Clinical and experimental rheumatology最新文献

Objectives: To explore the heterogeneity and the corresponding clinical significance of lymphocyte subsets in dermatomyositis patients with anti-melanoma differentiation-associated gene 5 positive autoantibody (anti-MDA5+ DM).

Methods: 268 anti-MDA5+ DM patients and 536 gender-age matched healthy controls (HCs) were retrospectively enrolled. Patients' clinical data, serological parameters, peripheral blood lymphocyte subsets, imagological examinations, treatment regimens and follow-up were collected. Cluster analysis based on peripheral blood lymphocyte subsets was conducted in anti-MDA5+ DM patients.

Results: The absolute number of CD3+ T lymphocytes, CD3+CD4+ T cells, CD3+CD8+ T cells, CD3-CD19+ B cells and CD16+CD56+ NK cells were significantly reduced in anti-MDA5+ DM patients compared with HCs. The absolute counts of the above cell subsets were remarkably reduced in non-survivors compared to the survivors of anti-MDA5+ DM. Cluster analysis based on lymphocyte subsets divided anti-MDA5+ DM patients into cluster 1(n=125) and cluster 2 (n=143). Patients in cluster 1 presented with lower counts of CD3+ T cells, CD3+CD4+ T cells, CD3+CD8+ T cells, CD3-CD19+ B cells and NK cells compared with cluster 2. Notably, RP-ILD rate, three-month and six-month death rate in cluster 1 were dramatically higher than in cluster 2, p<0.001, respectively.

Conclusions: Lymphocytes and their subsets were significantly altered in anti-MDA5+ DM patients. There was remarkable heterogeneity of lymphocyte subsets in anti-MDA5+ DM patients between survivors and non-survivors. Anti-MDA5+ DM patients were divided into two groups with distinct symptoms and survival rate by cluster analysis based on lymphocyte subsets.

Objectives: We aim to evaluate the utility of two novel quantitative PET/CT-derived parameters, Total Inflammatory Vascular Volume (TIVV) and Total Inflammatory Glycolysis Volume (TIGV), in assessing disease activity, treatment response, and predicting relapse in patients with large vessel giant cell arteritis (LV-GCA).

Methods: Three LV-GCA patients underwent baseline and serial follow-up 18F-FDG PET/CT scans. Disease activity was assessed using conventional visual methods (Meller's scale and PETVAS) and the novel quantitative parameters TIVV and TIGV, calculated using a semiautomated method based on FDG uptake thresholds relative to liver SUVmean.

Results: In Case 1, treatment initially deemed ineffective by visual criteria showed the greatest reduction in inflammatory burden using TIVV/TIGV. In this patient, the application of quantitative parameters could have prevented multiple ineffective treatment changes. In Case 2, increasing TIVV and TIGV values preceded clinical relapse, which was undetected by visual assessment. In Case 3, declining quantitative values, despite persistent visual hypermetabolism, supported our decision to continue therapy and aligned with clinical remission.

Conclusions: In all cases, TIVV and TIGV provided an earlier and more accurate assessment of vascular inflammation than traditional methods. Therefore, TIVV and TIGV may offer more accurate and standardized measures for evaluating disease activity and guiding treatment in LV-GCA. These metrics could address limitations of current visual and semiquantitative approaches but warrant validation in large studies.

Objectives: Systemic sclerosis (SSc) is a chronic autoimmune disease characterised by skin and internal organ involvement. Despite the acknowledgment that cardiovascular (CV) complications are a leading cause of death in SSc, the extent of CV risk and major adverse cardiac events (MACEs) remains unclear. Aim of this study is to evaluate the association between SSc and the risk of MACEs through a systematic literature review and meta-analysis, focusing on non-fatal stroke (nfS) and non-fatal myocardial infarction (nfMI) as secondary outcomes.

Methods: We systematically searched for cohort and prospective studies published up to November 2024. We included studies reporting hazard ratios (HRs) with 95% confidence intervals (CIs) for SSc and cardiovascular outcomes. Random-effects meta-analyses were conducted to estimate pooled HRs. Heterogeneity was assessed using the I² statistic, and publication bias was evaluated via Egger's test.

