Background: Osteoarthritis (OA) is a degenerative joint disease with limited therapeutic options, and its molecular mechanisms remain poorly understood.
Methods: We employed a multi-faceted approach combining transcriptome-wide association studies (TWAS), chemical-genomic enrichment analysis (CGSEA), and network pharmacology to identify OA-related chemicals and construct a disease-drug interaction network. Molecular docking was performed to assess melatonin's binding affinity to ferroptosis-related proteins. Melatonin was selected as a candidate for further investigation. In vitro experiments were conducted using SW1353 chondrocytes to validate the effects of melatonin on IL-1β-induced ferroptosis, extracellular matrix degradation, and inflammatory responses.
Results: Molecular docking confirmed melatonin's strong binding affinity to ferroptosis-related proteins. In vitro experiments with IL-1β-stimulated SW1353 chondrocytes revealed that melatonin reversed IL-1β-induced ferroptosis by restoring SLC7A11/GPX4 expression, reducing ROS accumulation, and suppressing P53 activation. Melatonin also mitigated extracellular matrix degradation (via COL2A1/MMP13 modulation) and inflammatory responses (via COX-2/iNOS downregulation).
Conclusion: These findings demonstrate that melatonin alleviates OA progression by inhibiting ferroptosis and inflammation, offering a novel therapeutic strategy. This study integrates computational and experimental validation to elucidate melatonin's mechanism in OA, supporting its clinical potential. Key points • Identification of melatonin as a potential therapeutic agent for osteoarthritis (OA) by TWAS, CGSEA, and network pharmacology conjoint analysis. • Molecular docking shows strong binding capacity of melatonin to iron death-related proteins (e.g., GPX4, SLC7A11). • Experimentally confirmed that melatonin significantly reversed IL-1β-induced iron death in chondrocytes by restoring SLC7A11/GPX4 expression, inhibiting P53 activation and reducing ROS accumulation.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by small vessel inflammation, which can lead to renal hemorrhage. Some forms of ANCA-associated vasculitis, such as microscopic polyangiitis, may lead to aneurysm formation, particularly renal aneurysm, which may resolve with appropriate immunosuppressive therapy. However, maintenance treatment should be administered cautiously to patients with ANCA-associated vasculitis and end-stage renal disease (ESRD) owing to the lower relapse rate and increased risk of infectious complications associated with immunosuppressive therapy. Herein, we describe a case involving a woman with ANCA-associated vasculitis and ESRD who did not receive maintenance immunosuppressive therapy and subsequently experienced right and left renal hemorrhages 8 and 14 years after the initiation of dialysis, respectively. Treatment choices for ANCA-associated vasculitis are based on individual factors such as disease severity and level of vasculitis activity. This case report highlights ANCA-associated vasculitis with two episodes of aneurysm-related bleeding, emphasizing that maintenance immunosuppressive therapy may be critical for patients having ANCA-associated vasculitis with ESRD, particularly those with persistently high ANCA titers.
Background: Xanthine oxidase inhibitors (XOis) are commonly used to treat gout and hyperuricemia. Beyond urate-lowering effects, XOis may influence cardiovascular outcomes via oxidative stress pathways. Prior evidence, including post hoc analyses of the CARES trial, suggests increased mortality after XOi discontinuation, raising concern for a potential "withdrawal syndrome." However, evidence from real-world outpatient populations is limited.
Objective: This study aims to evaluate whether the recent discontinuation of XOi therapy is associated with an increased risk of acute cardiovascular events in patients with gout.
Methods: We conducted a retrospective cohort study using the Merative MarketScan database. Adults with gout initiating allopurinol or febuxostat were included. Discontinuation was defined as no XOi supply in the prior 90 days during the 121- to 180-day window post-initiation. The primary outcome was hospitalization or outpatient diagnosis of acute myocardial infarction or ischemic stroke. Cox proportional hazards models with stabilized inverse probability weights were used to estimate hazard ratios (HRs), adjusting for demographic and clinical covariates.
