pSS Patients Research Articles

Comparison between 100% autologous serum and 100% platelet‐rich plasma eye drops and their impact on the treatment efficacy of dry eye in primary Sjogren syndrome

Purpose: The aim of the study was to compare the difference in the composition of 100% autologous serum (AS) and 100% platelet‐rich plasma (PRP) eye drops and assess their impact on the clinical out‐comes after the treatment of severe dry eye (DE) in primary Sjogren Syndrome patients (pSS).Methods: 22 patients with severe DE in pSS were treated with 100% AS (22 eyes) and 100% PRP (22 eyes) eye drops 5 times per day as monotherapy. The quantification of growth factors (GFs) as fibroblast growth factor (FGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet‐derived growth factor (PDGF), nerve growth factor (NGF), transforming growth factor (TGF‐b), insulin‐like growth factor(IGF), fibronectin and substance P in hemoderivates was performed. The main outcomes: Ocular Surface Disease Index (OSDI), Best Corrected Visual Acuity (BCVA), the Schirmer test, tear break‐up time (TBUT), corneal and conjunctival staining according to the Oxford scale, conjunctival hyperaemia and Meibomian gland parameters. The results were compared at the baseline, 1 and 3 months after the treatment. The clinical results were correlated with the concentration of GFs.Results: Significant differences were observed in the concentration of FGF, EGF, fibronectin, VEGF, PDGF AB, NGF, PDGF, substance P, TGF‐β in PRP compared to AS. There was a statistically significant improvement in BCVA, the Schirmer test, TBUT, Meibomian gland parameters, and the reduction of the OSDI scores, Oxford staining and conjunctiva hyperaemia in each group. There were many correspondences between the level of GFs and the mean change of the clinical outcomes. No adverse events were reported.Conclusions: Despite the fact that blood derivatives differ in their composition, they seem to be effective, safe in the treatment of severe DE in pSS patients. The signs and symptoms of DE were reduced in both groups. The obtained clinical results and the composition of hemoderivates may indicate the superiority of PRP in relieving the signs and symptoms of DE in pSS patients.

Identification of inflammatory markers as indicators for disease progression in primary Sjögren syndrome.

Primary Sjögren syndrome (pSS) is a systemic autoimmune disorder that affects various systems in the body, resulting in symptoms such as dry eyes and mouth, pain, and fatigue. Inflammation plays a critical role in pSS and its associated complications, with chronic inflammation being a common occurrence in patients with pSS. This review of the literature highlights inflammatory markers that could serve as indicators to predict disease progression in pSS. Laboratory markers are frequently and significantly increased in pSS patients, including erythrocyte sedimentation rate, C-reactive protein, complement proteins, S100 proteins, cytokines (IFNs, CD40 ligand, soluble CD25, rheumatoid factors, interleukins, and TNF-α), and chemokines (CXCL13, CXCL10, CCL2, CXCL11, and CCL25). These inflammatory markers can be used as prognostic indicators for disease progression in pSS. In conclusion, the results from the studies reported in this review indicate that high levels of inflammatory markers may serve as markers for disease progression of pSS, which, in turn, may be valuable in predicting disease outcome.

Identification of ferroptosis-related diagnostic markers in primary Sjögren's syndrome based on machine learning.

Primary Sjogren's syndrome (pSS) is a common autoimmune disorder that affects up to 0.3-3% of the global population. Ferroptosis has recently been identified to play a significant role in autoimmune diseases. However, the molecular mechanisms of ferroptosis in the initiation and progression of pSS remains unclear. To investigate the molecular mechanisms underlying the occurrence and progression of pSS, we utilized a comprehensive approach by integrating data obtained from the Gene Expression Omnibus (GEO) database with data from the FerrDb database to identify the ferroptosis-related differentially expressed genes (DEGs). Furthermore, we implemented an innovative transcriptomic analysis method utilizing a computer-aided algorithm to establish a network between hub genes associated with ferroptosis and the immune microenvironment in pSS patients. Our results revealed significant differences in the gene expression profiles of pSS samples compared to normal tissues, with 1,830 significantly up-regulated genes and 1,310 significantly down-regulated genes. In addition, our results showed a significant increase in the proportions of B cells and CD4+ T cells in pSS samples compared to normal tissues. AND then, our analysis revealed that a combination of six ferroptosis-related genes, including TBK1, SLC1A4, PIK3CA, ENO3, EGR1, and ATG5, could serve as optimal markers for the diagnosis of pSS. The combined analysis of these six genes accurately diagnosed the occurrence of pSS. This study offers valuable insights into the pathogenesis of pSS and highlights the importance of targeting ferroptosis-related DEGs, which suggests a novel treatment strategy for pSS.

