Dysregulated serum lipid profile is associated with inflammation and disease activity in primary Sjögren's syndrome: a retrospective study in China.

PURPOSE: To investigate the relationship between the lipid profiles of patients with primary Sjögren's syndrome (pSS) and other clinical characteristics, laboratory examination, disease activity, and inflammatory factors. In addition, the risk factors for hyperlipidemia-related complications of pSS and the effect of hydroxychloroquine (HCQ) usage on the lipid profile were incorporated into this study. METHODS: This is a single-center, retrospective study that included 367 patients who were diagnosed with pSS at Tongji Hospital, School of Medicine, Tongji University, China from January 2010 to March 2022. Initially, demographic information, clinical characteristics, medication records, and complications of the patients were gathered. A case-control analysis compared the 12 systems involvement (ESSDAI domain), clinical symptoms, and laboratory tests between pSS patients with and without dyslipidemia. A simple linear regression model was employed to investigate the relationship between serum lipid profile and inflammatory factors. Logistics regression analysis was performed to assess variables for hyperlipidemia-related complications of pSS. The paired t-test was then used to evaluate the improvement in lipid profile among pSS patients. RESULTS: 48.7 % of all pSS patients had dyslipidemia, and alterations in lipid levels were related to gender, age, and smoking status but not body mass index (BMI). Dyslipidemia is more prevalent in pSS patients who exhibit heightened autoimmunity and elevated levels of inflammation. Higher concentrations of multiple highly inflammatory factors correlate with a more severe form of dyslipidemia. Non-traditional cardiovascular risk factors may contribute to hyperlipidemia-related complications of pSS, such as increased, low complement 3 (C3) and low C4. According to our study, HCQ usage may protect against lipid-related disease in pSS. CONCLUSION: Attention should be paid to the dyslipidemia of pSS. This research aims to clarify the population portrait of pSS patients with abnormal lipid profiles and provides insights into the correlation between metabolism and inflammation in individuals with pSS and the potential role they play in the advancement of the disease. These findings provide novel avenues for further understanding the underlying mechanisms of pSS pathogenesis.

Functional significance of DNA methylation: epigenetic insights into Sjögren's syndrome.

Sjögren's syndrome (SjS) is a systemic, highly diverse, and chronic autoimmune disease with a significant global prevalence. It is a complex condition that requires careful management and monitoring. Recent research indicates that epigenetic mechanisms contribute to the pathophysiology of SjS by modulating gene expression and genome stability. DNA methylation, a form of epigenetic modification, is the fundamental mechanism that modifies the expression of various genes by modifying the transcriptional availability of regulatory regions within the genome. In general, adding a methyl group to DNA is linked with the inhibition of genes because it changes the chromatin structure. DNA methylation changes the fate of multiple immune cells, such as it leads to the transition of naïve lymphocytes to effector lymphocytes. A lack of central epigenetic enzymes frequently results in abnormal immune activation. Alterations in epigenetic modifications within immune cells or salivary gland epithelial cells are frequently detected during the pathogenesis of SjS, representing a robust association with autoimmune responses. The analysis of genome methylation is a beneficial tool for establishing connections between epigenetic changes within different cell types and their association with SjS. In various studies related to SjS, most differentially methylated regions are in the human leukocyte antigen (HLA) locus. Notably, the demethylation of various sites in the genome is often observed in SjS patients. The most strongly linked differentially methylated regions in SjS patients are found within genes regulated by type I interferon. This demethylation process is partly related to B-cell infiltration and disease progression. In addition, DNA demethylation of the runt-related transcription factor (RUNX1) gene, lymphotoxin-α (LTA), and myxovirus resistance protein A (MxA) is associated with SjS. It may assist the early diagnosis of SjS by serving as a potential biomarker. Therefore, this review offers a detailed insight into the function of DNA methylation in SjS and helps researchers to identify potential biomarkers in diagnosis, prognosis, and therapeutic targets.

Tofacitinib in the treatment of primary Sjögren's syndrome-associated interstitial lung disease: study protocol for a prospective, randomized, controlled and open-label trial.

INTRODUCTION: Tofacitinib, a selective inhibitor of JAK1 and/or JAK3, is considered to alleviate the pulmonary condition of primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD) through its anti-inflammatory and antifibrotic effects. METHODS AND ANALYSIS: This is a single-center, prospective, randomized, open-label trial. The trial will compare a 52-week course of oral tofacitinib with traditional therapy cyclophosphamide (CYC) combined with azathioprine (AZA) in the treatment of pSS-ILD. A total of 120 patients will be randomly assigned into two treatment groups with a 1:1 ratio and followed for 52 weeks from the first dose. The primary endpoint of the study is the increase of forced vital capacity (FVC) at 52 weeks. Secondary endpoints include high-resolution computed tomography (HRCT), diffusion capacity for carbon monoxide of the lung (DLCO), the Mahler dyspnea index, the health-related quality of life (HARQoL) score, the cough symptom score, EULAR Sjögren's syndrome disease activity index (ESSDAI), and safety. DISCUSSION: This study will be the first randomized controlled trial to investigate tofacitinib compared to the traditional regimen of CYC in combination with AZA in the treatment of pSS-ILD, which will provide data on efficacy and safety and further elucidate the role of the JAK-STAT signaling pathway in the development of pSS-ILD. ETHICS AND DISSEMINATION: Before starting the experiment, the research proposal, informed consent (ICF) and relevant documents in accordance with the ethical principles of the Helsinki Declaration and the relevant requirements of the local GCP rules for ethical approval shall be submitted to the ethics committee of the hospital. The ethical approval of this study is reviewed by the Ethics Committee of Tongji Hospital and the ethical approval number is 2021-LCYJ-007. When the experiment is completed, the results will also be disseminated to patients and the public through publishing papers in international medical journals. TRIAL REGISTRATION: The study was registered on the Chinese Clinical Trial Registry, www.chictr.org.cn ; ID ChiCTR2000031389.

