Journal of Internal Medicine最新文献

Background: Previous observational studies have reported an increased risk of venous thromboembolism (VTE) among non-steroidal anti-inflammatory drug (NSAID) users compared with non-users. However, these studies may have been subject to bias due to unmeasured confounders related to patient conditions requiring NSAIDs. We employed an active comparator new user cohort design, using acetaminophen as the active comparator.

Methods: New users of either NSAIDs or acetaminophen aged 18-65 years were identified from a Japanese health insurance claims database. The adjusted hazard ratio (aHR) of VTE among new NSAID and acetaminophen users within 60 days of prescription was calculated using propensity score overlap weighting and Cox regression. To examine how a naïve comparison between users and non-users of NSAIDs might affect the results, we repeated the analysis using non-users of NSAIDs as the comparator group instead of acetaminophen users.

Results: Among 4,282,421 new NSAID users and 2,728,202 new acetaminophen users, 1504 (0.022%) developed VTE during follow-up. New NSAID users had a significantly lower incidence of VTE compared with new acetaminophen users (aHR, 0.70; 95% confidence interval [CI], 0.62-0.80). When compared with non-users, NSAID users had a significantly higher incidence of VTE (aHR, 3.18; 95% CI, 2.85-3.55).

Conclusion: Although new NSAID users had a lower incidence of VTE than new acetaminophen users, they had a higher incidence compared with non-users. Assuming that acetaminophen does not increase VTE risk, these findings suggest that NSAIDs themselves may not increase VTE risk.

The etiology of Alzheimer's disease (AD) remains under active debate. In this perspective, we explore the hypothesis that a primarily infection-caused chronic dysregulation and weakening of human innate immunity via the underexpression, degradation, and inactivation of innate immune proteins necessary for direct antimicrobial effects and regulation of host defense and autophagy could lead to AD. Key evidence relates to the fact that important innate immune proteins such as LL-37-which can bind Aβ and block amyloid formation-as well as Apolipoprotein E, antiviral interferons, and TNF-α can be degraded and deactivated by enzymes produced by the common oral anaerobic pathogen Porphyromonas gingivalis (Pg). Pg produces numerous virulence factors; of particular importance for AD are Pg's gingipain cysteine proteases. Deleterious effects of chronic Pg infection and gingipains include a systemic downregulation and paralysis of the interferon response, particularly the antiviral interferon-lambda response, which enables replication of endemic herpesviruses. The result is a chronic, low-level viral infectious assault on gut, nerves, and brain causing the production of Aβ antimicrobial peptides, accumulation of Aβ plaques, phosphorylation of Tau, progressive neuroinflammation, and neurodegeneration. The resultant innate immune system dysregulation, as an AD etiology, ties together the well-known amyloid cascade hypothesis and the infectious theory of AD into a unified explanation of the pathology and cause of AD. If this theory holds true, it suggests preventative approaches: (1) test for and eradicate Pg from oral flora, and/or directly deactivate the gingipains; and (2) reduce Herpesvirus exacerbations by the use of antiviral drugs and/or vaccines (e.g., Bacillus Calmette-Guérin).

Gene therapy is emerging as a groundbreaking strategy for treating epilepsy, offering new hope to patients who do not respond to conventional medications. Despite advancements in anti-seizure treatments, nearly 30%-40% of individuals with epilepsy continue to experience uncontrolled seizures, highlighting the urgent need for more effective and long-lasting solutions. By addressing the underlying causes of epilepsy at the genetic level, gene therapy represents a paradigm shift in treatment. Two key approaches are being explored: (1) activating or supplementing beneficial genes to suppress seizures and (2) silencing harmful genes or pathways that contribute to epilepsy. To achieve these objectives, viral vectors, such as adeno-associated viruses and lentiviruses, have shown promise in delivering targeted genetic interventions. In parallel, cutting-edge techniques such as optogenetics, chemogenetics, and clustered regularly interspaced short palindromic repeat-based gene editing are enhancing the precision of these therapies, enabling greater control over neuronal activity. However, significant challenges exist, including ensuring safe and efficient gene delivery, maintaining long-term therapeutic effects, and mitigating potential side effects. This review examines recent developments in gene therapy for epilepsy, assessing its potential to deliver targeted, long-lasting treatments for drug-resistant epilepsy. By examining current strategies, therapeutic targets, and emerging technologies, it provides insights into the promising future of gene therapy as a transformative tool in epilepsy treatment and summarizes current clinical trials utilizing gene and cell therapy technologies for epilepsy.

Background: Granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA) are distinct forms of antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Increasing evidence suggests overlapping features, particularly in proteinase 3 (PR3)-ANCA-positive EGPA and GPA with eosinophilia. This study aimed to characterize overlapping EGPA/GPA forms and assess their clinical and therapeutic implications.