Secretagogue effect of PDE4 inhibitor apremilast on human salivary gland organoids obtained from primary Sjögren's syndrome patients.

The aim of the study was to culture vital salivary gland organoids obtained through labial or parotid biopsy of primary Sjögren's syndrome (pSS) patients in order to evaluate their morphological and functional features in basal condition and after stimulation with Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) activator forskolin and phosphodiesterase 4 (PDE4) inhibitor apremilast, their in vitro regenerative capacity and the immune-histological resemblance with original tissue. Salivary gland tissues from five pSS patients were processed to obtain vital organoids; swelling assay and cell proliferation tests were performed after forskolin and apremilast application. Immunochemistry evaluation on original salivary gland tissue and corresponding organoids was performed, and secretomics analysis was conducted to assess their functional status. After application of forskolin and apremilast, we observed organoid swelling after 30 minutes, compatible with a positive functional status and enhancement of saliva production. In 3 cases, apremilast induced organoid proliferation. All cases were positive for cytokeratin 14 (CK14) and most for cytokeratin 5 (CK5). All the cases were positive for amylase; its secretion, and thus functional status of organoids, was confirmed by its high concentration in the culture medium. A focal ductal differentiation was found in some cases, highlighted by epithelial membrane antigen (EMA) positivity. The more differentiated EMA positive areas were negative for the staminal marker CK14, showing a sort of "complementary staining". Our data highlighted that differentiated cells and vital functional organoids that recapitulate the development of original salivary glands can be obtained from pSS epithelium. For the first time, the direct stimulating effect of PDE4 inhibitor apremilast on pSS human salivary gland organoids is reported, opening new perspectives on targeting oral dryness with drugs that combine secretagogue and immunomodulatory effects.

Risk analysis of breast cancer and breast fibrocystic change in female primary Sjögren's syndrome patients.

Sjögren's syndrome is an autoimmune disease with the chronic inflammation of glandular tissues, typically salivary and lacrimal glands. Since mammary tissue shares the glandular structure, Sjögren's syndrome may also target mammary tissue to cause breast diseases. We therefore determined whether primary Sjögren's syndrome (pSS) is associated with the increased risk of breast cancer (BC) and breast fibrocystic change (FC). Total 282 female patients with pSS were recruited from a medical center in Taiwan, and patients' medical records were reviewed to identify BC and ultrasonographic breast FC. The prevalence, incidence and risk factors for BC and breast FC in pSS patients were determined, and the risk factors for these breast diseases were subsequently analyzed. Our results showed that pSS patients had the increased prevalence and incidence of BC, and high anti-SSA(Ro) antibody titers were found to be associated with the increased risk of BC. Breast FC was also found highly prevalent in these patients. Comorbidity analysis as risk factor for BC in pSS patients showed diabetes mellitus was strongly associated with the increased risk of BC (odds ratio = 10.4, P = .0006), whereas breast FC was inversely associated with the risk of BC (odds ratio = 0.077 P = .0158). These data indicated that pSS is association with the increased risk of BC and with the high prevalence of ultrasonographic breast FC. Our results also suggest that, in pSS patients, the high anti-SSA(Ro) antibody titers and diabetes mellitus confer the increased risk of BC, whereas the absence of ultrasonographic breast FC predicts the higher risk of BC.

Rapamycin can alleviate the submandibular gland pathology of Sjögren's syndrome by limiting the activation of cGAS-STING signaling pathway.

Sjögren's Syndrome (SS) is also known as autoimmune exocrine gland disease. Previous studies have confirmed that adaptive immunity plays an important role in the development of this disease. But less is known about the role of the innate immune system. To identify the core pathways, and local infiltrated immune cells in the local immune microenvironment of SS. We verified the activation of these core genes and core signaling pathways in SS model mice by in vivo experiment and transcriptome sequencing. Finally, we identified 6 core genes EPSTI1, IFI44L, MX1, CXCL10, IFIT3, and IFI44. All the 6 genes had good diagnostic value. Based on multi-omics sequencing results and experimental studies, we found that cGAS-STING signaling pathway is most relevant to the pathogenesis of SS. By in vivo experiments, we verified that autophagy is the key brake to limit the activation of cGAS-STING signaling pathway. Maladaptive activation of autophagy and cGAS-STING signaling pathway are central contributors to the SG pathogenesis of pSS patient. Regulating autophagy by rapamycin may be a possible treatment for Sjögren's syndrome in the future.

