Int J Rheum Dis
· 2026 Feb · PMID 41641559
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OBJECTIVE: Systemic sclerosis (SSc) is a rare autoimmune disease with high mortality, often due to cardiopulmonary complications. Hydroxychloroquine (HCQ), commonly used in other rheumatic diseases, has immunomodulatory...OBJECTIVE: Systemic sclerosis (SSc) is a rare autoimmune disease with high mortality, often due to cardiopulmonary complications. Hydroxychloroquine (HCQ), commonly used in other rheumatic diseases, has immunomodulatory and potentially cardioprotective effects, but its role in SSc remains unclear. This study aimed to evaluate the association between HCQ use and the risk of mortality, ischemic heart disease (IHD), and pulmonary hypertension (PH) in a large real-world SSc cohort. METHODS: This retrospective cohort study utilized de-identified electronic medical records from the TriNetX Research network. Adults with an SSc diagnosis (ICD-10-CM: M34) were divided into HCQ users and non-users. After 1:1 propensity score matching for demographics, comorbidities and medications, outcomes including mortality, PH, acute myocardial infarction (MI), cerebral infarction, conduction heart disease, and myocarditis were assessed over 5 years. Risk ratios (RR) and Kaplan-Meier hazard ratios were calculated. RESULTS: Out of 17 395 HCQ users and 58 576 non-users, 15 485 propensity score matched pairs were analyzed. Over 5 years, HCQ users showed higher PH (RR 1.124, 95% CI, 1.052-1.200, p < 0.001) but lower mortality (RR 0.719, 95% CI, 0.674-0.767, p < 0.001), indicating potential survival benefits. No significant differences were observed for IHD, MI, cerebral infarction, conduction disorders, or myocarditis. CONCLUSION: Our research indicated that although patients on HCQ had a higher prevalence of PH, they exhibited lower mortality rates, suggesting a possible survival benefit. Further prospective studies are needed to explore these findings and clarify HCQ's role in SSC management.
Zhang X, Yang S, Li J
… +3 more, Mao J, Ma J, Shen H
Int J Rheum Dis
· 2026 Feb · PMID 41626711
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INTRODUCTION: Neutrophil extracellular traps (NETs) significantly contribute to rheumatoid arthritis (RA) pathogenesis, though their exact mechanisms remain unclear. In this research, we explored how NETs influence RA de...INTRODUCTION: Neutrophil extracellular traps (NETs) significantly contribute to rheumatoid arthritis (RA) pathogenesis, though their exact mechanisms remain unclear. In this research, we explored how NETs influence RA development through the PANoptosis core molecule AIM2. METHODS: Enzyme-linked immunosorbent assay and Quant-iT Pico Green measured AIM2 and cell-free DNA (cfDNA) levels in synovial fluid. Immunohistochemistry examined the levels of AIM2 in synovial tissues. In vitro, the CCK-8 assay evaluated cell proliferation. Western blot detected the expression changes of AIM2, PANoptosis-related proteins, and NF-κB pathway-related proteins. Real-time quantitative PCR measured mRNA levels of IL-1β, IL-18, and IL-6. Immunofluorescence quantified AIM2, Caspase-8, GSDMD, and p-MLKL fluorescence intensity and cfDNA/AIM2 co-localization. An AIM2-silenced cell model was established to examine changes in the AIM2, PANoptosis-related proteins, and NF-κB pathway-related proteins (Western blot), fluorescence intensity (IF), inflammatory cytokine transcription (RT-qPCR), and RA-FLS migration (scratch and transwell assays). RESULTS: Our results showed an increase in AIM2 expression in RA synovial fluid and tissues, which correlates with both cfDNA high levels and clinical disease activity scores. In vitro, in RA fibroblast-like synoviocytes (RA-FLSs), NETs elevated AIM2 and PANoptosis-related protein levels, activated the NF-κB signaling pathway, and enhanced the release of inflammatory cytokines. Treatment with DNase1 and AIM2 silencing resulted in lower levels of PANoptosis proteins and AIM2, inhibited NF-κB signaling, and decreased cytokine production. CONCLUSION: This is the first time exploring the pathogenic mechanism of NETs-induced PANoptosis in RA, and targeting AIM2 may represent a potential new therapeutic approach for RA.