Results: Eleven studies (n=12,235 SSc patients included) were included initially; SSc was associated with an increased risk of MACE (pooled HR 1.8, 95% CI 1.4-2.3), albeit with high heterogeneity (I²=89.2%). Removal of overlapping datasets confirmed a significantly elevated risk (pooled HR 1.9, 95% CI 1.3-2.7), with persistent heterogeneity (I²=88.72%). Subgroup analyses showed significant geographic variation. For secondary outcomes, SSc was associated with higher risks of nfS (pooled HR 1.5, 95% CI 1.2-1.9) and nfMI (pooled HR 2.5, 95% CI 1.9-3.5), with a decrease in heterogeneity.

Conclusions: Patients with SSc face a significantly increased risk of major CV events, including stroke and myocardial infarction. These findings underscore the need for tailored CV risk assessment and management strategies in SSc.

Objectives: To determine the prevalence of myocarditis with newly diagnosed idiopathic inflammatory myopathy (IIM) and assess the utility of serum cardiac biomarkers as initial screening for myocarditis.

Methods: We prospectively enrolled patients with IIM at the Johns Hopkins Myositis Center between 7/1/2022-3/30/2023. 26 patients underwent cardiac serum biomarkers, electrocardiography, and cardiac imaging (transthoracic echocardiogram and cardiac magnetic resonance imaging (CMR). Myocarditis was diagnosed with CMR using 2009 Lake Louise Criteria. Clinical cardiac outcomes, including heart failure events, cardiac hospitalisation, and arrhythmia events were also assessed at follow-up.

Results: 27% (7/26) met the Lake Louise Criteria for myocarditis by CMR. Of patients found to have myocarditis, 71% (5/7) were symptomatic with dyspnoea on exertion, pleuritic chest pain, or with palpitations. The most common diagnosis among those with myocarditis was IIM/SSc overlap disease (5/7, 71%), and the most common antibody was Anti-Ku (3/7, 43%). When compared to patients without myocarditis, those with myocarditis more frequently had elevations in both troponin and NT-proBNP (100% vs. 42%, p=0.003) or an abnormal EKG (100% vs. 37%, p=0.004) with reduced ejection fraction on echocardiogram yielding a poor sensitivity with only 2/7 (29%) of patients with myocarditis demonstrating an EF of <50%.

Conclusions: Myocarditis occurred in 27% of this cohort, with IIM/SSc overlap being the most common subgroup. Anti-Ku was the most prevalent autoantibody, indicating a potentially higher risk for these patients. All had elevated cardiac biomarkers and abnormal EKGs, suggesting these could be useful for screening and further tests like cardiac MRI.

Objectives: Psoriatic arthritis (PsA) arises in roughly 20-30% of individuals with psoriasis (PsO); notably, >80% of PsA cases are preceded by PsO after a clinically silent interval of immunogenetic priming and subclinical synovio-entheseal inflammation. Identification of this at-risk and subclinical window is hindered by absent staging criteria, validated biomarkers, and standardised surveillance, limiting opportunities for early intervention to prevent irreversible joint damage.

Methods: We conducted a structured narrative review of PubMed (through June 2025) targeting studies on: 1. immunogenetic and molecular drivers of PsO-to-PsA transition, 2. temporal staging frameworks and risk-stratification algorithms, 3. screening instruments and polygenic risk models, 4. imaging modalities for occult inflammation, and 5. pharmacologic and lifestyle interventions aimed at disease interception.

Results: Long-term factors (PsO severity, nail disease, family history, obesity) and short-term indicators (arthralgia, imaging-detected enthesitis or synovitis) help stratify PsA risk. Advanced ultrasound and MRI can reveal subclinical inflammation in asymptomatic PsO, though predictive validity remains to be confirmed. Observational data hint at a possible delay in PsA onset with early bDMARD exposure, but randomised prevention trials are lacking. Lifestyle interventions appear promising yet remain untested.

Conclusions: Framing PsA as a staged continuum supports a precision-medicine model that integrates genetic profiling, validated screening, advanced imaging, and targeted intervention. Prospective, biomarker-driven trials and integrated dermatology-rheumatology pathways are needed to validate predictive algorithms and establish effective prevention and early-treatment strategies.