Multimodal Single-Cell Sequencing of B Cells in Primary Sjögren's Syndrome.

B cells are important in the pathogenesis of primary Sjögren's syndrome (pSS). Patients positive for Sjögren's syndrome antigen A/Sjögren syndrome antigen B (SSA/SSB) autoantibodies are more prone to systemic disease manifestations and adverse outcomes. We aimed to determine the role of B cell composition, gene expression, and B cell receptor usage in pSS subgroups stratified for SSA/SSB antibodies. Over 230,000 B cells were isolated from peripheral blood of patients with pSS (n=6 SSA-, n=8 SSA+ single positive and n=10 SSA/SSB+ double positive) and four healthy controls and processed for single-cell RNA sequencing (scRNA-seq) and single-cell variable, diversity, and joining (VDJ) gene sequencing (scVDJ-seq). We show that SSA/SSB+ patients present the highest and lowest proportion of naïve and memory B cells, respectively, and the highest up-regulation of interferon-induced genes across all B cell subtypes. Differential usage of IGHV showed that IGHV1-69 and IGHV4-30-4 were more often used in all pSS subgroups compared with controls. Memory B cells from SSA/SSB+ patients displayed a higher proportion of cells with unmutated VDJ transcripts compared with other pSS patient groups and controls, indicating altered somatic hypermutation processes. Comparison with previous studies revealed heterogeneous clonotype pools, with little overlap in CDR3 sequences. Joint analysis using scRNA-seq and scVDJ-seq data allowed unsupervised stratification of patients with pSS and identified novel parameters that correlated to disease manifestations and antibody status. We describe heterogeneity and molecular characteristics in B cells from patients with pSS, providing clues to intrinsic differences in B cells that affect the phenotype and outcome and allowing stratification of patients with pSS at improved resolution.

Transcriptional profiling upon T cell stimulation reveals down-regulation of inflammatory pathways in T and B cells in SLE versus Sjögren’s syndrome

Systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS) share clinical as well as pathogenic similarities. Although previous studies suggest various abnormalities in different immune cell compartments, dedicated cell-type specific transcriptomic signatures are often masked by patient heterogeneity. Here, we performed transcriptional profiling of isolated CD4, CD8, CD16 and CD19 lymphocytes from pSS and SLE patients upon T cell stimulation, in addition to a steady-state condition directly after blood drawing, in total comprising 581 sequencing samples. T cell stimulation, which induced a pronounced inflammatory response in all four cell types, gave rise to substantial re-modulation of lymphocyte subsets in the two autoimmune diseases compared to healthy controls, far exceeding the transcriptomic differences detected at steady-state. In particular, we detected cell-type and disease-specific down-regulation of a range of pro-inflammatory cytokine and chemokine pathways. Such differences between SLE and pSS patients are instrumental for selective immune targeting by future therapies.

Respiratory infection risk in primary Sjögren's syndrome complicated with interstitial lung disease: a retrospective study.

To explore clinical and laboratory characteristics of primary Sjögren's syndrome (pSS) complicated with interstitial lung disease (ILD) and investigate the risk factors for respiratory infections in pSS-ILD. A cohort of 162 pSS-ILD patients in Peking University People's Hospital from 2015 to 2020 were included, and all medical records were completely collected. We screened 53 patients suffering from respiratory infections as study cases, compared with 109 age- and sex-matched controls. Differences between infection group and control group were compared. Univariate and multivariate binary logistic regression tests were conducted to identify potential risk factors for respiratory infections in pSS-ILD patients. Among 162 pSS-ILD patients, 32.72% (53/162) suffered from respiratory infections. The most frequent type of ILD was nonspecific interstitial pneumonia (32.08%, 51/159), and the most common type of pathogen was bacteria (64.25%, 34/53). Infection group showed higher levels of ESSDAI (P < 0.001), CRP (P < 0.001), ESR (P = 0.003), and C3 (P = 0.020) but lower level of DLCO-SB (P = 0.015). Univariate logistic model revealed that PAH and the use of glucocorticoid increased infection risk in pSS-ILD patients. On multivariate logistic regression analysis, PAH (OR = 3.993, 95% CI = 1.192-13.373, P = 0.025) and severe reduction of DLCO (DLCO-SB < 40%, OR = 4.625, 95% CI = 1.281-16.702, P = 0.019) were significantly associated with increased risk of respiratory infections in pSS-ILD patients. Among pSS-ILD patients, the most frequent type of ILD was nonspecific interstitial pneumonia. In patients with infection, bacteria were the most common pathogen. Higher levels of ESSDAI, CRP, ESR, and C3 may be correlated with increased infection risk. PAH and reduction of DLCO were identifiedas independent risk factors. Key Points • ILD and infectious diseases severely affect pSS patient conditions. • Higher levels of ESSDAI, CRP, ESR, and C3 may be correlated with increased infection risks in pSS-ILD. • PAH and reduction of DLCO were identified as independent risk factors for lower respiratory infection.