Methods: We conducted a European, multicenter, observational study, including 135 patients with overlapping EGPA/GPA features. Definitions were based on ACR/EULAR classification criteria and other clinical and biological findings. Clinical, biological, and histological characteristics were analyzed using unsupervised hierarchical clustering approach. Comparisons were made with established EGPA and GPA control cohorts.

Results: Three clusters emerged: Cluster 1, a hybrid phenotype (pulmonary nodules, PR3-ANCA positivity, high relapse rate); Cluster 2, a systemic inflammatory phenotype (constitutional symptoms, PR3-ANCA positivity, moderate renal involvement); and Cluster 3, a severe vasculitis form (severe renal disease, alveolar hemorrhage). Including typical EGPA and GPA control cohorts revealed two main clusters a posteriori: an EGPA cluster and a GPA cluster. Cluster 1 overlapped with both EGPA and GPA clusters, whereas Clusters 2 and 3 predominantly aligned with GPA. Kaplan-Meier analysis revealed that Cluster 1 and the typical EGPA cohort had the best overall survival, whereas Cluster 3 had the poorest survival. Relapse-free survival was highest in typical EGPA and poorest in Cluster 3 and typical GPA.

Conclusion: This study delineates the heterogeneity of EGPA/GPA overlap and underscores the need for personalized treatment approaches. Future prospective studies should explore targeted therapies, including rituximab and IL-5 blockade, in these overlapping AAV subtypes.

Objectives: To assess factors associated with rapidly progressive interstitial lung disease (ILD) (RP-ILD) at time of ILD diagnosis in a multicentric retrospective cohort study of antisynthetase syndrome (ASyS). We used a complementary unsupervised approach, hierarchical clustering, to delineate distinct phenotypes among ASyS patients with ILD.

Methods: A total of 132 patients with ASyS, defined according to the 2024 ACR/European Alliance of Associations for Rheumatology (EULAR) ASyS classification criteria, and ILD, diagnosed by CT scan, were included. RP-ILD was defined by the presence of respiratory failure at ILD diagnosis or rapid ILD progression during the first 3 months.

Results: In our study, 39% of patients had RP-ILD at ILD diagnosis. Multivariate logistic regression analysis with cluster-robust SE identified the factors associated with RP-ILD at ILD diagnosis as male sex (aOR = 9.7 [1.6-59.5], p = 0.006), fever (aOR = 128 [12.6-1300], p < 0.001), organizing pneumonia (OP) pattern (aOR = 66.8 [3.4-1316], p = 0.006), and pleural effusion (aOR = 20.2 [1.1-373], p = 0.04), whereas RP-ILD was associated with lower likelihood of severe muscle disease (aOR = 0.004 [0.0001-0.13], p = 0.002). Clustering analysis identified four distinct groups: Cluster 1 (n = 62) included patients with systemic presentation, non-RP-ILD at ILD diagnosis, and anti-Jo-1 antibodies with good prognosis; Cluster 2 (n = 40) included older age patients with more RP-ILD at ILD diagnosis, pleuropericarditis, and a higher mortality rate.

Conclusion: Fever, pleural effusion, and OP pattern were independently associated with RP-ILD in ASyS patients. Unsupervised cluster analysis identified a severe inflammatory phenotype in ASyS patients with ILD.

Background and aims: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease globally, but its prevalence and severity remain poorly characterized in the general population. Our aim was to estimate the prevalence of MASLD and the risk of advanced fibrosis in a large Swedish general population cohort.

Methods: From the Swedish CArdioPulmonary bioImage Study (SCAPIS) cohort, we analyzed 27,763 participants aged 50-64 years who underwent extensive clinical characterization. MASLD was defined as <48 HU on non-contrast liver computed tomography (CT) imaging. The risk for advanced fibrosis was assessed using the dynamic aspartate aminotransferase (AST)/alanine transaminase (ALT) ratio.

Results: MASLD was present in 18.1% of participants and was more common in men than women (25.5% vs. 11.2%). Prevalence increased with cardiometabolic burden: from 7.0% among those without obesity, hypertension, or Type 2 diabetes mellitus (T2DM) to 70.2% among those with all three conditions. MASLD risk was elevated in individuals with obesity alone (adjusted odds ratio [aOR] 5.56; 95% CI = 4.89-6.31), T2DM alone (aOR = 2.66; 95% CI = 2.13-3.33), or hypertension alone (aOR = 1.78; 95% CI = 1.59-1.99). The combination of all three conferred the highest risk (aOR = 17.1; 95% CI = 14.0-20.9). Among persons with MASLD, 24.8% were classified as at risk for advanced fibrosis. Fibrosis risk was independently associated with hypertension (aOR = 1.44; 95% CI = 1.24-1.66), T2DM (aOR = 1.24; 95% CI = 1.06-1.46), male sex (aOR = 1.20; 95% CI = 1.02-1.42), and alcohol consumption (aOR per gram/day = 1.02; 95% CI = 1.01-1.03).