Cao G, Wu Z, Du Y
… +4 more, Dai D, Sun Y, Jia X, Cai H
Int J Rheum Dis
· 2026 Feb · PMID 41607310
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INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disorder with unclear molecular mechanisms, complicating early diagnosis and treatment. This study aimed to identify hub genes and pathways driving RA patho...INTRODUCTION: Rheumatoid arthritis (RA) is a chronic autoimmune disorder with unclear molecular mechanisms, complicating early diagnosis and treatment. This study aimed to identify hub genes and pathways driving RA pathogenesis and assess their therapeutic potential. METHODS: Gene expression datasets related to RA were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and analyzed by functional enrichment and protein-protein interaction network construction. Machine learning approaches, including LASSO regression, random forest, and SVM-RFE, were used to screen hub genes. Pathway associations were explored using Gene Set Enrichment Analysis (GSEA). Experimental validation was performed in collagen-induced arthritis (CIA) rat models and MH7A synovial fibroblast cells through Western blot and functional assays. RESULTS: A total of 106 DEGs were identified in RA synovial tissues, including 76 upregulated and 30 downregulated genes. Enrichment analyses revealed involvement in cytokine-cytokine receptor interaction, lymphocyte-mediated immunity, and immunoglobulin complexes. SDC1 emerged as a key hub gene across all three machine learning methods. GSEA indicated its significant correlation with the JAK-STAT pathway. In CIA rats, SDC1 expression was markedly elevated alongside p-JAK2 and p-STAT3 levels. Silencing SDC1 in MH7A cells reduced cell proliferation, decreased p-JAK2 and p-STAT3 expression, and promoted apoptosis. CONCLUSIONS: This study identifies SDC1 as a central hub gene in RA pathogenesis through activation of the JAK2-STAT3 signaling pathway. These findings highlight SDC1 as a potential biomarker for early diagnosis and a promising target for therapeutic intervention, providing new insights into RA management.
Int J Rheum Dis
· 2026 Feb · PMID 41603146
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OBJECTIVE: To evaluate the clinical characteristics, disease burden, and treatment patterns of axial spondyloarthritis (axSpA) using the recently proposed Assessment of Spondyloarthritis International Society (ASAS) defi...OBJECTIVE: To evaluate the clinical characteristics, disease burden, and treatment patterns of axial spondyloarthritis (axSpA) using the recently proposed Assessment of Spondyloarthritis International Society (ASAS) definition of difficult-to-manage axSpA (D2M-axSpA). METHODS: A total of 383 patients with axSpA were enrolled. This multicenter cross-sectional study was conducted in three tertiary care centers, enrolling consecutive axSpA patients from outpatient clinics. Patients were classified as D2M-axSpA based on prior use of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) and persistent disease activity based on the ASAS definition. Logistic regression analysis identified factors associated with D2M-axSpA. RESULTS: Among patients, 11.2% met the D2M-axSpA criteria. The cohort was 58.7% male, with a mean age of 43.5 ± 10.5 years. Radiographic axSpA was present in 70.8%, and 69.2% of patients had received biological therapy. D2M-axSpA patients exhibited higher inflammatory markers (ESR, CRP), increased disease activity (BASDAI, ASDAS-CRP), and greater functional impairment (BASFI, ASQoL). Peripheral arthritis (p = 0.001), enthesitis (p = 0.031), smoking history (p = 0.037), and comorbidities (p = 0.020) were significantly more frequent in D2M-axSpA. Among D2M-axSpA patients, 22/383 (5.7%) fulfilled the treatment-refractory criteria. Radiographic findings revealed higher rates of sacroiliac ankylosis, lumbar syndesmophytes, symphysitis, and ischial enthesitis, as well as mSASSS scores. Logistic regression identified anterior uveitis (OR: 4.474, p = 0.007), peripheral arthritis (OR: 2.684, p = 0.021), and comorbidities (OR: 2.878, p = 0.013) as independently associated factors. CONCLUSION: Findings highlight the clinical and radiographic burden of D2M-axSpA and emphasize the need for optimized treatment strategies, particularly in patients with comorbidities, a history of anterior uveitis or peripheral arthritis, and those with a smoking history.
Huang C, Fan H, Zheng Z
… +12 more, Ma W, Wei Z, Han H, Liang A, Mu X, Zou W, Hao J, Liu F, Liu L, Liu S, Zhao L, Wu Z
Int J Rheum Dis
· 2026 Feb · PMID 41603078
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OBJECTIVE: Recent studies suggest that immune cells and plasma metabolites may play significant roles in osteoarthritis pathogenesis. However, the causal relationships between these factors and osteoarthritis are unclear...OBJECTIVE: Recent studies suggest that immune cells and plasma metabolites may play significant roles in osteoarthritis pathogenesis. However, the causal relationships between these factors and osteoarthritis are unclear. METHODS: Based on the genome-wide association study (GWAS) database, 731 immune cell phenotypes and 1400 metabolites were evaluated for their possible mediating effects on osteoarthritis via two-step Mendelian randomization (MR). Sensitivity analyses were conducted to assess the robustness of our findings. RESULTS: Our findings revealed that 17 immune cell phenotypes were positively associated with osteoarthritis, suggesting their potential as risk factors. Conversely, 23 immune cell phenotypes exhibited a negative association, indicating possible protective roles against osteoarthritis. Furthermore, we identified 51 metabolites as potential risk factors for osteoarthritis. Conversely, 34 metabolites were deemed protective factors. Notably, 49 plasma metabolites partially mediated the relationship between 35 immune cell phenotypes and osteoarthritis, with leucine levels showing the highest mediation proportion (19.3%) between HLA DR+ CD4+ %lymphocytes and osteoarthritis. CONCLUSION: Our study revealed a substantial impact of specific immune cell phenotypes and plasma metabolites on the progression of osteoarthritis, enhancing the understanding of the complex interplay between immunity and metabolism in osteoarthritis pathogenesis. Further research is necessary to clarify the underlying mechanisms driving these associations.
