Arthritis & Rheumatology最新文献

{"title":"Machine Learning to Predict Remission Between 6 and 24 Months in Rheumatoid Arthritis: Insights From JAK, an International Registry Collaboration","authors":"Zubeyir Salis PhD,&nbsp;Denis Mongin PhD,&nbsp;Denis Choquette MD,&nbsp;Louis Coupal MD,&nbsp;Catalin Codreanu MD, PhD,&nbsp;Florenzo Iannone MD, PhD,&nbsp;Roberto Caporali MD,&nbsp;Tore K. Kvien MD, PhD,&nbsp;Sella Provan MD, PhD,&nbsp;Ruth Fritsch-Stork MD, PhD,&nbsp;Dan Nordström MD, PhD,&nbsp;Nina Trokovic PhD,&nbsp;Karel Pavelka MD, PhD,&nbsp;Jakub Závada MD, PhD,&nbsp;Ana Rodrigues MD, PhD,&nbsp;Ziga Rotar MD, PhD,&nbsp;Prodromos Sidiropoulos MD, PhD,&nbsp;Irini Flouri MD, PhD,&nbsp;Céline Lamacchia PhD,&nbsp;Michele Iudici MD, PhD, MPH,&nbsp;Delphine Courvoisier PhD,&nbsp;Kim Lauper MD, PhD,&nbsp;Axel Finckh MD, MS, MPH","doi":"10.1002/art.70165","DOIUrl":"10.1002/art.70165","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To develop, externally validate, and simplify a machine learning model to predict remission between 6 and 24 months in patients with rheumatoid arthritis (RA) initiating tumor necrosis factor inhibitors, JAK inhibitors, interleukin-6 inhibitors, abatacept, or rituximab using data from 11 international registries in the JAK-pot collaboration.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 21,675 treatment courses for model training, 5,418 courses for internal validation, and 1,807 courses from Switzerland for external validation. Remission was defined as a Clinical Disease Activity Index score ≤2.8 within 6 to 24 months after treatment initiation or switching. An XGBoost model was trained on 63 baseline demographic and clinical variables. Model performance was evaluated using the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Predictor contributions were quantified using Shapley Additive Explanations values. A simplified model using the top 10 predictors and a logistic regression benchmark were also evaluated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In external validation, the full model achieved an AUC of 0.797 (95% confidence interval 0.774–0.821), sensitivity of 0.804, specificity of 0.650, PPV of 0.454, and NPV of 0.902. The simplified model performed comparably (AUC 0.802). Logistic regression using the same 10 predictors achieved an AUC of 0.809. Key predictors included patient global assessment, 28-tender joint count, previous biologic/targeted synthetic disease-modifying antirheumatic drug exposure, and Health Assessment Questionnaire Disability Index score.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Using routinely collected baseline data across 11 registries, prediction of remission showed limited discrimination and was best suited to ruling out remission. Performance was similar for a 10-variable model and logistic regression, indicating limited incremental value of model complexity without richer predictors.</p>\u0000 \u0000 <div>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":"2232-2245"},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.70165","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147619481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Novel Noncoding Genetic Variants of Serum Urate Using Whole-Genome Sequencing in 7,339 Chinese Participants","authors":"Qilong Tan PhD,&nbsp;Hanyi Zhou BSc,&nbsp;Junlin Jia MSc,&nbsp;Jiameng Cui MSc,&nbsp;Liyang Sun MBBS,&nbsp;Weifang Zheng MBBS,&nbsp;Huakang Tu PhD,&nbsp;Xiaohang Xu PhD,&nbsp;Mengying Wang PhD,&nbsp;Dan Zhou PhD,&nbsp;Wenyuan Li ScD,&nbsp;Xifeng Wu MD, PhD","doi":"10.1002/art.70150","DOIUrl":"10.1002/art.70150","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate the genetic architecture of low-frequency and rare variants of serum urate (SU) in East Asian populations, and to clarify its role as a heritable and modifiable risk factor for gout and cardiometabolic diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted the largest two-stage, whole-genome sequencing–based, genome-wide scan for SU levels in East Asians, analyzing 9.1 million variants across 7,339 Han Chinese participants from the Healthy Zhejiang One Million People (HOPE) cohort.