Arthritis & Rheumatology最新文献

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.

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Objectives: 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.

Methods: 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).

Results: 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).

Conclusions: In adults aged 50 years or older with osteoarthritis initiating an opioid, tramadol initiation was associated with lower risks of mortality 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.