rats, CDs2-P@M accumulates in the diseased joints, reducing ROS and inflammatory cytokines, reprogramming macrophage phenotypes, inhibiting osteoclast activation, and markedly improving arthritis symptoms. This approach targets the RA microenvironment, minimizing MTX toxicity and effectively reshaping immune homeostasis, halting inflammation and tissue destruction, thus offering a new paradigm for RA immunotherapy.

Osteoarthritis (OA) is a common degenerative joint disease that can lead to chronic pain and disability. The pathogenesis of OA involves chronic low-grade inflammation, characterized by the degradation of chondrocytes, inflammation of the synovium, and systemic low-grade inflammation. This inflammatory response accelerates the progression of OA and contributes to pain and functional impairment. Primary cilia play a crucial role in cellular signal transduction and the maintenance of cartilage matrix homeostasis, and their dysfunction is closely linked to inflammatory responses. Given these roles, primary cilia may significantly contribute to the pathogenesis of OA. This review explores inflammation-associated signaling pathways in OA, including NF-κB, MAPK, JAK/STAT, and PI3K/AKT/mTOR signaling. In addition, we place particular emphasis on cilia-mediated inflammatory modulation in OA. Primary cilia mediate chondrocyte responses to mechanical loading and inflammatory cytokines via pathways including NF-κB, MAPK, TRPV4, and Hedgehog signaling. Notably, alterations in the length and incidence of primary cilia in chondrocytes during OA further underscore their potential role in disease pathogenesis. The identification of biomarkers and therapeutic targets related to primary cilia and inflammatory pathways offers new potential for the treatment and management of OA.

Rheumatoid arthritis (RA) frequently leads to foot deformities, significantly impacting pain, mobility, and quality of life. Surgical and pharmacological treatments are prescribed to manage symptoms, but their long-term effects on foot function remain unclear. This study evaluates the impact of different treatment approaches, including surgery, methotrexate (MTX), and biological therapy (Bio), on foot functionality and pain progression over five years.

A longitudinal cohort study was conducted with 103 RA patients classified into five groups: surgery, MTX < 10 years, MTX ≥ 10 years, Bio < 10 years, and Bio ≥ 10 years. Data from 2018 and 2023 were compared using the Visual Analog Scale (VAS), the Manchester Foot Pain and Disability Index (MFPDI), and the Foot Function Index (FFI). Statistical analyses included ANOVA, Kruskal-Wallis, and ROC curve analysis to assess differences between groups and identify key progression factors.

Patients with ≥10 years of disease duration and non-biological treatment (MTX ≥ 10 years) experienced the most severe deterioration in foot function, with a mean FFI increase of +11.89 points (p < 0.01). In contrast, MTX < 10 years was the only group to show an improvement in foot function (FFI: -5.29, p = 0.02). The surgery group exhibited moderate but highly variable functional changes, while patients on biological therapy showed less progression in pain and disability compared to their non-biologic counterparts. Hallux abductus valgus severity increased across all groups.

Patients with long-standing RA on non-biologic therapy exhibited the greatest decline in foot function, whereas early treatment with MTX (<10 years of disease duration) appeared to slow deterioration. Surgery did not consistently provide functional benefits, and biologics helped mitigate progression, though outcomes varied. These findings underscore the importance of early intervention and personalized treatment strategies for foot preservation in RA.

Skeletal muscle disease in patients with early-stage rheumatoid arthritis (RA) is understudied. The objective of this study was to identify whether patients with early RA (symptoms <6 months) have impaired skeletal muscle health.

Participants with early RA (n = 10) and age-, sex-, and BMI-matched healthy controls (n = 10) underwent cross-sectional clinical, physiological, and muscle biomechanical property assessments. Upper and lower extremity muscles underwent in vivo passive biomechanical property-tone, stiffness, and elasticity-assessments via myotonometry (MyotonPro®). In vitro muscle force production and stiffness were assessed using 3D bioengineered myobundles derived from myoblasts obtained from vastus lateralis muscle biopsies.

Despite similar muscle mass and self-reported physical activity behaviors for patients with early RA and healthy controls, patients with early RA had poorer self-reported physical function, self-reported physical health, and right-hand grip strength (p < 0.05 for all). Early RA muscle tone and stiffness were lower than in controls (p < 0.05) and had an inverse association with prednisone use (rho = -0.72, p = 0.02). While 3D bioengineered myobundle force production and passive stiffness were similar to controls, early RA myobundle stiffness correlated with swollen joint count (rho = -0.67, p = 0.04).