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We verified associations at common and low-frequency loci and identified a novel, replicable male-specific locus at <i>MAN1A2</i>, along with a candidate low-frequency male-specific locus at <i>CPE</i>. Furthermore, using the STAARpipeline framework, we probed rare missense and putative loss-of-function variant aggregates in genes such as <i>SLC22A12</i>, <i>SLC2A9</i>, and <i>G6PC2</i>, which were validated in our replication data set or the UK Biobank. Moreover, we identified and replicated novel associations with rare promoter variants near <i>HDC</i> and <i>SLC22A12</i>, highlighting their potential role in the context of noncoding regulation. Additionally, deep learning–based fine-mapping revealed transcription factors such as HNF1A, RUNX1, and SRF as potential up-regulators of SU-associated genes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>By resolving East Asian–specific allelic architecture and revealing ancestral diversity in SU genetics, this study advanced translational opportunities for precision urate-lowering therapies and prioritized novel candidates for future research.</p>\u0000 </section>\u0000 </div>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":"2351-2364"},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147502158","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Metabolic Dysregulation on Macrophage Polarization in Rheumatoid Arthritis","authors":"Xinyue Zhang MSc,&nbsp;Xiaoyue Deng MD, PhD,&nbsp;Shixiong Wei MD, PhD,&nbsp;Mengtao Li MD, PhD,&nbsp;Xiaofeng Zeng MD, PhD","doi":"10.1002/art.70253","DOIUrl":"10.1002/art.70253","url":null,"abstract":"<p>Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by complex immune dysregulation in which macrophages play a central pathogenic role. Macrophages accumulate extensively in RA synovium, and their abundance and functional phenotypes are correlated with disease activity and severity. Disturbed macrophage polarization is a key feature of RA progression, characterized by an increased proportion of classically activated (M1) macrophages and a reduced proportion of alternatively activated (M2) macrophages. M1 macrophages produce proinflammatory mediators that sustain synovial inflammation and contribute to progressive joint damage. Accumulating evidence indicates that immune cell functions are closely linked to metabolic programs. The synovial microenvironment in RA is marked by hypoxia, acidosis, and nutrient limitation, which lead to substantial metabolic reprogramming during macrophage polarization. Importantly, metabolic changes occur not merely secondary to polarization but actively shape the phenotypic transition of macrophages. In this review, we summarize the current evidence on how dysregulation of glucose, lipid, and amino acid metabolism regulates the phenotype switching of macrophages in RA. We discuss the roles of key metabolic enzymes and intermediates in macrophage polarization, consider the diagnostic potential of metabolic biomarkers, and highlight therapeutic opportunities targeting metabolic pathways, thereby resolving macrophage imbalance and improving RA outcomes.</p><p>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":"2203-2220"},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skin Transcriptomics Reveal Shared Molecular Mechanisms for Skin and Lung Involvement in Systemic Sclerosis","authors":"Jana Zielonka MD, MHS,&nbsp;Ningshan Li PhD,&nbsp;Yunqing Liu PhD,&nbsp;Xiting Yan PhD,&nbsp;Zuoheng Wang PhD,&nbsp;Maria Ramirez MD,&nbsp;Andres Figueroa MD,&nbsp;Asawari Korde MSc, PhD,&nbsp;Hill Yin MS,&nbsp;Clemente Britto MD,&nbsp;Inderjit Singh MBChB,&nbsp;Huanxing Sun PhD,&nbsp;Erica Herzog MD, PhD,&nbsp;Carol Feghali-Bostwick PhD,&nbsp;Monique Hinchcliff MD, MS,&nbsp;Changwan Ryu MD, MPH,&nbsp;Jose L. Gomez MD, MS","doi":"10.1002/art.70163","DOIUrl":"10.1002/art.70163","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Systemic sclerosis (SSc) is characterized by dysregulated immunity, microvascular damage, and progressive fibrosis. SSc-related interstitial lung disease (SSc-ILD) is the leading disease-specific cause of death; it is therefore important to identify biomarkers associated with SSc-ILD. We hypothesized that the skin transcriptome would provide mechanistic clues that could further our understanding of lung impairment in SSc-ILD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a multistage analysis of SSc transcriptomes using weighted gene correlation