Arthritis Research & Therapy最新文献

Background: Sjögren's syndrome (SS) is a chronic systemic autoimmune disease in which CD4⁺ T cells play a critical role. Recent advances in immunometabolism suggest that metabolic reprogramming contributes to autoimmune pathogenesis. This study investigates the role of fatty acid synthase (FASN) in CD4⁺ T cell dysfunction in SS.

Methods: Peripheral blood CD4⁺ T cells were isolated from SS patients and healthy controls. FASN expression was assessed via PCR, Western blot, and immunofluorescence. Functional and metabolic assays, including flow cytometry, Seahorse analysis, transcriptomic profiling, and global metabolomics (Q300) were performed using murine and human CD4⁺ T cells treated with the FASN inhibitor orlistat. Rescue experiments were conducted with oleic acid (OA) and palmitoleic acid (PA). In vivo efficacy was evaluated in NOD/LtJ and experimentally-induced SS (ESS) mouse models.

Results: FASN was significantly upregulated in CD4⁺ T cells from SS patients and activated murine T cells, correlating with disease activity markers. Orlistat-mediated FASN inhibition suppressed T cell proliferation, activation (CD25/CD69), and glycolytic metabolism, while enhancing oxidative phosphorylation (OXPHOS), leading to elevated ROS and mitochondrial dysfunction. Metabolomics identified reduced OA and PA levels upon FASN inhibition. Exogenous OA and PA partially restored metabolic balance and activation markers. In murine models, orlistat reduced salivary gland lymphocytic infiltration, pro-inflammatory cytokines (IL-17/TNF-α), and improved salivary flow.

Conclusion: FASN drives CD4⁺ T cell hyperactivation and metabolic reprogramming in SS. Its inhibition shifts cell metabolism from glycolysis to OXPHOS, reducing inflammation and ameliorating disease in preclinical models. These results identify FASN as a potential therapeutic target for SS.

Objective: Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease in which early and atypical presentations frequently challenge existing classification frameworks. The Systemic Lupus Erythematosus Risk Probability Index (SLERPI) was developed as a probabilistic diagnostic aid, but its real-world performance relative to established classification criteria across disease phenotypes remains incompletely characterized.

Methods: In this multicenter, cross-sectional study, we evaluated 1,281 participants, including 655 expert-confirmed SLE patients and 626 controls with other rheumatic diseases. Diagnostic performance of SLERPI, ACR-1997, SLICC-2012, and EULAR/ACR-2019 criteria was assessed against expert clinical diagnosis as the reference standard. Subgroup analyses were performed for early disease (≤ 1 year), sex, disease duration, and major organ involvement. Concordance and discordance between criteria were examined using UpSet plots, detailed phenotypic comparisons, and hierarchical cluster analysis of discordant cases. Net reclassification improvement (NRI) was used to quantify incremental diagnostic information.

Results: All four systems demonstrated high diagnostic accuracy, with sensitivities ranging from 95.1-99.2% and specificities from 87.7-90.4%. SLERPI achieved the highest sensitivity (99.2%) and AUC (0.989), particularly excelling in early disease (≤ 1 year, sensitivity 98.0%, AUC 0.987). Net reclassification improvement favored SLERPI over ACR-1997 (+ 2.7%), SLICC-2012 (+ 1.6%), and EULAR/ACR-2019 (+ 4.3%). Concordance across systems was substantial, with 91.6% of patients classified by all four sets. Discordant cases (8.4%) revealed phenotype-specific patterns: ACR-1997 frequently missed immunologically active or hematologic-dominant cases, while EULAR/ACR-2019 underperformed in mucocutaneous-predominant disease. Cluster analysis identified four coherent subgroups, underscoring heterogeneity in missed classifications. SLERPI showed the lowest discordance, with residual misclassifications confined to hematologic-dominant phenotypes.

Conclusion: SLE classification frameworks show substantial overlap in real-world practice, with discordance driven by phenotype-specific prioritization of disease domains rather than random failure. SLERPI complements established classification criteria by supporting identification of early and atypical SLE presentations, while traditional criteria remain essential for research standardization. Integrating probabilistic diagnostic tools with classification frameworks may enhance SLE recognition across diverse clinical contexts.

Background: Patients with rheumatoid arthritis (RA) are at a higher risk for sarcopenia than the general population. Exercise therapy can improve muscle strength in older adults; however, its efficacy in older patients with RA has not been fully established. This study aimed to evaluate the efficacy of a personalized exercise program on physical function in older patients with RA at high risk for sarcopenia.

Methods: A single-centre, parallel-group, two-arm, superiority randomized controlled trial was conducted in patients with RA aged 60-85 years who were at risk of sarcopenia. The intervention group (n = 69) underwent a 16-week personalized exercise program in addition to nutritional guidance and standard care, whereas the control group (n = 65) received only nutritional guidance and standard care. The primary outcome was the change in the total Short Physical Performance Battery (SPPB) scores from baseline to week 16.

Results: A total of 140 patients were randomized. Of these, 134 initiated the assigned intervention. There was a 0.2-point difference in SPPB total score from baseline to week 16 between the intervention group (+ 0.4 points) and the control group (+ 0.2 points); 95% confidence interval: -0.1 to 0.5; p = 0.206. Regarding the secondary outcomes at week 16, there was a tendency for improvement in the chair-stand test, grip strength, and the mental component score.

Conclusion: The 16-week personalized exercise therapy did not improve the total SPPB scores. However, the intervention may improve standing ability, grip strength, and mental health-related quality of life in older patients with RA at high risk of sarcopenia.

Trial registration: This study was registered with UMINCTR (trial number: UMIN000044930).