SLAMF3 promotes Th17 differentiation and is reversed by iguratimod through JAK1/STAT3 pathway in primary Sjögren's syndrome

ObjectiveThe signaling lymphocytic activation molecule family of receptors (SLAMF) is involved in the activation of T cells and plays important roles in the pathogenesis of autoimmune diseases. The purpose of this study is to observe the expression of SLAMF3 on CD4 + T cells and its effect on the differentiation of T helper 17 (Th17) in primary Sjögren's syndrome (pSS). Furthermore, we found iguratimod (IGU) could effectively reverse the aberrant Th17 differentiation through JAK1/STAT3 signaling. MethodsPeripheral blood mononuclear cells from 40 pSS and 40 healthy control subjects were enrolled for analysis of expression of SLAMF3 on CD4 + T and Th17 cells by flow cytometry. Serum IL-17 and SLAMF3 were detected by ELISA assay. Labial biopsies from 20 pSS patients and 20 non-pSS controls were performed immunohistochemical for staining expression of CD4, IL-17, and SLAMF3. Under the priming conditions with anti-CD3/CD28 or CD3/SLAMF3 antibodies on CD4 + T cells extracted from pSS and controls, the proportion of Th17 cells in CD4 + T cells and the amount of soluble IL-17A were assessed by flow cytometry and ELISA. Furthermore, RNA sequencing was performed for the transcriptomics study. Additionally, RNA level of RORγt and IL-17A and the protein level of RORγt, p-JAK1 and p-STAT3, were detected by real-time PCR and western blot. ResultsThe expression levels of SLAMF3 on CD4 + T and Th17 cells in the peripheral blood and salivary glands in pSS patients were significantly elevated than that in control groups. The serum IL-17A and SLAMF3 in pSS patients were much higher compared with the control group. Although co-stimulation of CD3/SLAMF3 could promote CD4 + T cells differentiate into Th17 cells both in pSS and controls, the CD4 + T cells from pSS have a more sensitive response in Th17 differentiation with the SLAMF3 stimulation. Transcriptomics results showed the CD3/SLAMF3 stimulation caused the activation of Th17 signaling and JAK1/STAT3 pathway. Quantitative PCR and western blotting confirmed the IGU (iguratimod), which is a safe clinical drug in treatment of autoimmune diseases, effectively reversed the increased Th17 proportion, the expression levels of RORγt, pJAK1, and pSTAT3 caused by CD3/SLAMF3 stimulation. ConclusionSLAMF3 upregulates Th17 cell differentiation of CD4 + T cells and IL-17A secretion through enriching RORγt and activating the transcriptomics participating in the pathogenesis of primary Sjögren's syndrome. IGU could inhibit the process through this therapeutic target in pSS.

Associations between TNFSF13B polymorphisms and primary Sjögren's syndrome susceptibility in primary Sjögren's syndrome patients: A meta-analysis.