analysis, gene set enrichment analysis, and single-cell RNA sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified seven modules correlated with skin and lung function involvement. Unsupervised clustering of these genes classified patients into two groups, one of which showed severe multiorgan involvement characterized by increased skin fibrosis and decreased lung function (<i>P</i> &lt; 0.05). The KRAS pathway was enriched in the severe cluster. Deconvolution of the severe cutaneous signature in SSc skin and lungs showed increased expression in stromal cells and monocytes, whereas the KRAS pathway was enriched in stromal cells only. Profiling KRAS and downstream signaling in lungs from individuals with SSc-ILD demonstrated activation of these pathways (<i>P</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We found a severe cutaneous transcriptomic signature of SSc associated with multiorgan involvement. By deconvoluting the severe cutaneous signature, we have identified pathways enriched in specific cell types, including KRAS in stromal cells and a combination of stromal and immune cells in the severe signature. The severe SSc signature can provide a framework for understanding shared mechanisms in skin and lung fibrosis and may help identify additional molecular pathways.</p>\u0000 </section>\u0000 </div>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":"2328-2340"},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147599213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nerve Growth Factor is Sufficient to Cause Multiple Osteoarthritis-Relevant Pathologic Features in Naïve Murine Knee Joints","authors":"Alia M. Obeidat PhD,&nbsp;Michael D. Newton PhD,&nbsp;Jun Li MD,&nbsp;Baofeng Hu MD,&nbsp;Shingo Ishihara PhD,&nbsp;Lindsey Lammlin PhD,&nbsp;Lucas M. Junginger BS, MBA,&nbsp;Easton C. Farrell MSE,&nbsp;Lai Wang PhD,&nbsp;Frank C. Ko PhD,&nbsp;Richard J. Miller PhD,&nbsp;Carla R. Scanzello MD, PhD,&nbsp;Tristan Maerz PhD,&nbsp;Rachel E. Miller PhD,&nbsp;Anne-Marie Malfait MD, PhD","doi":"10.1002/art.70168","DOIUrl":"10.1002/art.70168","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Nerve growth factor (NGF), a key mediator of pain, is increased in osteoarthritic (OA) joints. Antibodies against NGF show analgesic effects in painful knee OA, but clinical development was stopped because of side effects in the joints. Knowledge about the biologic effects of NGF on joint tissues is limited. Therefore, we explored the effects of repeated intra-articular (IA) injections of NGF into naïve murine knee joints on sensitization, joint innervation, and histopathology.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Naïve 10- to 15-week-old male wildtype C57BL/6 mice were injected with NGF (50 or 500 ng) or vehicle IA twice a week for four weeks, and effects on knee swelling, knee hyperalgesia, joint histopathology, and bone were assessed. Single cell RNA sequencing (scRNAseq) of the synovium was performed. Na_V1.8-tdTomato reporter mice were used to assess joint innervation. Dorsal root ganglia (DRGs) of mice underwent bulk RNAseq after three IA injections of NGF or vehicle.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with vehicle, repeated IA injections of NGF caused dose-dependent increases in knee swelling, knee hyperalgesia, synovial pathology, bone mineral density in the medial subchondral bone, and medial preosteophytes, but no overt cartilage damage. NGF caused increased sprouting of nociceptors in the medial synovium that was preceded by up-regulation of axonal growth pathways in the DRGs. ScRNAseq of the synovium revealed up-regulated genes related to neuronal sprouting, synovial fibrosis, and ossification, with a key role for lining fibroblasts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In naïve mouse knees, NGF induced many pathologic changes observed in OA, including nociceptor sprouting, suggesting a critical role for NGF in OA pathogenesis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":"2246-2260"},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.70168","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T Cell Plasticity in Systemic Lupus Erythematosus Revealed by Large-Scale T Cell Receptor Repertoire and Transcriptome Studies","authors":"Yasuo Nagafuchi MD, PhD,&nbsp;Masahiro Nakano MD, PhD,&nbsp;Kaitlyn