Results: Among 508,872 patients initiating XOi therapy, 23.6% discontinued therapy within the first 121- to 180-day post-initiation timeframe. Discontinuers were younger with fewer comorbidities at baseline. After weighting, groups were well balanced. XOi discontinuation was associated with a modest but statistically significant increased risk of acute cardiovascular events (HR, 1.05; 95% CI, 1.01-1.09; p = 0.019). The magnitude of the effect increases among patients with preexisting hypertension diagnoses (HR, 1.13; 95% CI, 1.03-1.23; p = 0.006).
Conclusions: In this large real-world cohort, early discontinuation of XOi therapy was linked to a small but significant elevation in cardiovascular risk. These findings support prior signals of potential harm from XOi withdrawal, particularly among patients with cardiovascular disease, and highlight the importance of sustained therapy adherence. Key Points • Xanthine oxidase inhibitor (XOi) discontinuation was associated with a modest but significant increase in acute cardiovascular events in a large national cohort of patients with gout. • Even early discontinuation after XOi initiation may increase cardiovascular risk, underscoring the importance of treatment persistence. • Adherence to XOi therapy may be an important factor in reducing cardiovascular risk among gout patients.
Aims: To investigate the relationship between serum urate levels and gout flares and how these vary at different times of the year.
Methods: A cohort of people with incident gout was established using a large UK primary care database (Clinical Practice Research Database). Clinician-recorded gout flares and serum urate (SU) measurements were identified and described using joinpoint linear regression modelling. The relationship between SU level, flare frequency, month of the year and mean monthly temperatures was explored and correlations tested using Pearson correlation coefficients.
Results: 249,157 individuals (mean follow-up 6.7 years) experienced 417,101 flares and had 341,457 SU measurements (mean SU 437 µmol/L, standard deviation (SD) 106 µmol/L). SU levels peaked the day before a flare (487 µmol/L). Mean SU in the year preceding a flare was 474 µmol/L compared with 432 µmol/L in the year post-flare. SU levels did not near pre-flare levels in the year following a flare. Flares were most frequent, and SU was highest, in the summer months (June to August). The correlation co-efficient between flares and months of the year was 0.94, whereas the correlation with temperature was less strong (0.70).
Conclusions: SU measurement in the year following a gout flare is not indicative of the peak (pre-flare) SU levels that an individual may have experienced. Clinicians should consider this when considering SU measurements in the diagnosis of gout. Patients may find it helpful to be informed of the seasonality of gout flares and advised to take extra caution to reduce the risk of flares during summer months. Keypoints • Serum urate (SU) levels drop precipitously during gout flares and remain low for several months. • Correlations exist between flare rate and summer months, and with seasonal variation in SU levels. • Clinicians should be aware of how gout flares affect SU when interpreting SU levels.
Objective: Familial Mediterranean Fever (FMF) and Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Adenitis (PFAPA) syndrome are autoinflammatory diseases that may present with similar clinical symptoms. The presence of a non-confirmatory MEFV gene variant and overlapping clinical features can complicate differential diagnosis between the two conditions. The aim of this study is to evaluate the distinctive power of the Eurofever/PRINTO classification criteria, developed for FMF cases with non-confirmatory MEFV genotypes, in differentiating FMF from PFAPA.
Method: The study included 126 patients diagnosed with FMF according to the Yalcinkaya-Ozen diagnostic criteria who also carried a non-confirmatory MEFV genotype as defined in the Eurofever/PRINTO genetic and clinical FMF classification criteria. For comparison, data from 32 patients diagnosed with PFAPA according to the modified Marshall criteria and carrying a non-confirmatory MEFV genotype were also included in the analysis. The diagnostic performance of the Eurofever/PRINTO criteria was evaluated both in patients with FMF and PFAPA.
Results: The Eurofever/PRINTO genetic and clinical FMF criteria demonstrated a sensitivity of 96.8%, specificity of 71.9%, positive predictive value (PPV) of 93.1%, and negative predictive value (NPV) of 85.2%; the positive likelihood ratio (PLR) was 3.43 and the negative likelihood ratio (NLR) was 0.04. It was observed that 28.1% of PFAPA patients carrying a non-confirmatory MEFV genotype were misclassified as having FMF.
