Primary Sjogren's Syndrome Research Articles

PRMT5 participates in B cell overactivation in patients with primary Sjogren's syndrome (pSS) through RSAD2-mediated NF-κB signaling.

There are new evidences that protein arginine methyltransferase 5 (PRMT5) is widely involved in the progression of various diseases, but its effect is unclear on Primary Sjogren's syndrome (pSS). The main purpose of this study is to explore the regulatory effect of PRMT5 on pSS and its potential mechanisms. CD40L treated CD19 + B cells to construct a cell model of pSS. CCK-8 assay and Annexin V-FITC/PI kits were used to measure cell proliferation and apoptosis. ELISA assay was used to determine the contents of IL-6 and TNF-α in CD19 + B cells. And commercial kits were used to detect the levels of immunoglobins (IgG, IgM, and IgA) in CD40L-treated CD19 + B cells. And successfully constructed a pSS mouse model. The results revealed an increase in the expression of PRMT5 in CD19 + B cells from patients with pSS. After CD40L treatment, the knockdown of PRMT5 prominently decreased cell viability, the production level of immunoglobulins (IgG, IgM, and IgA), and the content of IL-10, increased the content of IL-6 and IL-8, and promoted the apoptosis of pSS CD19 + B cells. Mechanistically, PRMT5 negatively regulated the RSAD2 and nuclear factor kappa-B (NF-κB) signaling pathway. Furthermore, overexpression of RSAD2 and p65 significantly rescued the effect of PRMT5 knockdown on proliferation, immunoglobin production and secreting cytokines in CD40L-treated CD19 + B cells. More importantly, inhibition of PRMT5 significantly inhibited the symptoms of pSS mice. Low-expression of PRMT5 through inactivation of RSAD2/NF-κB signalling pathway alleviates the hyperactivity of B cells, which may provide theoretical basis and potential therapeutic targets for clinical treatment of pSS.

Unravelling the Mechanism behind Ineffective Erythropoiesis in Sickle Cell Disease: The Role of GATA-1

Background & Objectives: Ineffective erythropoiesis (IE) is an important factor in many types of anemias, including beta-thalassemia. Recently, a study by El Hoss et al provided compelling evidence for IE being an important part of the pathophysiology of sickle cell anemia (SCA) (PMID: 32855279). Furthermore, we developed a clinical index to measure IE and showed that patients with the SS genotype, but not SC, had increased IE compared to healthy donors (HD) (PMID: 34670360). However, the molecular mechanisms of IE in SCA, its relationship to disease heterogeneity and its potential as a therapeutic target, remain unknown. Importantly, GATA1, an essential erythroid transcription factor known to be downregulated in haematological conditions presenting with IE, has not been previously investigated in SCA. Thus, the aim of this project is to investigate the molecular basis of IE in SCA by focusing on GATA1 functions in erythropoiesis. Methods: HUDEP-2 cells, gene-edited sickle HUDEP-2 (SS HUDEP-2) (PMID: 32405513) cells and CD34+ cells isolated from individuals with HbSS and healthy donors, were differentiated ex vivo using a two-phase culture and (i) erythroid differentiation kinetics, (ii) markers of oxidative stress, (iii) GATA1 expression and (iv) antioxidant response factors NRF2, FOXO3 and heme-oxygenase 1 (HO-1) were assayed every other day during phase 2. IE was also studied in SS Berkeley transgenic mouse (PMID: 16166585). Both the spleen and the bone marrow were investigated in AA, AS and SS mice. Results: No significant differences were observed in the differentiation kinetics and in levels of oxidative stress in in vitro differentiated HUDEP-2 and SS HUDEP-2 cells. Moreover, GATA1 levels were similar in both cases. Importantly, ex vivo differentiation of human SS CD34+ cells showed a striking delay accompanied by high oxidative stress and a decrease in GATA1 protein levels (Figure 1) compared to normal controls. We also found a significant decrease in FOXO3, NRF2 and HO-1 levels in SS erythroblasts compared to healthy donor erythroblasts. IE was evident in SS mice compared to AA and AS controls. SS mice presented with higher levels of reactive oxygen species (ROS) in both the bone marrow and the spleen tissue. Histological studies showed that the SS Berkley mouse has a very congested bone marrow with a disorganized architecture. Moreover, we showed a significant decrease in GATA1 protein in SS spleen and bone marrow erythroid cells. Conclusion: Using ex vivo differentiation of primary SS cells and an in vivo mouse model for SCA, we show for the first time that aberrant GATA-1 levels play a key role during IE in SCA. During SS erythropoiesis, a significant reduction in the protein levels of the GATA1 erythroid master transcription factor and of FOXO3 and NF-E2, important transcriptional regulators of the oxidative stress response occur. These same changes were not seen in SS HUDEP-2 cells, suggesting that abnormalities of the bone marrow niche are central to abnormal erythropoiesis in SCA. Modification of the bone marrow niche and manipulation of GATA-1 levels may be important therapeutic tools in SCA.