A. Lagattuta MD, PhD,&nbsp;Mineto Ota MD, PhD,&nbsp;Hiroaki Hatano MD, PhD,&nbsp;Haruka Takahashi MD, PhD,&nbsp;Takahiro Itamiya MD, PhD,&nbsp;Hajime Inokuchi MD,&nbsp;Soumya Raychaudhuri MD, PhD,&nbsp;Tomohisa Okamura MD, PhD,&nbsp;Keishi Fujio MD, PhD,&nbsp;Kazuyoshi Ishigaki MD, PhD","doi":"10.1002/art.70218","DOIUrl":"10.1002/art.70218","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We aimed to characterize CD4⁺ T cell plasticity in human systemic lupus erythematosus (SLE) by leveraging T cell receptor (TCR) repertoire features as markers of prior lineage states, integrating TCR and transcriptomic profiling to delineate plasticity patterns and evaluate their association with clinical disease activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used TCR repertoire data as molecular signatures alongside a transcriptomic data set. Using a large-scale ImmuNexUT database of patients with autoimmune disease, including 117 with SLE, we quantified T cell plasticity across 13 fine-grained T cell types. We analyzed 6,392 samples in total. We defined “cell type” and “disease” signatures and evaluated plasticity by correlations between these signatures and by within-donor TCR clonotype overlap. Replication was performed in independent bulk and single-cell cohorts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We identified two orthogonal signatures of the repertoire and transcriptome, the cell type and disease signatures, allowing us to investigate CD4⁺ T cell plasticity comprehensively. Among all possible patterns, the strongest signal was observed between effector Treg cells (eTreg cells) and Th1 cells, and this was replicated in an independent cohort. SLE Th1 cells exhibited Treg-like TCR features and transcriptomic profiles, and eTreg cells showed increased clonotype sharing with Th1 cells compared with healthy controls. The Th1 “Tregness” score positively correlated with SLE disease activity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our study identifies a Treg-associated Th1 state in human SLE, consistent with Treg cell to Th1 cell plasticity.</p>\u0000 \u0000 <div>\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </div>\u0000 </section>\u0000 </div>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":"2292-2304"},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.70218","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147831430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Connections","authors":"","doi":"10.1002/art.70369","DOIUrl":"10.1002/art.70369","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":""},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/art.70369","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149251150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-Grade Proteinuria in Lupus Nephritis: Why “Mild” Is Often Misleading","authors":"Ana Malvar MD,&nbsp;Valeria Alberton MD,&nbsp;Brad H. Rovin MD","doi":"10.1002/art.70227","DOIUrl":"10.1002/art.70227","url":null,"abstract":"","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":"78 11","pages":"2183-2185"},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147979678","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The secretome of UC-MSC reprogrammed to a glycolytic metabolism promotes Treg generation and naive CD4 T cells stability in PBMC from rheumatoid arthritis patients.","authors":"Noymar Luque-Campos, Carolina Pradenas, Eliana Lara-Barba, Yesenia Flores-Elías, Bruno Torres-Gonzalez, Francisca Troncoso, Yeimi Herrera-Luna, Felipe A Bustamante-Barrientos, Constanza Aros-Valdivia, María Jesus Araya-Sapag, Cesar Merino-Flores, Bianca Bustamante, Guilhem Graveron, Jonathan Morales-Reyes, Alexander Ortloff, Pablo Cruz, Alvaro A Elorza, Andrea Matamoros, Karina Oyarce, Claudia Altamirano, Ana María Vega-Letter, Francisco Espinoza, Catalina Infante, Mauricio Quezada-Diez, María Paz Hernandez-Cáceres, Rafael Contreras-Lopez, Yves-Marie Pers, Yessia Hidalgo-Fadic, Roberto Elizondo-Vega, Farida Djouad, Patricia Luz-Crawford","doi":"10.1002/art.70382","DOIUrl":"https://doi.org/10.1002/art.70382","url":null,"abstract":"<p><strong>Objective: </strong>Rheumatoid arthritis (RA) is characterized by persistent inflammation and dysregulated T cell responses. Mesenchymal stromal cells (MSCs) have immunomodulatory properties, but their clinical efficacy remains variable. We investigated whether metabolic reprogramming of umbilical cord-derived MSCs (UC-MSCs) toward glycolysis enhances their immunoregulatory function and the underlying mechanisms.