In this exploratory study, patients with early RA exhibited multiple skeletal muscle deficits across clinical, physiologic, and biomechanical domains compared to controls with similar muscle mass and physical activity. In vivo and in vitro skeletal muscle biomechanical assessments may be useful to identify these deficits to better understand and improve RA muscle health.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease closely related to aging with unclear pathogenic mechanisms. This study aims to identify the biomarkers in RA, aging and autophagy using bioinformatics and machine learning and explore the binding stability of taurine to target utilizing computer-aided drug design (CADD).

We identified differentially expressed genes (DEGs) for RA, then crossed with gene libraries for aging and autophagy to identify common genes (Co-genes). We performed Gene Ontology (GO), Kyoto Encyclopedia of the Genome (KEGG), and ClueGO analysis for Co-genes. The Co-genes were subjected to support vector machine-recursive feature elimination (SVM-RFE), Degree, and Betweenness algorithms to get hub genes, then verified by an artificial neural network (ANN). After continuing to perform least absolute shrinkage and selection operator (LASSO) and weighted gene co-expression network analysis (WGCNA) on Co-genes, the results were crossed with hub genes to obtain genes, which were imported into various validation sets for receiver operating characteristics (ROC) to identify key genes. We analyzed the microRNA/TF network, enriched pathways, and immune cell infiltration for key genes. The binding stability of taurine with the target protein was verified by CADD. Finally, we used Western blot for in vitro experimental verification.

We obtained 74 Co-genes enriched in RA, cellular senescence, and regulation of programmed cell death. The model prediction of hub genes works well in ANN. The key genes (MMP9, CXCL10, IL15, FOXO3) were tested in ROC with excellent efficacy. In RA, FOXO3 expression was down-regulated while MMP9, CXCL10, and IL15 expression were upregulated, and FOXO3 was negatively correlated with MMP9, CXCL10, and IL15. Two miRNAs (hsa-mir-21-5p, hsa-mir-129-2-3p) and four TFs (CTCF, KLF, FOXC1, TP53) were associated with key genes. The immune cells positively correlated with MMP9, CXCL10, and IL15 expression and negatively correlated with FOXO3 expression were Plasma cells, CD8 T cells, memory-activated CD4 T cells, and follicular helper T cells, aggregating in RA. The binding stability of taurine with FOXO3 was verified by molecular docking and molecular dynamics simulation. In vitro experiments have indicated that taurine can upregulate the expression of FOXO3 and treat RA through the FOXO3-Parkin signaling pathway.

MMP9, CXCL10, IL15, and FOXO3 are biomarkers of RA, cellular senescence, and autophagy. Taurine might be a promising drug against RA via targeting cellular senescence and autophagy through FOXO3.

Computed tomography (CT) has traditionally been underutilized in the imaging of inflammatory arthritis due to its limitations in assessing soft tissue inflammation and concerns over radiation exposure. However, recent technological advancements have positioned CT as a more viable imaging modality for arthritis, offering high specificity and sensitivity in detecting structural bone changes. However, advances in ultra-low-dose CT protocols and AI-driven image reconstruction have significantly reduced radiation exposure while maintaining diagnostic quality. Dynamic CT and spectral CT techniques, including dual-energy CT (DECT), have broadened CT's application in assessing dynamic joint instabilities and visualizing inflammatory changes through material-specific imaging. Techniques such as CT subtraction imaging and iodine mapping have enhanced the detection of active soft-tissue inflammation, virtual non-calcium reconstructions, and the detection of bone marrow edema. Possible CT applications span various forms of arthritis, including gout, calcium pyrophosphate deposition disease (CPPD), psoriatic arthritis, and axial spondyloarthritis. Beyond its diagnostic capabilities, CT's ability to provide detailed structural assessment positions is a valuable tool for monitoring disease progression and therapeutic response, particularly in clinical trials. While MRI remains superior for soft tissue evaluation, CT's specificity for bone-related changes and its potential for integration into routine arthritis management warrant further exploration and research. This review explores the current and emerging roles of CT in arthritis diagnostics, with a focus on novel applications and future potential.

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting articular joints and skeletal muscle. To assess the role of cytokines upon muscle strength in RA, we developed an in vitro tissue-engineered human skeletal muscle model (myobundle). Myobundles were generated using primary skeletal muscle cells from the vastus lateralis muscle of RA patients and age-matched healthy controls. RA myobundles were more sensitive to 5 ng/mL IFN-γ, exhibiting reduced contractile force and altered contraction kinetics. Addition of IL-6 with or without IFN-γ led to a small but significant increase in striated fibers. Gene sets involved in the response to hypoxia, MTOR1 signaling, and the unfolded protein response were enriched in IFN-γ-treated RA myobundles, but not IFN-γ-treated controls. Tofacitinib increased contractile force, myosin heavy chain, and PIM1 protein levels in RA myobundles treated with IFN-γ. Thus, in RA muscle, low levels of IFN-γ selectively increase gene pathways that reduce contractile force.