Xpo-1 Antagonism Transcriptionally Reprograms and Is a Therapeutic Vulnerability in GATA-3 Driven T-Cell Lymphomas

Background: The transcription factor GATA-3, via the oncogenic transcriptional program it directs, is a bona fide proto-oncogene, and thus therapeutic target, in a subset of T-cell lymphomas (TCL). The eukaryotic translation initiation factor eIF4E, in complex with helicase and scaffolding factors, facilitates 40S ribosome and Met-tRNA recruitment, both of which are rate-limiting steps in the initiation of translation. Pathways that converge on eIF4E, including PI3K/AKT/mTOR-dependent phosphorylation of 4E-BP1, are frequently activated in GATA-3 PTCL. Within the nucleus, eIF4E specifically binds oncogenic mRNAs, and then forms a complex with a co-factor (LRPPRC) and the nuclear export receptor XPO1. In contrast to bulk mRNA, these eIF4E-bound mRNA are dependent upon XPO1 for nuclear export. Therefore, as we have shown that GATA-3 is oncogenic in T-cell lymphomas (TCL), we hypothesized that selective XPO1 inhibition may transcriptionally reprogram these TCL and is a novel therapeutic vulnerability. Methods: XPO1 expression was examined by immunohistochemistry or flow cytometry in TCL specimens and in TCL that emerge in multiple genetically engineered mouse (GEM) models. Transcripts that are eIF4e clients and dependent upon XPO-1 for nuclear export were identified in an unbiased manner by eIF4e RNA immunoprecipitation (eIF4e-RIP) and RNA-seq. The extent to which XPO1 antagonism transcriptionally reprograms TCL cells, and its value as a therapeutic strategy, was examined pharmacologically with selinexor in ex vivo and in vivo studies using primary TCL specimens and GEM/PDX models, respectively. Results: Among the PTCL cases (n=53) examined, XPO1 expression was observed in 62%, and was highly expressed in CTCL, particularly in patients with large cell transformation. We sought to further understand the extent to which XPO1 expression is associated with T-cell lymphomagenesis. We utilized multiple GEM TCL models in which Smarcb1 (SNF5) or PTEN were conditionally deleted in CD4 + T cells. In both GEM models, a significant increase in XPO-1 expression was associated with the emergence of a malignant clone. A significant reduction in cell viability and increased apoptosis was observed in TCL cell lines and primary specimens treated in vitro/ex vivo with selinexor. In both GEM models, and a PDX model, selinexor treatment similarly decreased TCL progression in vivo. Given these findings, we elected to examine XPO1's potential role in transporting oncogenic, and eIF4e client, transcripts. We performed eIF4e-RIP and RNA-seq in two representative cell lines. Gene set enrichment analysis utilizing the eIF4e client RNA identified demonstrated enrichment for pathways with an established role in TCL (e.g. TCR), including GATA-3. We subsequently performed eIF4e-RIP and quantified GATA-3 transcripts by qRT-PCR in cell lines (n=4), a PDX, and in primary SS specimens (n=2). Compatible with the RNA-seq data, significant enrichment in GATA-3 transcripts was observed. These findings imply that GATA-3 transcripts are dependent upon XPO1 for nuclear export. To directly examine this, the ratio of cytoplasmic to nuclear (C:N) GATA-3 transcripts were examined by qRT-PCR in cell lines treated with selinexor. A significant decrease in the C:N ratio was observed upon XPO1 inhibition, confirming that nuclear export of GATA-3 transcripts is XPO1 dependent. We similarly examined the extent to which GATA-3 target genes are eIF4e clients and XPO1 dependent for nuclear export. We had previously described GATA-3 target genes by integrated ChIP-seq/RNA-seq. Integration of this prior dataset with our eIF4e-RIP sequencing data demonstrated that ≈21-30% of previously described GATA-3 target genes were also eIF4e clients. We selected a few such targets, including ITK, for further validation. These GATA-3 targets were eIF4e clients and dependent upon XPO1 for nuclear export. Finally, we examined expression of these proteins in a diverse panel of T-cell lymphoma/leukemia cell lines and a primary SS specimen after brief exposure to selinexor, and compatible with our findings, a significant decrease in protein expression was observed. Conclusions: Collectively then, our findings demonstrate that XPO1 antagonism, by impairing the nuclear export of both GATA-3 and many of its target gene mRNA, is a novel strategy to transcriptionally reprogram and therapeutically target GATA-3 driven TCL.