Objectives: Rheumatoid arthritis (RA) is characterised by systemic inflammation, which elevates the risk of atherothrombotic cardiovascular (CV) events. Although Janus kinase inhibitors (JAKi) are effective in controlling RA inflammation, post-marketing data (ORAL Surveillance) have suggested an increased risk of major adverse CV events (MACE) in patients receiving tofacitinib (TOFA). The pathophysiological mechanisms for these findings remain unclear, especially regarding platelet aggregation and tissue factor (TF) expression, two key drivers of thrombosis. In this study, we aimed to investigate the effects of TOFA on platelet aggregation and TF-mediated coagulation pathways to elucidate potential pro- or anti-thrombotic properties at the cellular level.

Methods: Platelet-rich plasma (PRP) from 12 healthy volunteers was incubated with TOFA (20 or 40 ng/mL), and maximal platelet aggregation (AGGmax) in response to ADP was measured by light transmission aggregometry (LTA) at 30, 60, and 90 minutes. In parallel, platelets from 14 RA patients were evaluated at baseline and at 1, 3, and 6 months of TOFA treatment (5 mg bid). Human umbilical vein endothelial cells (HUVECs) were exposed to TOFA (20 or 40 ng/mL) and/or IL-6 (0.5 ng/mL) to assess TF mRNA (by real-time PCR) and TF procoagulant activity (by factor Xa generation assay).

Results: TOFA did not alter ADP-induced platelet aggregation ex vivo in either healthy volunteers or RA patients. However, it significantly reduced IL-6-induced TF mRNA expression and activity in HUVECs. These in vitro results suggest that TOFA may counteract IL-6-mediated prothrombotic mechanisms at the endothelial level.

Conclusions: Despite clinical concerns raised by ORAL Surveillance, our findings indicate no direct enhancement of platelet reactivity by TOFA. Instead, TOFA attenuated IL-6-driven TF expression in endothelial cells, pointing to a possible protective effect on vascular thrombogenic pathways. Further studies are warranted to reconcile these in vitro observations with real-world data on CV outcomes in RA.

Objectives: Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) complicates disease management due to the limited methotrexate (MTX) use. Janus kinase (JAK) inhibitors are effective as monotherapy, but the impact of concomitant MTX in RA-ILD remains unclear and controversy. We compared the clinical course of patients with RA-ILD receiving JAK inhibitors with or without MTX.

Methods: We analysed consecutive RA-ILD patients treated with JAK inhibitors in the KEIO-RA cohort (2013-2025), a retrospective single-centre longitudinal cohort. Patients were stratified by concomitant MTX use. The primary outcome was JAK inhibitor retention rates for 24 months and secondary outcomes included ILD progression (KL-6, %FVC, and HRCT scores), arthritis activity improvement (CDAI), glucocorticoid dose reduction, and adverse events.

Results: We evaluated 86 treatment courses; 26.7% (n=23) received JAK inhibitors with MTX. The overall 24-month retention rate was 42.3%. Retention rates did not differ between MTX and non-MTX groups (47.9% vs. 41.7%, p=0.43). Among courses on therapy ≥12 months, there was no significant difference between ILD progression between MTX and non-MTX groups, as indicated by KL-6 levels (309.0 to 324.0 U/mL, p=1.00; 525.0 to 507.0 U/mL, p=0.57, respectively), %FVC (96.9% to 96.7%, p=0.56; 80.6% to 82.0%, p=0.88, respectively), and HRCT score (4 to 3, p=0.72; 4 to 4, p=0.81, respectively), as well as arthritis improvement, glucocorticoid dose reduction, and safety. Multivariable analysis identified prior exposure to multiple bDMARDs or JAK inhibitors as an independent predictor of discontinuation.

Conclusions: In RA-ILD, our study found no significant differences in the effectiveness of JAK inhibitors for both ILD and arthritis, retention, and safety, with or without MTX.

Objectives: Voclosporin, a novel calcineurin inhibitor, is emerging as a promising treatment for lupus nephritis (LN). It inhibits T and B cell activation with unique pharmacokinetic profile and superior safety. To optimise clinical management, a comprehensive assessment of real-world safety is urgently needed.

Methods: A retrospective observational study was performed that analysed data from the FDA adverse event reporting system (FAERS) database from 2021Q4 to 2024Q3. Advanced data mining techniques were utilised to identify safety signals associated with voclosporin. The research focused on instances where voclosporin was considered the primary suspect (PS) drug, and incidents of adverse events (AEs) were categorised utilising the Medical Dictionary for Regulatory Activities standardised preferred terms and system organ class classifications (SOCs).