Autoimmune diseases (AD) present substantial challenges for early diagnosis and precise treatment due to their intricate pathogenesis and varied clinical manifestations. While existing diagnostic methods and treatment strategies have advanced, their sensitivity, specificity, and real-time applicability in clinical settings continue to exhibit significant limitations. In recent years, fluorescent probes have emerged as highly sensitive and specific biological imaging tools, demonstrating substantial potential in AD research.This review examines the response mechanisms and historical evolution of various types of fluorescent probes, systematically summarizing the latest research advancements in their application to autoimmune diseases. It highlights key applications in biomarker detection, dynamic monitoring of immune cell functions, and assessment of drug treatment efficacy. Furthermore, this article analyzes the technical challenges currently encountered in probe development and proposes potential directions for future research. With ongoing advancements in materials science, nanotechnology, and bioengineering, fluorescent probes are anticipated to achieve higher sensitivity and enhanced functional integration, thereby facilitating early detection, dynamic monitoring, and innovative treatment strategies for autoimmune diseases. Overall, fluorescent probes possess substantial scientific significance and application value in both research and clinical settings related to autoimmune diseases, signaling a new era of personalized and precision medicine.

To systematically review operational definitions of old(er) age in rheumatoid arthritis (RA) patients and investigate differences in disease-modifying anti-rheumatic drug (DMARD) efficacy, safety and drug survival between young(er) and old(er) patients.

A systematic review was performed on studies conducting research in an old(er) RA patient population. Two reviewers independently performed data extraction and risk of bias assessment. Operational definitions of old(er) age were described using frequency statistics. For studies comparing effects of DMARDs, random effects meta-analyses estimated pooled odds ratios (ORs) of young(er) vs. old(er) patients reaching remission, experiencing adverse events (AEs) and discontinuing drug treatment due to unfavourable events.

This review included 324 studies. The operational definition for old(er) age ranged from 40.0 to 77.3 years. The most frequent definition was 65 (45.1 %), followed by 60 years or older (20.4 %). Fifty-eight percent of studies reported no reason for using a specific age-threshold. Seventy-nine studies evaluated DMARD efficacy, safety and/or survival, with 37 eligible for meta-analysis. No statistically significant difference in reaching remission was observed between old(er) and young(er) patients (OR=0.76 (95 %-CI: 0.57-1.02)) (n = 11 studies). AEs and drug discontinuation were experienced more often in old(er) patients (OR=1.33 (95 %-CI: 1.01-1.74) (n = 19 studies) and OR=1.12 (95 %-CI: 1.02-1.23) (n = 25 studies), respectively).

Definitions of old(er) age vary across studies including RA patients. Old(er) age appears to affect DMARD safety and discontinuation. To ensure meaningful comparisons across studies, studies should justify the chosen definition and report and account for potential impacts of indicators of ageing, such as multimorbidity, polypharmacy, and geriatric syndromes.

Rheumatoid arthritis (RA) is a chronic inflammatory multisystemic disorder that can cause significant deformity and disability. Vitamin D has a role in Th1-medicated autoimmune diseases like RA. Furthermore, some observational studies have concluded that Vitamin D supplementation reduces the severity of RA.

This study aimed to find out any correlation between Vitamin D levels and severity of early RA.

This study settings and design were a cross-sectional single-center observational study.

This was an observational study. All patients with early RA were screened and evaluated as per protocol. No extra tests were done.

Pearson's Chi-square test for independence of attributes/Fisher's exact test was used to find the association between the categorical variables as appropriate.

We found that all patients of early RA had moderate-tosevere disease activity without any relation with their Vitamin D level ( P > 0.05).

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by complex immune interactions. Elucidating the causal relationships between blood cell perturbations, immune cell subsets, and RA can provide valuable insights into its pathogenesis.

This study employed bidirectional two-sample Mendelian Randomization (MR) to explore the causal effects of blood cell perturbations on RA risk, with a focus on immune cell mediation. Genetic data from large-scale Genome-Wide Association Studies (GWAS) were utilized to select instrumental variables (IVs) for exposure, mediator, and outcome. Inverse Variance Weighted (IVW) analysis was applied, supplemented by sensitivity tests. Mediation analysis was conducted to assess the indirect effects mediated by immune cells.

Significant causal associations were identified between perturbations in reticulocytes, monocytes, and lymphocytes and specific immune cell subsets, including CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + terminally differentiated CD8 + T cells (CD45RA + TD CD8 + cells). Erythropoiesis perturbation was associated with a reduced RA risk, while perturbations in monocytes and lymphocytes were found to facilitate RA progression through immune-mediated mechanisms.