Predicting cardiovascular risk in a Chinese primary Sjögren's syndrome population: development and assessment of a predictive nomogram.

Background: Patients with primary Sjögren's syndrome (pSS) are at increased risk of cardiovascular morbidity as compared with the general population. Objectives: A retrospective study on 349 Chinese patients with pSS was conducted to identify potential risk factors for cardiovascular events and develop a cardiovascular risk nomogram. Design: This is a retrospective observational study. Methods: The study included 349 patients who were diagnosed with pSS at Tongji Hospital, School of Medicine, Tongji University, China from January 2010 to March 2022. The least absolute shrinkage and selection operator (LASSO) was used to select features for the cardiovascular risk model. The features selected in LASSO were used to build the cardiovascular risk model in a multivariate logistic regression analysis. C-index, receiver operating characteristic (ROC) curve, calibration plot, and decision curve analysis were used to assess the predictive model. Internal validation was performed by bootstrapping. Results: Sex, joint pain as an initial symptom, dry mouth, oral ulcers, dental caries, Raynaud's phenomenon, fatigue, diabetes, elevated thyroid-stimulating hormone (TSH) level, and elevated systolic blood pressure were included in the nomogram for the prediction of cardiovascular risk. Our model had good discrimination (C-index: 0.824, 95% confidence interval: 0.712-0.936) and good calibration (C-index in the interval validation: 0.8). Decision curve analysis indicated that our nomogram demonstrated clinical usefulness for intervention in a cardiovascular disease possibility threshold of 3%. Conclusion: The cardiovascular risk nomogram incorporating sex, initial joint pain, dry mouth, oral ulcer, dental caries, Raynaud's phenomenon, fatigue, diabetes, elevated TSH, and systolic blood pressure could be used in the prediction of cardiovascular risk in patients with pSS and the guidance of further treatment.

Chronic Epstein-Barr virus infection: A potential junction between primary Sjögren's syndrome and lymphoma.

Primary Sjögren's syndrome (pSS) is an autoimmune disease that targets exocrine glands, leading to exocrine dysfunction. Due to its propensity to infect epithelial and B cells, Epstein-Barr virus (EBV) is hypothesized to be related with pSS. Through molecular mimicry, the synthesis of specific antigens, and the release of inflammatory cytokines, EBV contributes to the development of pSS. Lymphoma is the most lethal outcome of EBV infection and the development of pSS. As a population-wide virus, EBV has had a significant role in the development of lymphoma in people with pSS. In the review, we will discuss the possible causes of the disease.

Predictors of poor prognosis in ANCA-associated vasculitis (AAV): a single-center prospective study of inpatients in China.

To identify potential predictors by assessing adverse outcomes in ANCA-associated vasculitis (AAV) patients. Eighty-nine untreated AAV patients were followed up to January 31, 2022, death, or loss of follow-up. Clinical characteristics, laboratory tests, treatment, and progress were collected, and disease activity was evaluated via Birmingham Vasculitis Activity Score (BVAS). We determined risk factors of high-risk events, defined as developing tumors, renal replacement therapy (RRT), and death. Patients and renal survivals were computed by the Kaplan-Meier curve analysis. Cox regression analysis was performed for assessing variables for predicting death. During 267 person-years follow-up, 46 patients occurred high-risk events, including 20 patients receiving RRT, 12 patients developing tumors, and 29 patients who died mostly from organ failure and infection. Decreased estimated glomerular filtration rate (eGFR) (P < 0.001) and complement 3 levels (P = 0.019) were associated with high-risk events. Patients with lower serum potassium tended to develop tumors (P = 0.033); with higher BVAS (HR = 1.290, 95%CI 1.075-1.549, P = 0.006) and lower eGFR (HR = 0.782, 95%CI 0.680-0.901, P = 0.001) were more likely to undergo RRT. Patients with cardio and renal involvement exhibited a lower frequency of renal survival and all-cause mortality. Through multivariate COX analysis, age (HR = 1.016, 95%CI 1.016-1.105, P = 0.006) and eGFR (HR = 0.982, 95%CI 0.968-0.997, P = 0.018) predicted death in AAV, separately. The BVAS and eGFR could be a great prognosticator for RRT, while age and eGFR can independently predict the death. Serum potassium level and immunoglobulins should be focused on their predictor value in development of cancer and renal outcomes in AAV patients.