Nationwide analysis of neuromyelitis optica in systemic lupus erythematosus and Sjogren's syndrome.

Neuromyelitis optica (NMO), also known as Devic's disease, is a rare inflammatory demyelinating disorder causing myelitis and optic neuritis. While there have been reports of systemic lupus erythematosus (SLE) and primary Sjogren's syndrome (SS) occurring with NMO, a formal association is not established. We aimed to investigate the occurrence of NMO in SLE and SS patients and study the clinical characteristics and outcomes of NMO and SLE/SS hospitalizations utilizing the national inpatient sample (NIS) database. The NIS database from 2016 to 2019 was used to extract data. Adult hospitalizations with the principal or secondary diagnosis of NMO were included. We classified NMO patients with and without concomitant diagnosis of SLE or Sjogren's syndrome. We evaluated and compared the clinical characteristics and outcomes of NMO hospitalizations with and without SLE or Sjogren's syndrome. STATA17 was used for data analysis. We also calculated the odds ratio of NMO in SLE and Sjogren's syndrome. There were a total of 16,360 adult hospitalizations with the principal or secondary discharge diagnosis of NMO. Among all NMO hospitalizations, 1425 (8.71%) had the primary or secondary diagnosis of SLE or SS. The odds of NMO in SLE and Sjogren's syndrome were noted to be 12.29 and 5.56, respectively. NMO with SLE/SS group had higher proportion of females (89.82% vs 79%, P value < 0.001), African Americans (56.63% vs 38.28, P value < 0.001), and Asians (5.73% vs 3.25, P value 0.04). The Charlson comorbidity index was higher for NMO-SLE/SS overlap (2.44 vs 1.28, P value < 0.001). There was no significant difference in overall mortality rates of both groups (2.11% vs 1.2%, P value 0.197). There were significantly higher reported seizures (14.73% vs 6.05, P value < 0.001) and paraplegia (21.75% vs 13.93%, P value < 0.001) in NMO-SLE/SS patients. These patients also had a longer length of stay in comparison to the reference group (7 vs 5 days, P value < 0.001) as well as higher total charges. NMO patients had a 12-fold higher risk of SLE and 5-fold higher risk of Sjogren's disease when compared to general population. Patients with overlap of NMO and SLE or Sjogren's were predominantly women and were more likely to be African-American. Co-existence of these autoimmune disorders was associated with poor prognosis in terms of higher morbidity for patients and increased health care burden. Key Points • NMO is a rare autoimmune disease seen predominantly in women in the middle age group with low overall mortality. • SLE and Sjogren's have increased odds of NMO in comparison to general population. • NMO patients have high rates of several complications such as paraplegia, quadriplegia, seizures, blindness, sepsis, and respiratory failure with even higher rates of seizures and paraplegia in those with concomitant SLE or Sjogren's.

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.