This study underscores the pivotal role of immune cell subsets in mediating the effects of blood cell perturbations on RA development. These findings suggest that targeting immune cell-mediated pathways, particularly those involving Tregs and CD8 + T cells, can provide new therapeutic strategies for RA management. Key Points • Causal Relationships: Mendelian randomization (MR) analysis identified significant causal relationships between specific blood cell disturbances (e.g., reticulocytes, monocytes, and lymphocytes) and rheumatoid arthritis (RA). • Role of Immune Cells: CD3 + CD39 + regulatory T cells (Tregs) and CD45RA + Terminally Differentiated CD8 + T cells (CD45RA + TD CD8 + cells) mediate the association between blood cell disturbances and RA. • Protective Role of Reticulocytes: Reticulocyte disturbances under potassium chloride (KCl) conditions are negatively associated with RA, potentially protecting joints from inflammatory damage by reducing oxidative stress. • Protective Role of Non-Classical Monocytes: Baseline disturbances in monocyte median side scatter are negatively associated with RA, suggesting non-classical monocytes may reduce RA-related inflammation. • Positive Association of Lymphocyte Disturbances with RA: Lymphocyte side scatter standard deviation under colchicine disturbances shows a significant positive association with RA, indicating abnormal T cell activation may exacerbate RA progression.AQ.

To evaluate clinical prognosis following the introduction of a first targeted therapy (TT) according to the serological profile of rheumatoid arthritis (RA) and to analyze differences in efficacy of TT.

This single-center retrospective study included patients with RA who received a first TT between 2000 and 2020. Patients were seropositive (IgM and/or IgA rheumatoid factors plus anti-CCP) or seronegative (without autoantibodies). Various data were collected at baseline and during follow-up. The primary endpoint was remission (assessed by DAS28) at one and two years.

Among 259 patients, 164 (63.3%) were seropositive and presented higher disease activity and more frequent erosive involvement than seronegative patients at TT introduction. The most prescribed first TTs were etanercept for seronegative RA (47 ([49.5%) versus 41 (25%), p < 0.001) and abatacept for seropositive RA (41 (25%) versus 6 (6.3%), p < 0.001). Remission rates and TT switches were not significantly different between groups. Initial DAS28-CRP and number of painful joints were independent prognostic factors associated with absence of remission at one year (OR 0.46 (0.26, 0.80), p = 0.007) and two years (OR 0.90 (0.82, 0.98), p = 0.027) respectively. Among seropositive patients, the two-year remission rate was not significantly different according to the therapeutic class received (cellular- versus cytokine-targeted).

Patients with seropositive RA showed more active and severe disease than patients with seronegative RA at the introduction of a first TT. Although the choice of the first TT varied according to serological profile and time of analysis, clinical prognosis at one and two years was similar between groups. Key Points • Seropositive versus seronegative RA was more active at start of first targeted therapy. • First-line TTs were etanercept for seronegative RA and abatacept for seropositive RA. • Rate of targeted therapy switches was comparable between both groups. • Remission rates at 1 and 2 years were similar in seropositive and seronegative RA. • Remission rates were similar for cellular and cytokine inhibitors in seropositive RA.

Aristolochic acids (AAs)-containing herbs have been used as medicinal remedies for thousands of years. However, exposure to AAI and AAII increases the risk of nephropathy and cancers. Our previous study identified AAIVa, an analogue without carcinogenicity or nephrotoxicity, exerted anti-inflammatory effects.

To explore AAIVa's anti-inflammatory mechanisms and assess its therapeutic potential in arthritis.

In this study, we employed in vitro assays on RAW 264.7 cells and explored the underlying mechanisms of AAIVa's anti-inflammatory effect through transcriptome analysis, identifying macrophage polarization-associated genes, IL-17 signaling, and Rheumatoid Arthritis (RA) pathway. Also, we used BALB/cAnSmoc-Zap70em(W163C)Smoc (SKG) mice, a model that spontaneously develops chronic arthritis closely resembling human RA, and revealed AAIVa's therapeutic potential in arthritis. AAIVa-treatment (10 mg/kg, i.g.) for 4 weeks protected SKG mice from mannan-accelerated arthritis symptoms, reducing inflammation and improving bone microstructure. We further isolated bone marrow-derived macrophages (BMDMs) and spleen primary cells from SKG and BALB/c mice to evaluate the impact of AAIVa on macrophage polarization and T cell differentiation. We found that AAIVa induced M2 macrophage polarization in BMDMs, and mitigated lipopolysaccharide-stimulated inflammation by increasing Tregs and decreasing Th17 cells. Subsequently, the elevation of M2 macrophages, increased Tregs expression and decreased Th17 cells in the ankle joints of SKG mice supported our in vitro observation.