B-cell activating factor (BAFF) is a key regulator of primary Sjögren's syndrome (pSS), which is characterized by B-lymphocyte hyperactivity. BAFF, also known as tumor necrosis factor ligand superfamily member 13B, is encoded by TNFSF13B. This study aimed to explore the possible relationships between five single-nucleotide polymorphisms (SNPs) of TNFSF13B (rs9514827, rs1041569, rs9514828, rs1224141, and rs12583006) and pSS susceptibility. We searched the following databases for articles on TNFSF13B polymorphism and pSS published up to January 2023: PubMed, Cochrane, Elsevier, Web of Science, CNKI, CQVIP, and WanFang. The odds ratios (with 95% confidence intervals) of genotypes and SNP alleles of TNFSF13B were investigated in patients with pSS to determine their relationships with pSS. This meta-analysis employing the fixed-effect model comprised three studies of pSS patients and randomly selected healthy controls (HCs), revealing statistically significant relationships between pSS susceptibility and two SNPs: rs1041569 and rs12583006. Because rs1041569 was not in Hardy-Weinberg equilibrium in the HC group, it was eliminated from the analysis. Polymorphisms in the BAFF (TNFSF13B) gene were related to vulnerability to pSS among pSS patients and HCs alike. The SNP rs12583006 was significantly related to pSS susceptibility in pSS patients.

High-content multimodal analysis supports the IL-7/IL-7 receptor axis as a relevant therapeutic target in primary Sjögren's syndrome

ObjectiveWhile the involvement of IL-7/IL-7R axis in pSS has been described in relation to T cells, little is known about the contribution of this pathway in relationship with other immune cells, and its implication in autoimmunity. Using high-content multiomics data, we aimed at characterizing IL-7R expressing cells and the involvement of IL-7/IL-7R pathway in pSS pathophysiology. MethodsAn IL-7 signature established using RNA-sequencing of human PBMCs incubated with IL-7 was applied to 304 pSS patients, and on RNA-Seq datasets from tissue biopsies. High-content immunophenotyping using flow and imaging mass cytometry was developed to characterize peripheral and in situ IL-7R expression. ResultsWe identified a blood 4-gene IL-7 module (IKZF4, KIAA0040, PGAP1 and SOS1) associated with anti-SSA/Ro positiveness in patients as well as disease activity, and a tissue 5-gene IL-7 module (IL7R, PCED1B, TNFSF8, ADAM19, MYBL1) associated with infiltration severity. We confirmed expression of IL-7R on T cells subsets, and further observed upregulation of IL-7R on double-negative (DN) B cells, and especially DN2 B cells. IL-7R expression was increased in pSS compared to sicca patients with variations seen according to the degree of infiltration. When expressed, IL-7R was mainly found on epithelial cells, CD4+ and CD8+ T cells, switched memory B cells, DN B cells and M1 macrophages. ConclusionThis exhaustive characterization of the IL-7/IL-7R pathway in pSS pathophysiology established that two IL-7 gene modules discriminate pSS patients with a high IL-7 axis involvement. Their use could guide the implementation of an anti-IL-7R targeted therapy in a precision medicine approach.

Cognitive Aspects of Prymary Sjögren’s Syndrome

AbstractBackgroundSjögren’s primary syndrome (PSS) is an autoimmune disease that affects the tear line exocrine glands and saliva and may also interfere with the central (CNS) and peripheral nervous systems. PSS patients presenting with the disease can be divided into a profile characterized by the greater intensity of symptoms such as pain, fatigue, and dryness and another with fewer symptoms but a more severe prognosis. Therefore, it was verified the involvement of the CNS through neuropsychological evaluation in the different profiles of PSS.Method24 women, 11 with profile 1 (more intense symptoms, PSS1), and 13 with profile 2 (worse prognosis, PSS2), performed neuropsychological assessment composed by: MoCa, Boston reduced version, FAS. Mann Withney’s nonparametric test compared the groups, and the variables were correlated by Spearman coefficient of SPSS 23.ResultThere was a predominance of women (100%) with a mean age of 49.91 ±10.56 years and schooling of 7,83 ± 2.79 years. The comparison between PSS1 and PSS2 showed no significant difference between age (PSS1 = 52,72±8.83; Pss2 = 47.53±11.64; p = 0.257), schooling (PSS1 = 528.18± 2.67;; Pss2 = 7.53±2.96, p = 0.451) and between the tests for profiles, Moca (p = .636), Boston (p = .194), FAS (p = 1.00). Between the tests, we can verify significant positive correlations between Moca x Boston; Moca x FAS_F; Moca x FAS_A; Moca x FAS_S; Moca x FAS, and the FAS variables among themselves. The correlation between age and schooling was not significant.ConclusionThere was no difference between age and schooling or neuropsychological assessment, considering the techniques used. Then, cognition may be preserved in this sample, reflecting a non‐involvement of the CNS in this disease. However, future studies that are being conducted need to complement these results by expanding the sample or using other instruments.