Efficacy and safety of platelet-rich plasma and autologous-serum eye drops for dry eye in primary Sjögren’s syndrome: a randomized trial

We compared the efficacy and safety of autologous-serum (AS) and platelet-rich plasma (PRP) eye drops for dry eye (DE) treatment in primary Sjögren’s syndrome (SS). This prospective, randomized, double-blinded clinical study included patients diagnosed with primary SS DE. Thirty-eight participants were randomly assigned to the AS or PRP groups. Corneal and conjunctival staining scores, Schirmer I test, tear film break-up time (TBUT), and ocular surface disease index (OSDI) scores were evaluated at 4 and 12 weeks. Conjunctival impression cytology (CIC) metaplasia grade and goblet cell density grade at 12 weeks were compared with those at baseline. Corneal and conjunctival staining scores and TBUT significantly improved at 4 and 12 weeks in both groups (all p < 0.005). No significant difference between the AS and PRP groups was observed at 4 and 12 weeks. The Schirmer I values, OSDI scores, CIC metaplasia grade, and goblet cell density grade did not significantly change at 4 and 12 weeks in either group. Both AS and PRP eye drops are effective for primary SS DE without a significant difference. Considering that the preparation time of PRP is shorter than that of AS, PRP can be a good alternative treatment for primary SS DE.

Pregnancy and Inflammatory Rheumatological Diseases: A Single-Center Retrospective Cohort Study.

Background Rheumatic diseases pose risks to pregnant women, leading to complications like preterm birth, congenital heart block, and pregnancy loss. These diseases are expected to deteriorate during pregnancy and further in the postpartum period. The impact of these diseases on the pregnancy will add further burden on the patient, fetus, physician, and healthcare system. Advances in diagnosis and treatment have improved outcomes making them similar to that of healthy women, but close follow-up in a multidisciplinary clinic is essential. The objective of this study is to study the outcome of pregnancy in women with rheumatological disease and the behavior of the disease during pregnancy. Methods A retrospective cohort study was conducted in King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia, to compare the outcomes of pregnancy across three rheumatological diseases: Sjogren syndrome (SS), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) from 2016 to 2021. A total of 128 pregnancies in 107 women with rheumatological diseases were included in this study. Pregnancy measures and outcomes were investigated by assessing maternal health, fetal health, and pregnancy complications, specifically maternal disease activity, medications to control the disease, infection, preterm birth, birth weight, abortions/stillbirths, mode of delivery, bleeding, preeclampsia, congenital heart block, and neonatal lupus. Results There were 55 patients with RA (63 RA pregnancies), 44 with SLE (54 SLE pregnancies), and eight with primary SS (11 SS pregnancies). In most of the pregnancies (n= 108; 95.58%), the patients were in clinical remission before pregnancy. Lupus nephritis, which was in remission before pregnancy, has been reported in nine (16.67%) out of 54 SLE pregnancies. Vaginal delivery was the most common mode of delivery (n=87; 67.97%). On the other hand, there were 38 cesarean sections (29.69%). Rheumatological disease flares occurred in 10 pregnancies (7.87%). One hundred and twenty-two live births were delivered. Preterm infants were born in 25 pregnancies (20.16%), and 16 (13.22%) of the newborns needed neonatal intensive care unit (NICU) care. Interestingly, congenital heart block (CHB) was found in five (12.2%) neonates out of 41 anti-SS-related antigen A (anti-SSA) positive mothers; one of those five died from heart block. Eleven neonates were delivered with positive serology, and five were diagnosed with neonatal lupus. Conclusion The outcome of pregnancy in patients with rheumatological disease is favorable. A multidisciplinary team approach and close clinical follow-up are the cornerstone for such success. A small dose of prednisolone (5 mg or less) is safe and will not have a negative impact on maternal or fetal health. CHB is a concern for pregnant women with positive anti-SSA.