</p><p><strong>Methods: </strong>UC-MSCs were reprogrammed toward glycolysis by pharmacologic inhibition of oxidative phosphorylation using oligomycin. Their immunomodulatory capacity was assessed in coculture with activated peripheral blood mononuclear cells (PBMCs) from 21 RA patients under direct-contact and conditioned-medium conditions. T cell proliferation, phenotype, and cell cycle were analyzed by flow cytometry. Anti-inflammatory effects were evaluated in a delayed-type hypersensitivity (DTH) murine model, and the contribution of the UC-MSC secretome and its protein fraction was investigated.</p><p><strong>Results: </strong>Glycolysis-reprogrammed UC-MSCs exhibited enhanced immunosuppressive activity compared with unmodified UC-MSCs, suppressing proinflammatory T cell responses, promoting Treg expansion, and preserving CD4⁺CD45RA⁺ naïve T cells. These effects were associated with T cell cycle arrest in G0. Conditioned-medium experiments showed that these effects were largely mediated by the MSC secretome, increasing Treg frequency from 16.5% to 30.2% and enriching the CD4⁺CD45RA⁺ naïve T-cell compartment from 9.7% to 29.1%, with the protein fraction accounting for most of this immunomodulatory activity. In vivo, the >3 kDa protein-enriched fraction attenuated DTH-associated inflammation and promoted an anti-inflammatory immune response.</p><p><strong>Conclusion: </strong>Metabolic reprogramming of UC-MSCs toward glycolysis enhances their immunomodulatory capacity through secretome-dependent mechanisms, primarily mediated by proteins within the >3 kDa fraction, supporting metabolism-based and cell-free strategies for MSC-based therapy in RA.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Risks of Mortality and Fractures in Patients With Osteoarthritis Initiating Tramadol Versus Other Opioids.","authors":"Sushama Kattinakere Sreedharas, Sungho Bea, Krista F Huybrechts, Nazleen F Khan, Jeffrey N Katz, Shruti Belitkar, Angela Y Tong, Katsiaryna Bykov","doi":"10.1002/art.70383","DOIUrl":"10.1002/art.70383","url":null,"abstract":"<p><strong>Objective: </strong>Tramadol is commonly used to manage pain in patients with osteoarthritis, but its comparative safety in this population remains largely unknown. The study aimed to evaluate the risks of all-cause mortality and fracture among patients with osteoarthritis initiating tramadol versus other prescribed opioids.</p><p><strong>Methods: </strong>We conducted a retrospective cohort study using Optum Clinformatics Data Mart (2005-2021). Adults aged ≥50 years with osteoarthritis initiating tramadol, codeine, hydrocodone, or oxycodone were included. Outcomes were all-cause mortality and fractures. Propensity score weighting balanced baseline characteristics, and weighted Cox proportional hazards models estimated adjusted hazard ratios (HRs) with 95% confidence intervals (CIs).</p><p><strong>Results: </strong>Among 1,057,635 patients (mean age 69.1 years; 62.5% female), 294,760 initiated tramadol, 97,048 codeine, 474,733 hydrocodone, and 191,094 oxycodone. During follow-up, 9,988 deaths and 10,455 fractures occurred. Tramadol showed similar mortality risk to codeine (HR 0.93, 95% CI 0.73-1.19) but lower risk compared with hydrocodone (HR 0.81, 95% CI 0.70-0.93) and oxycodone (HR 0.40, 95% CI 0.34-0.47). Fracture risk was comparable to codeine (HR 1.10, 95% CI 0.96-1.25) and lower than hydrocodone (HR 0.91, 95% CI 0.83-0.98) and oxycodone (HR 0.83, 95% CI 0.75-0.93).</p><p><strong>Conclusion: </strong>In adults aged 50 years or older with osteoarthritis initiating an opioid, tramadol initiation was associated with lower risks of death and fractures compared with hydrocodone and oxycodone, and similar risks compared with codeine. These findings suggest that tramadol may be a comparatively favorable option when opioid therapy is necessary, although its longer-term comparative safety remains uncertain.</p>","PeriodicalId":129,"journal":{"name":"Arthritis & Rheumatology","volume":" ","pages":""},"PeriodicalIF":9.9,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149259892","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}