Conclusions: The Eurofever/PRINTO genetic FMF classification criteria may serve as a helpful tool in identifying FMF patients and distinguishing them from PFAPA patients who share common genetic and clinical features. However, it should be considered that this set of criteria may lead to a misdiagnosis of FMF in PFAPA patients carrying non-confirmatory MEFV variants. Key Points • Our study highlights the high sensitivity but limited specificity of the Eurofever/PRINTO classification criteria in distinguishing FMF from PFAPA among patients with non-confirmatory MEFV variants, emphasizing the need for cautious interpretation in genetically overlapping cases. • Our findings underscore the importance of integrating clinical judgment with genetic and classification criteria when diagnosing autoinflammatory diseases in regions with a high prevalence of MEFV variants.
Objective: To quantify the burden of osteoarthritis (OA) and give an account of the most recent data on incidence, prevalence, and years lived with disability (YLDs) of OA for the North Africa and Middle East (NAME) region over time with a particular focus on changes from 1990 to 2021.
Method: In this epidemiological study, data from the Global Burden of Disease 2021 study were used. The prevalence, incidence, and YLDs of OA were obtained for both sexes in 21 countries of the NAME region. These estimates are reported in the form of all-age numbers and age-standardized rates, together with their 95% uncertainty intervals (UIs).
Result: The all-age numbers of incidence, prevalence, and YLDs in 2021 were about 2.7 million (95% UIs, 2.4 to 3.0), 30.5 million (27.1 to 33.7), and 1.0 million (0.5 to 2.1). From 1990 to 2021, the burden of OA was higher in females than in males, and the rates of prevalence and YLDs increased as age rose. However, the rate of incidence increased until the ages 60-64 and then decreased. Kuwait had the highest burden, whereas Afghanistan had the lowest burden. The highest burden among OA subgroups was related to knee OA, while hip OA had the least attributable burden. Overall, the burden of OA had a direct association with the sociodemographic index (SDI).
Conclusion: In summary, the prevalence, incidence, and YLD rates of osteoarthritis have shown an upward trend across most countries. The disease is positively associated with female sex, age, and SDI, implementing targeted medical prevention and treatment interventions in high-SDI countries. Key Points • This study presents a comprehensive analysis of the burden of osteoarthritis in North Africa and the Middle East from 1990 to 2021 using data from the Global Burden of Disease 2021 study. The findings highlight regional trends in osteoarthritis incidence, prevalence, and years lived with disability, offering valuable insights into healthcare planning and policy development.
Objectives: Premature T cell aging, marked by telomere shortening and cell cycle arrest, plays a key role in the pathogenesis of rheumatoid arthritis (RA). Growing evidence suggests that high glucose-induced metabolic dysfunction critically regulates both cellular aging and RA progression. This study explores how high glucose exacerbates T cell aging, providing novel insights into the mechanisms underlying RA development.
Methods: CD4+ T cells isolated from RA patients and healthy controls, along with HC-derived CD4+ T cells cultured in either low- or high-glucose conditions, were analyzed for aging markers including telomere length and cell cycle regulatory proteins to evaluate glucose-dependent effects. Cellular metabolism was characterized through: (1) glucose uptake (2-NBDG assay), (2) mitochondrial respiration (oxygen consumption rate analysis), and (3) mitophagy activity (DRP1/PINK1/parkin protein levels by immunoblotting). Mechanistic studies employed both pharmacological interventions (2-DG for glycolysis inhibition, succinyl phosphonate for OGDH inhibition, Mdivi-1 for DRP1 blockade) and genetic manipulation (DRP1 knockdown and overexpression) to delineate the roles of glucose metabolism and DRP1-mediated mitophagy in T cell aging.
Results: RA-derived CD4+ T cells exhibited increased glucose uptake and mitochondrial dysfunction. Enhanced mitophagy accelerated T-cell aging in RA. Mechanistically, high glucose promoted succinate accumulation, a key TCA cycle metabolite, leading to succinylation of Zinc Finger Protein 76 (ZNF76), a DRP1 transcription factor. This activated ZNF76, upregulating DRP1-mediated mitophagy and driving T-cell aging. Targeting glucose uptake and mitophagy may thus reverse T-cell dysfunction and ameliorate RA severity.