We provide first evidence that AAIVa exerts anti-arthritis effects, likely through modulation of macrophage polarization and restoration of the Th17/Treg balance. Our findings highlight AAIVa's mechanism of action and AAIVa's potential as a therapeutic candidate for autoimmune arthritis.

Achieving the primary treat-to-target (T2T) goal in rheumatoid arthritis (RA) remains challenging for many patients, reflecting limitations in the effectiveness of existing treatments. Our study examines factors influencing Janus kinase (JAK) inhibitor effectiveness by analyzing interindividual variability in demographic and clinical characteristics of real-world RA patients.

This observational retrospective study involves RA patients receiving tofacitinib, baricitinib, upadacitinib, or filgotinib between September 2017 and January 2025. Predictive factors of achieving the T2T goal at 6 months were identified through logistic regression analyses. Disparities in the treatment effectiveness retention based on predictive factors were assessed using the Kaplan-Meier estimate and compared with the log-rank test. The Cox model was applied to analyze whether the predictive factors identified could influence the retention of JAK inhibitor treatment effectiveness.

One hundred fifty patients were included: 81 (54%) achievers and 69 (46%) non-achievers of remission or, at least, low disease activity at 6 months of treatment. High disease activity at baseline, with respect to moderate activity, was identified as an unfavorable factor for achieving the T2T goal (Odds ratio adjusted: 0.96; 95% confidence interval: 0.92-0.99; p = 0.028). In treatment effectiveness retention rates, no differences were observed between patients with high versus moderate disease activity (p = 0.103). RA disease activity at baseline was not found to impact the survival of JAK inhibitor effectiveness (p = 0.106).

In RA, high disease activity at the initiation of treatment with tofacitinib, baricitinib, upadacitinib, or filgotinib does not preclude an effective treatment response but is associated with an increased risk of therapeutic failure. Factors not related to the achievement of the T2T goal at 6 months of JAK inhibitor treatment include: age, female sex, body mass index, RA disease duration, seropositivity for rheumatoid factor, seropositivity for anti-cyclic citrullinated peptides, JAK inhibitor selectivity, type and number of prior biologic treatments, concomitant use and number of prior conventional synthetic disease-modifying antirheumatic drugs, and number of prior JAK inhibitors. These conclusions are derived from a retrospective real-world study and should be confirmed in prospective studies.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that leads to the destruction of peripheral joint cartilage and bone tissue. Despite the advent of biological therapies in the past decades, the complete remission of RA patients is still out of reach. Therefore, the search for novel therapeutic approaches is still open in the field of RA. Proteasome inhibitors (PIs) were originally designed to be used in hematological malignancies like multiple myeloma. However, evidence has shown that they are potent inhibitors of the NF-κB pathway, which plays a pivotal role in inflammatory processes and RA. Furthermore, inhibition of cell activation and induction of apoptosis was also reported about PIs. In the present review, we summarize the current knowledge about the potential effects of PIs in RA based on reports from animal and human studies. We believe that there is substantial potential in the use of PIs in RA therapy either alone or in combination with the medications already used.

The chronic autoimmune disease rheumatoid arthritis (RA) affects primarily the synovial joints, leading to hip joint deformity and dysfunction manifestations such as acetabular protrusion and joint infection. We present the case of a female patient RA complicated by severe hip arthritis and acetabular protrusion syndrome. The disease progressed rapidly with elevated preoperative inflammatory markers, initially overlooking hip joint infection. The patient underwent total hip arthroplasty, and intraoperative synovial fluid bacterial culture revealed Gram-negative rod bacteria. Aggressive postoperative anti-infective therapy effectively controlled the infection. Therefore, early diagnosis and treatment of infections are particularly important.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent inflammation and joint destruction. Although the roles of inflammatory cytokines and metabolites in RA pathogenesis have caught a lot of attention, there is a lack of systematic studies, and their causal relationships remain unclear.

We conducted a two-step mendelian randomization analysis utilizing genetic data from genome-wide association studies (GWAS) of inflammatory cytokines, metabolites, and RA. The first step assessed the causal effect of 91 inflammatory cytokines and 1400 metabolites on RA risk using inverse variance weighted method, complemented by MR-Egger, weighted median, simple mode and MR-PRESSO to ensure robustness and assess pleiotropy. The second step evaluated the mediation effects of selected metabolites on the relationship between cytokines and RA.

The analysis identified 9 inflammatory cytokines, including IL-1α and IL-10, which significantly increase RA risk, while TNF-β exhibited a protective effect. Additionally, 6 metabolites were associated with increased RA risk, including 1-(1-enyl-palmitoyl)-2-arachidonoyl-GPE and arachidonate (20:4n6). Conversely, 5 metabolites, such as docosatrienoate (22:3n3) and Cholesterol, were found to reduce RA risk. The mediation analysis revealed that TNF-β may exerts its protective effect through its influence on specific metabolites, and X-24949, which accounted for a -2.58% mediated effect in the TNF-β-RA causal pathway.

