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Chinese Medical Journal Oct 2023Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully...
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully elucidated, B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients. It has long been identified that Janus kinases-signal transducer and activator of transcription (JAK-STAT) signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus. Recently, increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells. Signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development, respectively or synergically. These results reveal the potential application of Janus kinase inhibitors for treatment of pSS, which may fundamentally improve the quality of life and prognosis of patients with pSS.
PubMed: 37185152
DOI: 10.1097/CM9.0000000000002539 -
Frontiers in Pharmacology 2023To evaluate efficacy and safety of iguratimod (IGU) in the treatment of rheumatic and autoimmune diseases. Databases such as Pubmed, Embase, Sinomed were searched (as...
To evaluate efficacy and safety of iguratimod (IGU) in the treatment of rheumatic and autoimmune diseases. Databases such as Pubmed, Embase, Sinomed were searched (as of July 2022) to collect randomized controlled trials (RCTs) of IGU in the treatment of rheumatic and autoimmune diseases. Two researchers independently screened the literature, extracted data, assessed the risk of bias of the included literature, and performed meta-analysis using RevMan 5.4 software. A total of 84 RCTs and 4 types of rheumatic and autoimmune diseases [rheumatoid arthritis (RA), ankylosing spondylitis (AS), primary Sjögren's syndrome (PSS) and Autoimmune disease with interstitial pneumonia]. Forty-three RCTs reported RA and showed that IGU + MTX therapy can improve ACR20 (RR 1.45 [1.14, 1.84], = 0.003), ACR50 (RR 1.80 [1.43, 2.26], < 0.0000), ACR70 (RR 1.84 [1.27, 2.67], = 0.001), DAS28 (WMD -1.11 [-1.69, -0.52], = 0.0002), reduce ESR (WMD -11.05 [-14.58, -7.51], < 0.00001), CRP (SMD -1.52 [-2.02, -1.02], < 0.00001), RF (SMD -1.65 [-2.48, -0.82], < 0.0001), and have a lower incidence of adverse events (RR 0.84 [0.78, 0.91], < 0.00001) than the control group. Nine RCTs reported AS and showed that IGU can decrease the BASDAI score (SMD -1.62 [-2.20, -1.05], < 0.00001), BASFI score (WMD -1.07 [-1.39, -0.75], < 0.00001), VAS (WMD -2.01 [-2.83, -1.19], < 0.00001), inflammation levels (decreasing ESR, CRP and TNF-α). Thirty-two RCTs reported PSS and showed that IGU can reduce the ESSPRI score (IGU + other therapy group: WMD -1.71 [-2.44, -0.98], < 0.00001; IGU only group: WMD -2.10 [-2.40, -1.81], < 0.00001) and ESSDAI score (IGU + other therapy group: WMD -1.62 [-2.30, -0.94], < 0.00001; IGU only group: WMD -1.51 [-1.65, -1.37], < 0.00001), inhibit the inflammation factors (reduce ESR, CRP and RF) and increase Schirmer's test score (IGU + other therapy group: WMD 2.18 [1.76, 2.59], < 0.00001; IGU only group: WMD 1.55 [0.35, 2.75], = 0.01); The incidence of adverse events in IGU group was also lower than that in control group (IGU only group: RR 0.66 [0.48, 0.98], = 0.01). Three RCTs reported Autoimmune disease with interstitial pneumonia and showed that IGU may improve lung function. Based on current evidence, IGU may be a safe and effective therapy for RA, AS, PSS and autoimmune diseases with interstitial pneumonia. : (CRD42021289489).
PubMed: 38143490
DOI: 10.3389/fphar.2023.1189142 -
Scientific Reports Nov 2023To understand the biological impact of alternative pre-mRNA splicing, it is vital to know which exons are involved, what protein domains they encode, and how the...