Risk of subclinical atherosclerosis in primary Sjogren's syndrome: A systematic review and meta-analysis

BackgroundCurrently, the guidelines for prevention and management of atherosclerosis in patients with Sjogren's syndrome (SS) do not differentiate from those concerning the general population. ObjectivesThe present systematic review aimed to summarize evidence from primary studies assessing the risk of subclinical atherosclerosis in patients with primary SS (pSS). Methods and resultsLiterature was searched until June 2023. Eligible records were randomized controlled trials and observational studies comparing subclinical atherosclerosis markers between pSS patients and healthy controls. DerSimonian-Laird random effects models were used to calculate overall effect estimates. Totally, 19 observational studies comprising 1625 participants were included. Compared to healthy controls, pSS patients had significantly higher values of carotid-femoral intima-media thickness (cfIMT) (MD= 0.07 mm; 95 % CI= [0.04, 0.11]; p <0.001) and were more frequently diagnosed with atherosclerotic plaques (OR= 1.9; 95 % CI= [1.32, 2.74]; p <0.001). Moreover, pSS patients showed a decreased flow and nitrate-mediated dilation (MD = -2.48 %; 95 % CI= [-4.57, -0.39]; p = 0.02, MD= -2.11 %; 95 % CI= [-3.22, -1.01]; p <0.001, respectively). Similar results were observed for the pulse-wave velocity (MD= 0.7 m/s; 95 % CI= [0.36, 1.05]; p <0.001) and the ankle-brachial index (OR= 5.78; 95 % CI= [2.23, 14.99]; p = 0.003). Based on meta-regression analyses, only the disease duration and erythrocyte sedimentation rate were positively and significantly associated with higher cfIMT values. ConclusionPatients with pSS have an increased risk of subclinical atherosclerosis compared to healthy population and thus possibly require early and disease-specific intervention. Further research is warranted for more accurate cardiovascular risk management in SS.

Prognostic significance of pulmonary hypertension in patients with connective tissue disorders: review and meta-analysis

Abstract Background Pulmonary hypertension (PH) is a frequent complication of connective tissue disorders (CTD) with major impact on prognosis of the disease, especially in patients with systemic sclerosis (SSc). Recently suggested new classification based on the hemodynamic assessment of PH and currently available pharmacologic treatment can be associated with improved survival, therefore underlining the group of the patients with PH and most affected survival function is crucial. Objectives of our study were to perform systemic review and meta-analysis of published literature evaluating survival function in patients with SSc and Systemic lupus erythematosus (SLE) with and without PH, also to compare PH-associated survival function in between patients with SSc, systemic lupus erythematosus (SLE), other connective tissue disorders (CTD) and conditions characterized with PH. Methods Literature search strategies, inclusion and exclusion criteria, outcome measurements, and statistical methods were analyzed according to an established protocol of the cochrane collaboration steps and meta-analysis of observational studies in epidemiology recommendations (MOOSE). Case control studies evaluating PH-associated survival function in SSc (including interstitial lung disease -ILD) and SLE patients and also studies comparing survival function among SSc, various CTD entities and conditions associated with PH were included in the analysis. Results A total of 2114 papers were collected according to our searching criteria, of those 7 studies including 1470 SSc patients with PH and 1368 SSc patients without PH, also 4 studies including 108 SLE patients with PH and 1288 SLE patients without PH and evaluated survival function were selected. We also performed meta-analysis of 6 studies (including 777 SSc, 249 SLE, 41 idiopathic PH (IPH), 49 primary PH (PPH) and 29 primary Sjogren’s syndrome (pSS) patients) comparing PH-associated survival function in different subgroups. The mean pooled follow-up was 5.4 years (5.4±4.4 year). We observed that SSc patients with PH showed worst survival as compared to SSc patients without PH [RR (95 %CI) 2.20 (1.52 to 3.20); p&amp;lt;0.00001] (Figure1). Same pattern was observed in patients with SLE [RR (95 %CI) 5.20 (2.34 to 11.56); p&amp;lt;0.00001] (Figure 1). Overall, SSc patients with PH were characterized with lower survival function as compared to other reasons of PH including SLE [RR (95 %CI) 1.77 (1.43 to 2.19); p&amp;lt;0.00001] (Figure 2). Conclusions Patients with SSc associated PH are characterized with significantly lower survival function as compared to SSc patients without PH. Among various CTD and other entities of PH, SSc shows worst survival, underlining prognostic significance of detection and evaluation of PH according to currently established approach.Figure 1Figure 2

MICa/b-dependent activation of natural killer cells by CD64+ inflammatory type 2 dendritic cells contributes to autoimmunity.