This study explores the complex interplay between inflammatory cytokines, metabolites, and RA. The findings suggest potential biomarkers for early diagnosis and novel therapeutic targets, particularly those related to lipid metabolites and specific cytokines like TNF-β. Key message What is already known on this topic  Inflammatory factors and metabolites are considered to be related to the onset and progression of RA. What this study adds  We conducted a MR analysis to identify all inflammatory factors and metabolites associated with RA and calculated the mediation effect of inflammatory cytokines on RA through metabolites. This study contributes to a comprehensive understanding of the pathophysiological processes of RA. How this study might affect research, practice or policy  This has laid the groundwork for developing early diagnosis methods and future treatments.

Rheumatoid arthritis (RA) is a systemic inflammatory and autoimmune disorder in which monocytes/macrophage infiltrate synovial membrane, differentiating into the pro- and anti-inflammatory M1 and M2 macrophage phenotypes. Omentin-1 is one of the adipokines that has anti-inflammatory and immunomodulatory effects; nevertheless, investigators have yet to elucidate the function of omentin-1 in RA development. It is still unclear how omentin-1 affects human autoimmune disease and what its beneficial role is. Thus, we show that omentin-1 exhibits a therapeutic effect on RA.

Utilizing patient or animal tissue, MH7A cell-line, ELISA, and qPCR, we examined the expression of omentin-1 and inflammatory cytokines in the GEO databases. Omentin-1's effects on macrophage polarization were investigated using Immunofluorescence staining (IF) and qPCR. Additionally, the method by which omentin-1 regulates interleukins was discovered by IF labeling for STAT6 translocation, siRNA transfection, IPA software using several and pharmacological inhibitors. Omentin-1's effects were examined in an in vivo investigation using the type II collagen-induced arthritis model, micro-CT, and histological evaluation.

Results from the GSE97779 dataset and patients' tissues discovered that the level of omentin-1 and M2 macrophage markers are downregulated in human RA tissue samples compared to healthy tissue and negatively correlated with the expression of pro-inflammatory interleukins (ILs) and M1 macrophage. Stimulation of RA synovial fibroblasts with omentin-1 augmented IL-4 synthesis and subsequently enhanced anti-inflammatory ability as well as M2 polarization. The STAT6 transactivation through AMPK, PI3K, ERK, and JAK cascades regulates omentin-1-induced promotion of IL-4. Importantly, intra-articular injection of omentin-1 blocked collagen-induced arthritis-augmented pro-inflammatory response, cartilage degradation, and bone loss through upregulating IL-4 and M2 macrophages in vivo.

Our findings support a potential therapy goal for RA and a tenable mechanism to explain the relationship between omentin-1.

Background/Objectives: This study aimed to investigate the effectiveness of etanercept biosimilar 1 under real-world clinical conditions in patients with rheumatoid arthritis (RA), using not only clinical evaluation but also musculoskeletal ultrasound (MSUS). Methods: This multicenter, interventional, open-label, single-arm clinical trial conducted a 24-week follow-up. Patients with RA with moderate to high disease activity received weekly subcutaneous injections of etanercept biosimilar 1 at 50 mg/dose for 24 weeks. The effectiveness was evaluated with clinical indices and MSUS. Results: Twenty-three patients were evaluated during the study period. The primary endpoint involves a change in the Global OMERACT-EULAR Synovitis Score by MSUS in bilateral second-fifth metacarpophalangeal joints from baseline, demonstrating median (IQR) values of 0 (-4, 1), including 4 (1, 9.8) and 2 (0, 5) at baseline and 24 weeks, respectively. The clinical endpoints exhibited a good treatment response, with 15 (68%) and 18 (86%) patients achieving low disease activity or remission at 12 weeks and 24 weeks, respectively. Additionally, MSUS scores improved at both 12 and 24 weeks compared to baseline. The patients who achieved power doppler remission (total power doppler score = 0) at 24 weeks demonstrated a shorter disease duration and no previous use of biological disease-modifying antirheumatic drugs compared to those with no power doppler remission. Conclusions: Etanercept biosimilar 1 exhibited significant improvements not only in clinical indices but also in MSUS assessment, indicating its effectiveness at the structural level.