Ogata Y, Bamba M, Bamba K
… +2 more, Hisada R, Nakamura H
Int J Rheum Dis
· 2026 Jan · PMID 41572965
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AIM: Bucillamine is a conventional synthetic disease-modifying antirheumatic drug that can be used as a methotrexate alternative. However, which patients with rheumatoid arthritis can benefit from bucillamine treatment h...AIM: Bucillamine is a conventional synthetic disease-modifying antirheumatic drug that can be used as a methotrexate alternative. However, which patients with rheumatoid arthritis can benefit from bucillamine treatment has not been established. METHODS: Patients who had taken bucillamine and discontinued it in 2021 due to a nationwide supply shortage were included in this study. We followed up these patients regarding arthritis exacerbation after bucillamine discontinuation until March 2025. Baseline clinical patient characteristics were compared between the exacerbation and non-exacerbation groups. RESULTS: Thirteen of the 18 patients experienced arthritis exacerbation, whereas five remained exacerbation-free for up to 48 months. The baseline rheumatoid factor levels were significantly higher in the exacerbation group (49 U/mL) than in the non-exacerbation group (6 U/mL). Receiver operating characteristic and Kaplan-Meier analyses showed that baseline RF levels ≥ 28 U/mL predicted arthritis exacerbation after bucillamine discontinuation (sensitivity 76.2% and specificity 80.0%). CONCLUSION: Following bucillamine discontinuation, arthritis exacerbations occurred more frequently in patients with rheumatoid factor levels of 28 U/mL or higher, alongside an increase in these levels. Rheumatoid factor levels may serve as a useful biomarker for identifying patients who would benefit from continued bucillamine therapy.
Int J Rheum Dis
· 2026 Jan · PMID 41566632
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Osteoarthritis (OA) is a degenerative joint disease driven by complex biomechanical and inflammatory mechanisms, particularly in weight-bearing joints such as the knee. This review explores the pivotal role of biomechani...Osteoarthritis (OA) is a degenerative joint disease driven by complex biomechanical and inflammatory mechanisms, particularly in weight-bearing joints such as the knee. This review explores the pivotal role of biomechanics in OA pathogenesis, focusing on abnormal joint loading, malalignment, and instability as key contributors to cartilage degeneration and subchondral bone remodeling. Special attention is given to the interplay between obesity and OA, highlighting how mechanical overload and adipokine-mediated inflammation synergistically accelerate disease progression. Emerging interventions-including physical therapy, gait retraining, orthotics, high tibial osteotomy (HTO), and total knee arthroplasty (TKA)-are analyzed for their biomechanical impact. Novel technologies such as wearable sensors, finite element analysis (FEA), and digital twin models are discussed as tools for real-time assessment, predictive modeling, and personalized treatment planning. The review emphasizes the need for integrated, multiscale research strategies that account for individual biomechanical profiles and systemic factors like obesity. Advancing biomechanical precision in OA management holds promise for improving early diagnosis, optimizing interventions, and informing regenerative therapies aimed at restoring joint function and delaying disease progression.
Chen H, Dang Q, Shi Y
… +13 more, Hunter DJ, Wang X, Yang H, Si L, Duong V, Zhang M, Wang Z, Cao P, Cen H, Tang S, Ding C, Zhu Z, Liu Y
Int J Rheum Dis
· 2026 Jan · PMID 41555656
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AIM: Using data from the Global Burden of Disease (GBD) Study 2021, this study aims to estimate the comorbidity burdens of osteoarthritis (OA) at global, regional, and national levels from 1990 to 2021. METHODS: The age-...AIM: Using data from the Global Burden of Disease (GBD) Study 2021, this study aims to estimate the comorbidity burdens of osteoarthritis (OA) at global, regional, and national levels from 1990 to 2021. METHODS: The age-standardized prevalence and years lived with disability (YLD) rate for OA and 174 other Level-3 diseases from 204 countries and territories were extracted. A modified formula was employed to determine the comorbidity burdens for the co-occurrence of OA and one of the other 174 diseases. Cluster analysis was performed to identify different patterns in the comorbidity burden. RESULTS: Globally, the top three comorbidity burdens for OA in 2021 were from oral disorders, headache disorders, and age-related and other hearing loss (age-standardized comorbidity YLD rates 130.80/100 000, 124.09/100 000, and 79.54/100 000, respectively). From 1990 to 2021, the age-standardized comorbidity YLD rates for diabetes mellitus exhibited the greatest increases, with percentage changes of 108.41%. In high socio-demographic index (SDI) regions, the leading comorbidity burdens for OA were from headache disorders, oral disorders, and low back pain, whereas in low SDI regions, they were oral disorders, dietary iron deficiency, and headache disorders. Six clusters were identified, including oral disorders and headache disorders in the highest comorbidity burden with a mild changing cluster, and diabetes mellitus in the high comorbidity burden with a rapid growth cluster. CONCLUSIONS: The comorbidity burdens of OA have increased and show different patterns. These findings underscore the importance of addressing the comorbidity burdens in conjunction with tackling the OA burden.