To understand the biological impact of alternative pre-mRNA splicing, it is vital to know which exons are involved, what protein domains they encode, and how the translated isoforms differ. Therefore, we developed a computational pipeline (RiboSplitter) focused on functional effect prediction. It builds on event-based alternative splicing detection with additional filtering steps leading to more efficient statistical testing, and with detection of isoform-specific protein changes. A key methodological advance is reading frame prediction by translating exonic DNA in all possible frames, then finding a single open reading frame, or a single frame with matches to known proteins of the gene. This allowed unambiguous translation in 93.9% of alternative splicing events when tested on RNA-sequencing data of B cells from Sjögren's syndrome patients. RiboSplitter does not depend on reference annotations and translates events even when one or both isoform(s) are novel (unannotated). RiboSplitter's visualizations illustrate each event with translation outcomes, show event location within the gene, and align exons to protein domains.
Topics: Humans; RNA Precursors; RNA, Messenger; RNA Splicing; Alternative Splicing; Protein Isoforms
PubMed: 37968320
DOI: 10.1038/s41598-023-47348-6 -
Journal of Medicine and Life Aug 2023Autoimmune rheumatoid arthritis (RA) is a systemic condition closely correlated with a variety of autoantibodies (Abs) that could be considered diagnostic and prognostic...
Autoimmune rheumatoid arthritis (RA) is a systemic condition closely correlated with a variety of autoantibodies (Abs) that could be considered diagnostic and prognostic markers. The current research was designed to detect the diagnostic values for a number (n) of these auto-Abs in RA detection and to evaluate the accuracy of a combined diagnostic scheme. This prospective study was conducted between September 2021 and August 2022 and included 110 subjects with RA, 70 individuals with other autoimmune disorders as positive controls (PC), and 50 unrelated, apparently healthy individuals as healthy controls (HC). The eligibility criteria for all study groups were followed stringently. An enzyme-linked immunosorbent assay (ELISA) was employed to measure rheumatoid factors (RF), cyclic citrullinated peptide antibodies (CCP-Abs), mutated citrullinated vimentin antibodies (MCV-Abs), anti-perinuclear factor antibodies (APF-Abs), and anti-keratin antibodies (AKA). We calculated the specificity, sensitivity, and predictive values of all auto-Abs. Significantly higher levels of anti-CCP-Abs, anti-MCV-Abs, APF-Abs, and AKAs were reported in the RA patients compared to the HC and PC subjects. RF levels, however, were only statistically elevated when compared to the HC individuals. Anti-APF-Abs had a higher sensitivity rate (70.9%), and anti-CCP-Abs had a higher specificity rate (94.16%) compared to other auto-Abs, whereas the combined detection scheme revealed a higher sensitivity (81.81%) and excellent specificity (90.83%) compared to the two former auto-Abs. Anti-perinuclear factor-Ab was a highly sensitive test, and CCP-Ab was a surpassingly specific assay for identifying RA. Furthermore, the combined detection scheme is an essential serological approach for RA diagnosis and crucial in differentiating this disease from other autoimmune diseases, thus promoting early diagnosis and treatment.
Topics: Humans; Anti-Citrullinated Protein Antibodies; Prospective Studies; Arthritis, Rheumatoid; Autoantibodies; Rheumatoid Factor; Enzyme-Linked Immunosorbent Assay; Peptides, Cyclic; Biomarkers
PubMed: 38024817
DOI: 10.25122/jml-2023-0158 -
Journal of Rheumatic Diseases Jan 2024Interstitial lung disease (ILD) is often observed in connective tissue diseases (CTDs), frequently in rheumatoid arthritis, systemic sclerosis, primary Sjögren's... (Review)
Review
Interstitial lung disease (ILD) is often observed in connective tissue diseases (CTDs), frequently in rheumatoid arthritis, systemic sclerosis, primary Sjögren's syndrome, and inflammatory myositis. Early detection of ILDs secondary to rheumatic diseases is important as timely initiation of proper management affects the prognosis. Among many imaging modalities, high-resuloution computed tomography (HRCT) serves the gold standard for finding early lung inflammatory and fibrotic changes as well as monitoring afterwards because of its superior spatial resolution. Additionally, lung ultrasound (LUS) and magnetic resonance imaging (MRI) are the rising free-radiation imaging tools that can get images of lungs of CTD-ILD. In this review article, we present the subtypes of ILD images found in each CTD acquired by HRCT as well as some images taken by LUS and MRI with comparative HRCT scans. It is expected that this discussion would be helpful in discussing recent advances in imaging modalities for CTD-ILD and raising critical points for diagnosis and tracing of the images from the perspective of rheumatologists.