Potential Mechanisms of White Peony against Primary Sjögren's Syndrome Based on Network Pharmacology and Molecular Docking.

Background: Multiple system and organ damage occurs with the continuous progression of primary Sjögren's syndrome (pSS), and the lack of specific drugs against this disease is a huge challenge. White peony (WP), a widely used traditional Chinese herb, has been confirmed to have a therapeutic value in pSS. However, the specific mechanisms of WP in the treatment of pSS are unknown. Methods: The active ingredients and their targets in WP were searched on the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), and disease-related targets were collected from GeneCards, Online Mendelian Inheritance in Man (OMIM), and the Therapeutic Target Database (TTD). The overlapping targets were acquired by taking the intersection. A protein-protein interaction (PPI) network was structured using the STRING database. A disease-drug-ingredient-target (D-D-I-T) network was built using Cytoscape software. By filtering twice, core targets were acquired. Gene Ontology (GO) and Kyoto Encyclopedia Gene and Genome (KEGG) pathway enrichment analysis were accompanied by R packages. Finally, molecular docking was used to verify the abovementioned results. Results: In total, we screened 88 WP-related targets, 1480 pSS-related targets, and 32 overlapping targets. D-D-I-T Network analysis displayed six main active ingredients of WP, which played a significant therapeutic role in pSS. Further topological analysis selected seven core target genes, including IL-6, TNF, PPARγ, AKT1, CASP3, NOS3, and JUN. GO and KEGG analysis were used to elucidate pharmacological mechanisms, mainly acting in the AGE-RAGE signaling pathway. Molecular docking proved that paeoniflorin bound well with core targets. Conclusion: Our study revealed that IL-6, TNF, AKT1, CASP3, NOS3, and JUN may be pathogenic target genes, and PPARγ may be a protective target gene. The main active ingredients of WP mainly played a therapeutic role via the AGE-RAGE signaling pathway. These findings provide a fundamental and theoretical basis for the clinical application of WP.

The Efficiency of Hydroxychloroquine for the Treatment of Primary Sjögren's Syndrome: A Systematic Review and Meta-Analysis.

Objectives: This meta-analysis was conducted to evaluate the effects of hydroxychloroquine (HCQ) in the treatment of primary Sjögren's syndrome (pSS). Methods: Nine databases were searched for data collection. We used clinical features, including involvement in superficial tissues and visceral systems, and experimental findings, including Schirmer's test, unstimulated salivary flow rate (uSFR), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and immunoglobulins (IgG, IgM and IgA) as major outcome measures. The Downs and Black quality assessment tool and RevMan 5.3 were used to assess the methodological quality and statistical analysis, respectively. Results: Thirteen studies with pSS patients, consisting of two randomized controlled studies, four retrospective studies and seven prospective studies were analyzed. Results showed that HCQ treatment significantly improved the oral symptoms of pSS patients compared to non-HCQ treatment (P = 0.003). Similar trends favoring HCQ treatment were observed for uSFR (p = 0.05), CRP (p = 0.0008), ESR (p < 0.00001), IgM (p = 0.007) and IgA (p = 0.05). However, no significant improvement was observed in other clinical features, including ocular involvement, fatigue, articular lesions, pulmonary, neurological and lymphoproliferative symptoms, renal organs and other experimental parameters in the HCQ treatment group compared to the non-HCQ treatment group. Conclusion: HCQ treatment showed moderate efficacy to improve oral symptoms, uSFR, ESR, CRP, IgM and IgA. However, HCQ could not alleviate organ-specific systemic involvement. Systematic Review Registration:We have registered on the PROSPERO [https://www.crd.york.ac.uk/PROSPERO/], and the registration number is identifier [CRD42020205624].

MicroRNA-155 Suppresses Mesangial Cell Proliferation and TGF-ß1 Production via Inhibiting CXCR5-ERK Signaling Pathway in Lupus Nephritis.

Increasing evidence shows miR-155 plays an important role in regulating inflammatory processes in systemic lupus erythematosus (SLE), especially in lupus nephritis (LN). Because the chemokine CXCL13 is implicated in the pathogenesis of LN, here we examined whether miR-155 can modulate the activity of CXCL13 or its receptor CXCR5. We determined the expression of CXCL13 in normal and MRL/lpr mice and found elevated levels of CXCL13 in the kidneys of MRL/lpr mice compared with normal kidneys. Besides, CXCL13 expression was mainly detected in the glomerulus, specifically to mesangial areas. We then transfected a miR-155 mimic in human renal mesangial cells (HRMCs) to overexpress miR-155 and detected decreased protein levels of CXCR5 by western blot analysis. Transfection of the miR-155 mimic into CXCL13-treated HRMCs resulted in a significantly reduced proliferation rate of HRMCs as measured by the cell-counting assay and flow cytometry. Moreover, increased intracellular miR-155 also led to decreased phosphorylation of ERK and TGF-ß1 production. Together, these results revealed that miR-155 may play a role in the pathogenesis of LN.