Conclusions: In Sweden, almost one in five middle-aged adults is affected by MASLD, with a quarter of cases at risk of advanced fibrosis. Male sex, obesity, T2DM, and hypertension are important predictors of the prevalence and severity of MASLD.

Background: Evidence regarding the risk of new-onset myasthenia gravis (MG) following statin therapy initiation is limited.

Objectives: To investigate this potential adverse effect using multinational real-world population-based data.

Methods: A self-controlled case series (SCCS) study was conducted using electronic medical records and claims databases from Hong Kong, the United Kingdom (UK) and Japan. Individuals aged ≥18 years with first diagnosis of MG and initiated statins were included. Conditional Poisson regression compared the risk of MG in different risk periods (up to 2 years after initiation) with non-exposure period, adjusted for age. Pooled results based on meta-analysis across all study sites were reported.

Results: In total, 2267 MG cases were analysed. Combined across all study sites, a significantly increased risk of incident MG was observed during the first year after statin initiation compared to non-exposure period, with a higher risk from Days 0-179 (pooled incidence rate ratio [IRR] [95% CI]: 2.662 [1.276-5.553]) than Days 180-364 (1.407 [1.014-1.954]). No increased risk of MG was observed more than 1 year after statin initiation (1.011 [0.848-1.206]). Moreover, the magnitude of MG risk elevation within the first 180 days after statin initiation was more pronounced with higher intensity statin regimens.

Conclusion: In this multinational SCCS study, statin initiation may be associated with increased risk of new-onset MG during the first 6-12 months, with greater magnitude of risk elevation for higher intensity statin therapy. Consideration of the possibility of new-onset MG may be advisable within first 6-12 months after initiating statins, especially for medium-to-high-intensity statin therapy.

Increased urinary albumin excretion is a strong predictor for cardiovascular events in persons with and without decreased glomerular filtration rate and can be assessed with the urinary albumin-to-creatinine ratio (UACR), which is a selective, sensitive, and convenient method for patients. As UACR levels ≥30 mg/g indicate heightened risk for cardiovascular disease (CVD) and chronic kidney disease (CKD) progression, this biomarker may be used to personalize preventive care. Among individuals with UACR ≥30 mg/g, reducing the UACR by at least 30% from the pretreatment (baseline) value is associated with a reduction in the risk for both cardiovascular and kidney events. Monitoring change in the UACR after drug treatment starts can be used to determine a need for medication adjustments, such as dose escalations, switching drug class, or adding further drug classes in patients with UACR ≥30 mg/g. In this review, we discuss how the biomarker UACR may be used to determine CVD and CKD risk, guide treatment, and monitor treatment response, and that the UACR is an effective tool to personalize medicine in patients with CKD.

Objectives: To describe the rationale, design and data collection procedures of the Swedish CArdioPulmonary bioImage Study (SCAPIS) re-examination, which, in its further scope, aims to quantify and explain the development of atherosclerosis, pathological cardiovascular ageing, longitudinal decline in lung function and the malignant transformation of pulmonary nodules among middle-aged Swedes in the longitudinal SCAPIS.

Methods: SCAPIS re-examination is a prospective observational study reassessing approximately 15,000 participants (50% of the original SCAPIS cohort) from six university hospitals. Participants were aged 55-75 years at follow-up, occurring a median of 8.1 years after the baseline investigation. Standardized protocols replicated baseline imaging and functional assessments, including questionnaires, clinical assessments and extensive computer tomography imaging.

Results: Interim analyses of the first 5000 participants (50% women; median age 65.5 [61.8-69.1] years) indicated an expected age-related increase in the prevalence and treatment of hypertension (from 22% to 37%) and diabetes (from 4% to 8%), together with a modest rise in central adiposity. Body mass index (median 26.6 kg/m²) and the proportion of obesity (22%) remained largely stable, whereas current smoking decreased from 7.5% to 3.4%. The observed patterns were consistent in men and women.

Conclusion: Here we present the rationale, design, methods and management of incidental findings in the SCAPIS re-examination. By integrating serial imaging, functional testing and biomarker profiling, the re-examination will furnish unprecedented insight into cardiopulmonary disease dynamics in an ageing population. These data will underpin personalized risk prediction and inform preventive strategies, while serving as a benchmark for future population-based imaging cohorts.