Primary Sjögren's syndrome (pSS) is an inflammatory autoimmune disorder largely mediated by type I and II interferon (IFN). The potential contribution of innate immune cells, such as natural killer (NK) cells and dendritic cells (DC), to the pSS pathology remains understudied. Here, we identified an enriched CD16+ CD56hi NK cell subset associated with higher cytotoxic function, as well as elevated proportions of inflammatory CD64+ conventional dendritic cell (cDC2) subtype that expresses increased levels of MICa/b, the ligand for the activating receptor NKG2D, in pSS individuals. Circulating cDC2 from pSS patients efficiently induced activation of cytotoxic NK cells ex vivo and were found in proximity to CD56+ NK cells in salivary glands (SG) from pSS patients. Interestingly, transcriptional activation of IFN signatures associated with the RIG-I/DDX60 pathway, IFN I receptor, and its target genes regulate the expression of NKG2D ligands on cDC2 from pSS patients. Finally, increased proportions of CD64hi RAE-1+ cDC2 and NKG2D+ CD11b+ CD27+ NK cells were present in vivo in the SG after poly I:C injection. Our study provides novel insight into the contribution and interplay of NK and cDC2 in pSS pathology and identifies new potential therapy targets.

Pregnancy Outcomes in Patients with Primary Sjögren's Syndrome Undergoing Assisted Reproductive Therapy: A Multi-center Retrospective Study.

The aim of this work was to investigate the pregnancy outcomes in infertile patients with primary Sjögren's syndrome (pSS) undergoing assisted reproductive therapy (ART). A multi-center retrospective study was performed in pregnant women with pSS and ART from five tertiary hospitals from Guangdong Province from 2013 to 2022. Natural planned pregnancy in pSS and healthy people undergoing ART were selected as controls. Pregnancy outcomes were collected from medical records and compared among groups. Twenty-four pregnancies in pSS with ART, 70 natural planned pregnancies in pSS, and 96 pregnancies in healthy people with ART were analyzed. More than half of the pSS mothers undergoing ART have a past history of adverse pregnancy and spontaneous abortion was the most common (10/24, 41.7%). Primary infertility (25.0%) and recurrent spontaneous abortion (16.7%) were the leading causes of infertility in pSS. The major maternal adverse pregnancy outcome (APO) in pSS patients with ART was premature delivery (11/24, 45.8%), likely attributed to twin gestation (4/11, 36.4%) and fetal distress (3/11, 27.3%). Twenty-seven live infants were born from 22 successful deliveries. The live birth rate was 93.1% (27/29). The average delivery time was 36.1 ± 3.3weeks of gestation. The average birthweight was 2434.4 ± 722.1g, compared with 2844.9g in natural planned pregnancy in pSS, and 3072.1g from healthy mothers with ART (P < 0.001). Seven (25.9%) low-birthweight (LBW) infants were born, and the incidence was comparable to the other two groups (22.2% in natural pregnancy, 13.0% in healthy people, P = 0.09). No infants developed congenital heart block (CHB). ART is an effective method for infertility in patients with pSS. Premature delivery is the leading maternal APOs. The incidence of fetal APOs does not increase, while birthweight is lower in offspring from pSS mothers with ART.

Circulating CD8+ T Cell Subsets in Primary Sjögren's Syndrome.

Currently, multiple studies have indicated that CD8+ T lymphocytes play a role in causing damage to the exocrine glands through acinar injury in primary Sjögren's syndrome (pSS). The aim of this research was to assess the imbalance of circulating CD8+ T cell subsets. We analyzed blood samples from 34 pSS patients and 34 healthy individuals as controls. We used flow cytometry to enumerate CD8+ T cell maturation stages, using as markers CD62L, CD28, CD27, CD4, CD8, CD3, CD45RA and CD45. For immunophenotyping of 'polarized' CD8+ T cell subsets, we used the following monoclonal antibodies: CXCR5, CCR6, CXCR3 and CCR4. The findings revealed that both the relative and absolute numbers of 'naïve' CD8+ T cells were higher in pSS patients compared to the healthy volunteers. Conversely, the proportions of effector memory CD8+ T cells were notably lower. Furthermore, our data suggested that among patients with pSS, the levels of cytotoxic Tc1 CD8+ T cells were reduced, while the frequencies of regulatory cytokine-producing Tc2 and Tc17 CD8+ T cells were significantly elevated. Simultaneously, the Tc1 cell subsets displayed a negative correlation with immunoglobulin G, rheumatoid factor, the Schirmer test and unstimulated saliva flow. On the other hand, the Tc2 cell subsets exhibited a positive correlation with these parameters. In summary, our study indicated that immune dysfunction within CD8+ T cells, including alterations in Tc1 cells, plays a significant role in the development of pSS.