Results: The analysis of FAERS database identified 11,851 reports in which voclosporin was the PS drug. The median time to onset (TTO) of AEs is 54.50 days. These reports highlighted significant safety signals across various SOCs, especially in vascular disorders, skin and subcutaneous tissue diseases, and gastrointestinal disorders. Furthermore, several previously unreported adverse events associated with voclosporin were discovered, such as hypertensive urgency (ROR: 27.96, 95%IC: 11.53, 67.81), hypertrichosis (ROR: 15.17, 95%IC:5.66, 40.65), and gingival swelling (ROR: 16.38, 95%IC: 8.78, 30.57).

Conclusions: The present research provides a significant assessment of the postmarketing safety profile of voclosporin. However, additional studies are needed to corroborate and solidify these observations. Clinicians are advised to remain highly vigilant about the potential AEs associated with voclosporin and to carefully consider the appropriate dosing regimens when utilising this medication in clinical practice.

Objectives: Facet joint osteoarthritis (FJOA) is a degenerative spinal joint condition causing low back pain due to cartilage loss and joint damage. Although some studies have highlighted the importance of pyroptosis or autophagy in cartilage loss under FJOA, no report has identified the biomarkers between the two biological events. This direction demonstrates innovative potential and scientific value. The present study aimed to screen differentially expressed genes (DEGs) linked to pyroptosis and autophagy in FJOA and identify potential biomarkers for FJOA.

Methods: We collected the lumbar facet joints, performed transcriptome sequencing, used a variety of bioinformatics methods to obtain differentially expressed genes (DEGs), and obtained autophagy-related and pyroplosis-related genes (APRGs) from GeneCards database, and then screened out 17 APRGs. Two machine learning methods were used to identify potential biomarkers. Subsequently, clinical sample experiments and cellular experiments were carried out to validate.

Results: We found 7,783 DEGs in samples of FJOA patients and obtained 1,153 autophagy-related genes and 80 pyroptosis-related genes from the GeneCards database. 17 APRGs were screened out from the intersection of the three gene sets. Furthermore, CD274, DDX3X, Caspase-8, and MAPK14 were identified as FJOA characteristic biomarkers. We identified that DDX3X, Caspase-8, and MAPK14 were positively correlated with pyroptosis and autophagy in clinical samples and cell experiments, while CD274 was negatively correlated.

Conclusions: Our study identified CD274, DDX3X, Caspase-8, and MAPK14 in chondrocyte and articular cartilage of articular process with pyroptosis and autophagy in FJOA. Therefore, the four genes are expected to be promising therapeutic targets for FJOA, our findings may provide novel insight in clinic.

Objectives: The interaction of autoantibodies with solid tissues has been extensively studied in systemic lupus erythematosus (SLE), but their interaction with peripheral blood mononuclear cells (PBMCs) remains poorly understood. This study aimed to investigate the effects of autoantibodies on PBMCs in SLE.

Methods: We enrolled 31 SLE patients and 35 healthy controls. Serum antibodies recognising PBMC antigens were assessed by immunoblotting using membrane and cytoplasmic proteins isolated from PBMCs. PBMC antigens were identified by mass spectrometry. The effects of autoantibodies on PBMCs were evaluated using flow cytometry, quantitative real-time PCR (qPCR), and enzyme-linked immunosorbent assay (ELISA).

Results: Antibodies targeting a 55-kDa autoantigen were detected in 48.8% of SLE patients. Mass spectrometry identified SSB (La) protein as one of the potential antigens recognised by these autoantibodies, consistent with the strong association between anti-SSB antibodies and anti-55-kDa antibodies in clinical data. Anti-SSB antibodies exhibited significantly higher binding affinity to PBMCs compared to isotype IgG (23.0% vs. 10.6%, p<0.0001). Furthermore, anti-SSB antibodies promoted the mRNA expression of TNF-α, IL-1β, IL-4, and IL-6 in PBMCs, with IL-6 showing a more than 100-fold increase (p<0.001). The expression of IL-6 was suppressed by resatorvid, a TLR4 inhibitor. CD14-positive monocytes were identified as the primary source of IL-6 in PBMCs stimulated by anti-SSB antibodies.

Conclusions: Our findings demonstrate that anti-SSB antibodies promote cytokine production, particularly IL-6, in monocytes through a TLR4-dependent mechanism.