PubMed: 38130961
DOI: 10.4078/jrd.2023.0042 -
Clinical Rheumatology Apr 2024Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by inflammatory infiltration, and dysfunction of the salivary and lacrimal glands. This research...
INTRODUCTION
Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by inflammatory infiltration, and dysfunction of the salivary and lacrimal glands. This research aimed to explore the disease pathogenesis and improve the diagnosis and treatment of pSS by mining inflammation-associated biomarkers.
METHODS
Five pSS-related datasets were retrieved from the Gene Expression Omnibus (GEO) database. Inflammation-associated biomarkers were determined by the least absolute shrinkage and selection operator (LASSO) and support vector machines recursive feature elimination (SVM-RFE). Single sample gene set enrichment analysis (ssGSEA) was implemented to profile the infiltration levels of immune cells. Real-time quantitative PCR (RT-qPCR) verified the expression of biomarkers in clinical samples.
RESULTS
Four genes (LY6E, EIF2AK2, IL15, and CXCL10) were screened as inflammation-associated biomarkers in pSS, the predictive performance of which were determined among three pSS-related datasets (AUC > 0.7). Functional enrichment results suggested that the biomarkers were involved in immune and inflammation-related pathways. Immune infiltration analysis revealed that biomarkers were notably connected with type 2 T helper cells, regulatory T cells which were significantly expressed between pSS and control. TESTOSTERONE and CYCLOSPORINE were predicted to take effect by targeting CXCL10 and IL15 in pSS, respectively.
CONCLUSION
Four inflammation-associated biomarkers (LY6E, EIF2AK2, IL15, and CXCL10) were explored, and the underlying regulatory mechanisms and targeted drugs associated with these biomarkers were preliminarily investigated according to a series of bioinformatics methods based on the online datasets of pSS, which provided a reference for understanding the pathogenesis of pSS. Key Points • Inflammation-associated biomarkers (LY6E, EIF2AK2, IL15, and CXCL10) were firstly identified in Sjögren's syndrome based on LASSO and SVM-RFE analyses. • CXCL10, EIF2AK2 and LY6E were prominently positively correlated with immature B cells, while IL15 were significantly negatively correlated with memory B cells in Sjögren's syndrome. • LY6E, EIF2AK2, IL15, and CXCL10 were significantly more highly expressed in clinical Sjögren's syndrome samples compared to healthy control samples, which was consistent with the analysis results of the GEO database. •LY6E, EIF2AK2, IL15, and CXCL10 might be used as the biomarkers for the treatment and diagnosis of Sjögren's syndrome.
Topics: Humans; Sjogren's Syndrome; Interleukin-15; Biomarkers; Autoimmune Diseases; Inflammation
PubMed: 38376769
DOI: 10.1007/s10067-024-06901-y -
Frontiers in Immunology 2023Primary Sjogren Syndrome (pSS) is an autoimmune disease characterized by immune cell infiltration. While the presence of follicular T helper (Tfh) cells in the glandular...
BACKGROUND
Primary Sjogren Syndrome (pSS) is an autoimmune disease characterized by immune cell infiltration. While the presence of follicular T helper (Tfh) cells in the glandular microenvironment has been observed, their biological functions and clinical significance remain poorly understood.
METHODS
We enrolled a total of 106 patients with pSS and 46 patients without pSS for this study. Clinical data and labial salivary gland (LSG) biopsies were collected from all participants. Histological staining was performed to assess the distribution of Tfh cells and B cells. Transcriptome analysis using RNA-sequencing (RNA-seq) was conducted on 56 patients with pSS and 26 patients without pSS to uncover the underlying molecular mechanisms of Tfh cells. To categorize patients, we employed the single-sample gene set enrichment analysis (ssGSEA) algorithm, dividing them into low- and high-Tfh groups. We then utilized gene set enrichment analysis (GSEA), weighted gene co-expression network analysis (WGCNA), and deconvolution tools to explore functional and immune infiltration differences between the low- and high-Tfh groups.