Increased proportion of CD226 + CD14 + monocytes correlates with clinical features and laboratory parameters in patients with primary Sjögren's syndrome.

CD226 is widely expressed on the surface of immune cells as a co-stimulatory receptor, which is involved in the development of many autoimmune diseases. The purpose of this study was to investigate the proportion of CD226 on CD14 + monocytes in the peripheral circulation of patients with primary Sjögren's syndrome (pSS) and the clinical significance of pSS. The proportion of CD226 on the surface of CD14 + monocytes was measured by flow cytometry in 45 pSS patients and 25 healthy controls (HC). The correlations between the proportion of CD226 + CD14 + monocytes and the clinical features and laboratory parameters of pSS were analyzed. Meanwhile, we analyzed the change in proportion of CD226 + CD14 + monocytes before and after treatment, and the clinical significance of pSS was evaluated. The proportion of CD226 on CD14 + monocytes markedly increased in pSS patients compared to HC (p < .01). We found the proportion of CD226 + CD14 + monocytes was positively correlated with the disease activity and severity of pSS patients. The proportion of CD226 + CD14 + monocytes in pSS patients with decayed tooth, fatigue, interstitial lung disease (ILD), low WBC, high IgG, anti-Ro60, and anti-SSB positive increased compared to that in negative patients (p < .05). Furthermore, the proportion of CD226 + CD14 + monocytes was significantly higher in active patients than in nonactive patients (p < .01). Additionally, the proportion of CD226 + CD14 + monocytes decreased in seven pSS patients after treatment (p < .01). Our study suggested that an increased CD226 proportion on CD14 + monocytes was associated with the clinical manifestations, disease activity, and prognosis of pSS patients. CD226+ CD14 + monocytes may present a potential target and a biomarker for the prognosis and therapy of pSS patients.

Association between atherosclerosis and primary Sjogren's syndrome: A cross-sectional study.

Atherosclerosis (AS) risk increases in patients with systemic autoimmune diseases. The association and mechanism between primary Sjogren's syndrome (pSS) and AS haven't been explained for now. We did this cross-sectional study to clarify the prevalence and risk factors of AS in patients with pSS, and to further explore how immune cells and inflammatory cytokines work in the process. Patients with pSS were enrolled. General information, AS events, immune cells, inflammatory cytokines, and related clinical data were recorded. Prevalence of AS events was calculated. Correlation analysis between immune factors and AS quantitative parameters were conducted by SPSS v20.0. A total of 155 pSS patients were included with a median Framingham 10-year risk of 7%. Sixty-four AS events were recorded, with a prevalence of 41.3%. Carotid intima-media thickness was positively correlated to immunoglobulin (Ig) A (r = 0.245, p = 0.030) and negatively correlated to IgM (r = -0.227, p = 0.045). Left ankle-brachial pulse wave velocity (baPWV) was positively correlated to the course of disease (r = 0.352, p = 0.004), B cells (r = 0.410, p = 0.001), and T helper (Th) cells (r = 0.284, p = 0.029), while negatively correlated to IgM (r = -0.257, p = 0.042). Right baPWV was positively correlated to the course of pSS (r = 0.319, p = 0.010), B cells (r = 0.453, p < 0.001), Th cells (r = 0.302, p = 0.020), and C-reactive protein (CRP) (r = 0.286, p = 0.042). Use of hydroxychloroquine, cyclophosphamide, and glucocorticoids had no impact on AS events. The prevalence of AS in patients with pSS is reported to be 41.3%. Several risk factors have been associated with AS in these patients, including the duration of the disease, levels of Th cells, B lymphocytes, and CRP. Interestingly, IgM appears to have a protective effect against AS. It is worth noting that traditional therapy for pSS does not seem to have any effect in preventing AS events.