This study aimed to investigate in detail the efficacy of switching from etanercept reference product (RP) to etanercept biosimilar in patients with rheumatoid arthritis (RA) under real-world clinical conditions using clinical indices and musculoskeletal ultrasound (MSUS). This interventional, multicenter, open-label, single-arm clinical trial involved 24- or 52-week follow-up. This study enrolled patients with RA who had been treated with etanercept-RP for ≥ 24 weeks, achieved clinical low disease activity (LDA) or remission, and switched from etanercept-RP to etanercept biosimilar. This study included 20 patients. Of the 17 patients, 16 (94.1%; 95% confidence interval [CI]: 71.3-99.9) remained in LDA/remission on DAS28-ESR at 24 weeks. The dose of 50 mg/week was reduced to 25 mg/week at 24 weeks, and LDA/remission was sustained until 52 weeks in 9 (81.8%, 95% CI: 48.2-97.7] of 11 participants. DAS28-ESR, DAS28-CRP, SDAI, and CDAI scores showed no apparent worsening. The median total PD score remained 0. The switch from etanercept-RP to etanercept biosimilar and subsequent dose reduction demonstrated favorable outcomes, including MSUS evaluation.

Aggregation-induced emission (AIE) offers a promising solution for achieving lower background and more reliable signals in biomedical imaging. AIE materials also exhibiting photostability and resistance to photobleaching. These characters are crucial for monitoring musculoskeletal functions and offering targeted therapies for related diseases. This review compiles research on AIEgens targeting various molecules, cells, or tissues within the musculoskeletal system under physiological or pathological conditions and classifies them according to different clinical applications. A sort of AIEgens is applied in monitoring osteogenic differentiation and bone component analysis. Additionally, AIEgens targeting intra-articular inflammatory or rheumatic related molecules, such as reactive oxygen species, enable early-stage diagnosis and targeted therapies of arthritis. Researchers have also developed novel materials containing AIEgens for joint tissue repair. This review highlights the advantages of these applications while also exploring future demands and development directions in musculoskeletal system imaging and treatment, aiming to promote further design of AIEgens and their clinical applications in musculoskeletal diseases.

To evaluate the cost-effectiveness of longstanding personalized exercise therapy compared with usual care in people with rheumatoid arthritis (RA) and severe functional disability.

In this cost-utility analysis of a randomized controlled trial (n = 215), with 1 year follow-up, the study population comprised individuals with RA and reported severe difficulties in performing basic daily activities. Assessments were at baseline, 12, 26, and 52 weeks, with measurements of costs including medical and non-medical costs as recorded by patients and healthcare providers. Quality-adjusted life-years (QALYs) were estimated using the EuroQol 5 dimensions 5 levels (EQ-5D-5L) and EuroQol Visual Analogue Scale (EQ-VAS). Costs and QALY differences were analysed according to the intention-to-treat principle using cost-effectiveness acceptability curves.

The 1 year societal costs were non-significantly in favour of the usual care group, with a small difference of €180 [95% confidence interval (CI) €-4493 to €4852]. The QALYs were non-significantly in favour of the intervention group, by 0.02 according to the EQ-5D-5L (95% CI -0.05 to 0.09) and by 0.04 according to the EQ-VAS (95% CI 0.00 to 0.08). For a willingness-to-pay threshold of €50 000 per QALY, the intervention was the cost-effective strategy with 60% certainty.

This economic evaluation showed no clear economic preference for either group, as the intervention costs were higher in the intervention group, but partly compensated by other cost savings and improved QALYs. Despite severe RA, patients had better clinical outcomes compared with usual care, suggesting no economic reasons to refrain from exercise therapy.

Netherlands Trial Register NL8235, included in the International Clinical Trial Registry Platform (ICTRP) (https://trialsearch.who.int/Trial2.aspx?TrialID=NL8235).

Rheumatoid arthritis (RA) is a chronic inflammatory disease linked to epigenetic changes, particularly DNA methylation. While LDLRAD4 has been implicated in RA through GWAS, its role in RA via methylation remains unclear.

To investigate LDLRAD4 methylation patterns in RA and evaluate its potential as a diagnostic and inflammatory biomarker.

We assessed DNA methylation at specific CpG sites within LDLRAD4 in 150 RA patients and 150 healthy controls. Clinical data, including disease duration and inflammatory markers, were collected.

RA patients showed significant hypomethylation of LDLRAD4, especially in the LDLRAD4-43 and LDLRAD4-44 regions. ROC analysis yielded an AUC of 0.841, indicating strong diagnostic potential. Methylation levels correlated negatively with ESR, CRP and DAS28 in the RF+/CCP- subgroup.

LDLRAD4 DNA present hypomethylation in rheumatoid arthritis, and methylation levels are correlated with inflammatory indicator, possibly via TGF-β signaling. Further research is needed to explore its therapeutic potential.

Mycobacterium avium subspecies Paratuberculosis (MAP) is a bacterium known to cause Johne's disease in ruminants and has been implicated in several autoimmune diseases. This study aimed to investigate the potential association between MAP infection and Rheumatoid Arthritis (RA).