Conclusion: Elevated mitophagy induced by high glucose represents a cell-autonomous mechanism driving premature T cell aging in RA, presenting a novel therapeutic avenue for disease management. Key Points • Dysregulated glucose metabolism is a key driver of T cell aging and RA pathogenesis. • High glucose exposure triggers metabolic reprogramming, leading to succinate accumulation. • Accumulated succinate induces ZNF76 succinylation and enhances DRP1-dependent mitophagy-a phenotype consistently observed in CD4+ T cells from RA patients. • DRP1-dependent mitophagy drives T cell aging in RA.
Objective: Infection remains a leading cause of mortality in systemic lupus erythematosus (SLE), this study aimed to evaluate the impact of tacrolimus (TAC) use on infection risk in SLE patients.
Methods: A nested case-control study analyzed 3,176 SLE patients (1,509 infection cases; 1,667 controls) from SLE cohort (2010-2021). TAC exposure was defined as ≥ 30 consecutive days of use within 12 months preceding infection diagnosis or index date. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for associations between TAC use and infections risk. Drug combination effects of TAC was analyzed with cyclophosphamide (CYC), mycophenolate mofetil (MMF), hydroxychloroquine (HCQ), and glucocorticoids.
Results: After controlling for confounders (adjusted OR, 95% CI), TAC use was associated with a 60% lower overall infection risk versus other conventional immunosuppressants (0.40, 0.30-0.51), with stronger reductions in bacterial (0.50, 0.37-0.67) and skin/mucosal infections (0.30, 0.13-0.72). Significantly lower risks were observed at lower dosages (≤ 2 mg/d, OR 0.34, 0.24-0.47) and with prolonged use (> 365 days, OR 0.29, 0.19-0.46). Subgroup analyses confirmed enhanced protection in high-risk populations, such as severe disease activity (SLEDAI-2 K > 12, OR 0.32, 0.22-0.46) and CNS involvement (0.25, 0.09-0.71). TAC-HCQ co-therapy reduced infection risk (0.37, 0.27-0.52); separately, TAC counteracted glucocorticoid-associated risk (0.48, 0.30-0.77), and attenuated CYC/MMF-related risk (1.31, 0.83-2.06 vs. 4.25, 2.53-7.13 for CYC-MMF combinations).
Conclusions: TAC offers superior infection prevention versus other conventional immunosuppressants in SLE, advocating for TAC-centered regimens to optimize risk-benefit profiles. Key Points • TAC use was associated with lower infection risk compared to other conventional immunosuppressants, particularly for bacterial infections and skin/mucosal infections. • Dose-response relationships were identified between both TAC dosage and duration of use and lower infection risk in SLE patients.
Introduction: Kawasaki disease is a systemic pediatric vasculitis with a wide range of clinical presentations. Although often viewed as a single disease entity, emerging evidence indicates considerable phenotypic diversity. However, population-specific studies are still limited, especially in high-incidence areas like Japan. This study aimed to identify different clinical subgroups among patients with Kawasaki disease in Japan using cluster analysis.
Methods: We retrospectively reviewed 321 patients diagnosed with Kawasaki disease from 2020 to 2025 at a single center in Japan. Eighteen clinical and laboratory variables were used for principal component analysis and hierarchical clustering. The clusters were compared based on clinical features, treatment responses, and coronary outcomes. Temporal and seasonal trends were also examined.
Results: Three phenotypic clusters were identified: Cluster 1 included younger children with classical Kawasaki disease's features and low treatment resistance; Cluster 2 exhibited hepatobiliary involvement, high intravenous immunoglobulin resistance prediction scores, and frequent need for additional therapy; and Cluster 3 comprised older children with elevated inflammation markers, cervical lymphadenopathy, and delayed diagnosis. Postpandemic, Cluster 3 increased, and seasonal peaks were observed in winter (Cluster 3) and spring (Cluster 2).
Conclusion: Cluster analysis identified distinct Kawasaki disease subtypes in a high-incidence Japanese population, each with unique clinical and temporal features. These findings support using phenotypic clustering to improve risk stratification and guide personalized treatment approaches. Key Points • Three distinct Kawasaki disease phenotypes were identified in Japanese children, each with unique clinical features, biochemical profiles, and treatment responses. • Temporal and seasonal patterns suggest an interplay between environmental triggers and host genetic susceptibility in the expression of KD among Japanese children.
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