RESULTS
Patients with pSS had a higher positive rate of the antinuclear antibody (ANA), anti-Ro52, anti-SSA, anti-SSB and hypergammaglobulinaemia and higher levels of serum IgG compared to the non-pSS. Histopathologic analyses revealed the presence of Tfh cells (CD4CXCR5ICOS) in germinal centers (GC) within the labial glands of pSS patients. GSEA, WGCNA, and correlation analysis indicated that the high-Tfh group was associated with an immune response related to virus-mediated IFN response and metabolic processes, primarily characterized by hypoxia, elevated glycolysis, and oxidative phosphorylation levels. In pSS, most immune cell types exhibited significantly higher infiltration levels in the high-Tfh group compared to the low-Tfh group. Additionally, patients in the Tfh-high group demonstrated a higher positive rate of the ANA, rheumatoid factor (RF), and hypergammaglobulinaemia, as well as higher serum IgG levels.
CONCLUSION
Our study suggests that Tfh cells may play a crucial role in the pathogenesis of pSS and could serve as potential therapeutic targets in pSS patients.
Topics: Humans; Transcriptome; Hypergammaglobulinemia; Sjogren's Syndrome; Systems Biology; T Follicular Helper Cells; Antibodies, Antinuclear; Immunoglobulin G
PubMed: 37638029
DOI: 10.3389/fimmu.2023.1216379 -
Frontiers in Immunology 2023Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren's syndrome. Currently this relies on the histopathologic diagnosis of focal...
INTRODUCTION
Assessing labial salivary gland exocrinopathy is a cornerstone in primary Sjögren's syndrome. Currently this relies on the histopathologic diagnosis of focal lymphocytic sialadenitis and computing a focus score by counting lym=phocyte foci. However, those lesions represent advanced stages of primary Sjögren's syndrome, although earlier recognition of primary Sjögren's syndrome and its effective treatment could prevent irreversible damage to labial salivary gland. This study aimed at finding early biomarkers of primary Sjögren's syndrome in labial salivary gland combining metabolomics and machine-learning approaches.
METHODS
We used a standardized targeted metabolomic approach involving high performance liquid chromatography coupled with mass spectrometry among newly diagnosed primary Sjögren's syndrome (n=40) and non- primary Sjögren's syndrome sicca (n=40) participants in a prospective cohort. A metabolic signature predictive of primary Sjögren's syndrome status was explored using linear (logistic regression with elastic-net regularization) and non-linear (random forests) machine learning architectures, after splitting the data set into training, validation, and test sets.
RESULTS
Among 126 metabolites accurately measured, we identified a discriminant signature composed of six metabolites with robust performances (ROC-AUC = 0.86) for predicting primary Sjögren's syndrome status. This signature included the well-known immune-metabolite kynurenine and five phospholipids (LysoPC C28:0; PCaa C26:0; PCaaC30:2; PCae C30:1, and PCaeC30:2). It was split into two main components: the first including the phospholipids was related to the intensity of lymphocytic infiltrates in salivary glands, while the second represented by kynurenine was independently associated with the presence of anti-SSA antibodies in participant serum.
CONCLUSION
Our results reveal an immuno-lipidomic signature in labial salivary gland that accurately distinguishes early primary Sjögren's syndrome from other causes of sicca symptoms.
Topics: Humans; Sjogren's Syndrome; Prospective Studies; Kynurenine; Salivary Glands; Salivary Glands, Minor
PubMed: 37520535
DOI: 10.3389/fimmu.2023.1205616 -
BMC Pulmonary Medicine Jul 2023To investigate the clinical outcomes and risk factors associated with progressive fibrosing interstitial lung disease (PF-ILD) in patients with primary Sjögren's...