A total of 119 patients with RA and 120 healthy controls (HCs) were enrolled in the study. The participants were outpatient attendees at a rheumatology specialist's clinic, selected according to the 2010 ACR/EULAR Classification Criteria for RA. Their serum samples were analyzed for antibodies against two peptides, MAP_402718-32 and IRF5424-434, using an indirect enzyme-linked immunosorbent assay (ELISA).

A significant difference was found in the levels of anti-MAP antibodies between RA patients and HCs. RA patients were more likely to have anti-MAP_402718-32 antibodies (44.5%) vs. 10.8% in HCs. Among RA patients, treatment group patients had more antibodies (51.6%) against MAP_402718-32 than no-treatment group patients (36.4%), but this difference was not statistically significant. The antigen IRF5424-434 showed the highest antibody seroreactivity, being present in a higher percentage of RA patients (60.5%) compared to HCs (8.3%). This difference was statistically significant. There was a moderate correlation between IRF5424-434 and its MAP_402718-32 homolog.

The study findings suggest that anti-MAP antibodies are more prevalent in RA patients compared to healthy controls, potentially implicating MAP in the development of RA. The strong immunological response to the antigen IRF5424-434 warrants further investigation. Although the difference in antibody levels between previously diagnosed and newly diagnosed RA patients was not statistically significant, the overall higher prevalence of these antibodies in the RA cohort supports the hypothesis of MAP's involvement.

Background: Rheumatoid arthritis (RA) is a globally prevalent chronic inflammatory disease. Environmental exposures, such as air pollution and smoking, are considered potential risk factors. However, the causal relationships and underlying mechanisms between these factors and RA are not fully understood. Methods: This study utilized large-scale genome-wide association studies (GWASs) from European ethnic backgrounds and employed bidirectional two-sample Mendelian randomization (MR) to investigate the relationships between air pollution, smoking, and RA. Genetic correlations were assessed using linkage disequilibrium score regression (LDSC). Furthermore, mediation analysis was conducted to evaluate the potential mediating roles of iron metabolism and urinary biomarkers in these relationships. Results: The MR analysis revealed that genetically predicted lifetime smoking intensity was associated with an 85% increased risk of RA. Subgroup analysis differentiating between seropositive RA (SPRA) and seronegative RA (SNRA) showed a causal association with SPRA, but not with SNRA. C-reactive protein was identified as a mediator in the relationship between lifetime smoking and both RA and SPRA, mediating 18.23% and 32.45% of the effects, respectively. Genetic correlation analysis further confirmed a positive genetic association between smoking and both RA and SPRA. Conclusions: This study provides significant insights into the genetic and causal connections between air pollution, smoking, and the development of RA, highlighting the mediating role of C-reactive protein. These findings not only offer new perspectives on how smoking might enhance RA risk through inflammatory pathways but also underscore the importance of reducing smoking exposure in public health strategies.

Genistein (GEN), the predominant soy isoflavone in legumes, exhibits potential anti-rheumatoid arthritis (RA) effects. This study aims to explore the role of GEN in alleviating RA by regulating exosome secretion and the inflammatory microenvironment through the Rab27/nSMase2/Mfge8 pathway in collagen-induced arthritis (CIA) mice and in vitro. In vivo studies revealed that GEN treatment significantly reduced paw swelling in CIA mice and protected the integrity of knee and ankle joints in CIA mice. GEN supplementation caused a significant decrease in the levels of MMP-9 and pro-inflammatory factors TNF-α, IL-1β and IL-6. GEN also significantly diminished the expressions of β-catenin and exosomal Dvl3 and miR-221-3p in fibroblast-like synoviocytes (FLS). Molecular docking results showed that GEN had strong binding energy with Rab27a, nSMase2 and Mfge8, the key regulators of exosome secretion, respectively, which was confirmed by CETSA and DARTS detection. In vitro mechanism analysis demonstrated that GEN treatment simultaneously downregulated the expression of Rab27a, nSMase2 and Mfge8, and phenotypic analysis verified that GEN prevented the secretion of Alix+Hsp70+CD63+ exosomes induced by type II collagen (CII) from FLS. Further analysis showed that GEN inhibited the expression of the Wnt signaling pathway protein β-catenin and exosomal Dvl3 in FLS. Additionally, GEN inhibited CII-induced secretion of MMP-9 and TNF-α, IL-1β and IL-6 in FLS, and GEN also significantly inhibited CII-induced FLS migration. Notably, GEN inhibited the expression of miR-221-3p in FLS exosomes and enhanced osteoblast differentiation and mineralization in vitro. Collectively, this study clarified that GEN alleviates RA by inhibiting the secretion of FLS exosomes regulated by the Rab27/nSMase2/Mfge8 pathway and by inhibiting Dvl3/β-catenin and miR-221-3p.