BACKGROUND
To investigate the clinical outcomes and risk factors associated with progressive fibrosing interstitial lung disease (PF-ILD) in patients with primary Sjögren's syndrome-associated interstitial lung disease (pSjS-ILD).
METHODS
During 2015-2021, pSjS patients with ILD were retrospectively identified. Patients were grouped into non-PF-ILD and PF-ILD. Demographics, laboratory data, pulmonary function tests (PFTs), images, survival outcomes were compared between groups.
RESULTS
153 patients with SjS-ILD were reviewed, of whom 68 having primary SjS-ILD (pSjS-ILD) were classified into non-PF-ILD (n = 34) and PF-ILD groups (n = 34). PF-ILD group had persistently lower albumin levels and a smaller decline in immunoglobulin G (IgG) levels at the 3rd month of follow-up. The multivariate logistic regression analysis revealed that persistently low albumin levels were associated with PF-ILD. At the 12th month, the PF-ILD group experienced a smaller increase in FVC and a greater decline in the diffusion capacity of carbon monoxide (DLCO) than at baseline. The 3-year overall survival rate was 91.2%, and PF-ILD group had significantly poorer 3-year overall survival rate than non-PF-ILD group (82.4% vs. 100%, p = 0.011). Poor survival was also observed among female patients with PF-ILD.
CONCLUSIONS
Among patients with pSjS-ILD, the PF-ILD group had poorer 3-year survival outcomes. Persistent lower albumin level might be the risk factor of PF-ILD. Early lung function tests could be helpful for the early detection of PF-ILD.
Topics: Humans; Female; Pulmonary Fibrosis; Sjogren's Syndrome; Retrospective Studies; Lung Diseases, Interstitial; Risk Factors; Albumins; Lung; Disease Progression
PubMed: 37468847
DOI: 10.1186/s12890-023-02562-w -
Immunity & Ageing : I & A Sep 2023Primary Sjögren's syndrome (pSS) is a common chronic systemic autoimmune disorder which primarily affects the exocrine glands. Patients may have extraglandular disease...
BACKGROUND
Primary Sjögren's syndrome (pSS) is a common chronic systemic autoimmune disorder which primarily affects the exocrine glands. Patients may have extraglandular disease involving multiple organs, including the kidneys. This study aimed at investigating the clinical data and laboratory markers which were associated with renal function damage or renal involvement.
METHOD
One thousand two hundred eighty-eight adult pSS patients from the Department of Rheumatology and Clinical Immunology were enrolled in this retrospective cohort study. And there were 334 patients of them followed up for more than two years for analyzing demographic, clinical data and laboratory markers. Statistical analysis was performed by R software (Version 3.6.2).
RESULT
Nearly 95% of 1288 pSS patients were women, and the positive rates of anti-SSA (Sjögren's syndrome A) and anti-SSB were 63% and 27% respectively. 12% of the pSS patients presented renal involvement with eGFR < 60 mL/min/1.73 m, and the mean age of hospital presentation, serum creatinine and urea were the highest (P < 0.001), and ANA (antinuclear antibody)-positive, anti-SSB-positive and anti-scl-70-positive were more prevalent in this group. Multivariate analyses showed that age, urea, chlorine and anti-SSA indicate a significant association with renal dysfunction. Potassium, sodium and Jo-1 were also confirmed to be related with decreased renal function. The receiver operating characteristic (ROC) analysis including the above factors showed a good performance on the evaluation of renal injury including eGFR < 60 mL/min/1.73 m and eGFR 60 -90 mL/min/1.73 m in pSS, with area under curve (AUC) values of 0.957 and 0.821, and high sensitivity (71.1% and 84.4%) and specificity (95.5% and 70.5%). After a more than two years follow-up of anti-SSA positive patients, 34.14% of them developed decreased renal function, and 13.58% of them experienced a progression of renal injury with a 23.64% decrease in eGFR.
CONCLUSION
Age, urea, chlorine, and anti-SSA were highly associated with renal injury in pSS. Early screening for autoantibodies would be meaningful for evaluation and prevention of renal injury in pSS.
PubMed: 37735697
DOI: 10.1186/s12979-023-00375-3