A single-center study of clinical features of pediatric Sjögren’s syndrome

ObjectiveSjögren’s syndrome (SS) is a rare disease with unclear diagnostic criteria among the children and adolescents. The purpose of this study is to describe the clinical features of pediatric Sjögren’s syndrome and validate with Japanese diagnostic guidelines criteria of 2018.MethodsWe conducted a retrospective analysis of the clinical data of a cohort of 54 patients with pediatric Sjögren’s syndrome admitted to our hospital over a total of 10 years from September 2013 to September 2022.ResultsThe ratio of females to males was 49:5 among the 54 children (34 cases of primary SS and 20 cases of secondary SS), the average age of onset of symptoms for the first time was 9.9 years, and the average age at diagnosis was 10.2 years. In terms of subjective symptoms, 7 cases (13.0%) presented with dry mouth and 5 cases (9.3%) reported dry eyes. The positive rates were 9.3% for Schirmer I test, 70.4% for salivary gland function test, and 55.6% for salivary gland ultrasonography. The positive rates were 94.4% for Anti-Ro/SSA antibodies, 66.7% for Anti-La/SSB antibodies, 88.9% for ANA, 59.3% for RF, and the elevation rate of IgG was 63.0%. Among the EULAR Sjögren’s syndrome disease activity index (ESSDAI) domains, the biological, constitutional, glandular, cutaneous, and lymphadenopathy domains were most involved. Treatment consisted of glucocorticoids in 88.9% of the patients in our study and hydroxychloroquine in 92.6%. As per the Japanese version of the clinical practice guidance for Sjögren’s Syndrome in pediatric patients (2018), 5 cases were identified as Definite SS, 35 cases as Probable SS, and 14 cases as Possible SS. With respect to primary and secondary SS, there was essentially no significant difference between the groups in any of the above aspects.ConclusionsPatients with pediatric SS presented with a wide spectrum of clinical features, a low prevalence of reported symptoms of dry mouth and dry eyes, and various clinical manifestations with multi-system involvement. These are similar to other pediatric study cohorts in terms of epidemiology, auxiliary investigation results, disease activity scores, and treatment. The coincidence between our study and the Japanese version of the clinical practice guidance for Sjögren’s Syndrome in pediatric patients (2018) is good for the diagnosis of pediatric SS.

Three Signs to Help Detect Sjögren's Syndrome: Incidental Findings on Magnetic Resonance Imaging and Computed Tomography.

This study aimed to retrospectively investigate the prevalence of Sjögren's syndrome (SS) among patients with ranulas, parotid cysts, or parotid calcifications; identify the characteristic magnetic resonance imaging (MRI) or computed tomography (CT) findings of the lesions associated with SS; and compare the SS disease stages among SS patients with the three lesion types. A total of 228 patients with the lesions were classified into SS, possible SS, and non-SS groups. The prevalence of SS among patients with ranulas, parotid cysts, or parotid calcifications was 16%, 24%, and 40%, and the rates of either SS or possible SS were 25%, 41%, and 64%, respectively. SS was associated with (i) ranulas: ≤17 mm; (ii) parotid cysts: bilateral and multiple; and (iii) parotid calcifications: in females, bilateral, multiple, parenchymal, and no coexisting calcifications in other tissues. SS patients with ranulas were significantly younger and had lower submandibular gland stage scores on MRI/CT than those with other lesions. Additionally, in 58% and 15% of SS patients with ranulas and parotid calcifications, respectively, detection of the lesions led to the diagnosis of primary SS. Therefore, recognizing the prevalence of SS among patients with these lesions and the findings associated with SS can help detect undiagnosed SS.

Central retinal vein occlusion (CRVO) in primary Sjogren's syndrome (PSS).

We report a case of a young lady who presented with central retinal vein occlusion (CRVO) in the right eye. On probing, she gave a history of dry eyes which prompted us to investigate for an underlying systemic disease. Further testing revealed that the patient was positive for anti-nuclear antibody (ANA) speckled, rheumatoid factor, anti-pm/scl antibody, SSA, SSB, and anti-Ro52 antibodies. Two months later she developed dryness of skin. A diagnosis of CRVO in Primary Sjogren's syndrome was made.

Diagnostic Value of Labial Minor Salivary Gland Biopsy: Histological Findings of a Large Sicca Cohort and Clinical Associations.

(1) Background: The aim of this study was to analyze labial minor salivary gland biopsy (MSGB) findings of a large sicca cohort and to examine their associations with Sjogren's syndrome (SS)-associated laboratory markers, phenotypic characteristics and systemic manifestations. Moreover, we sought to explore the ability of MSGB to identify SS patients among subjects with pre-diagnosed fibromyalgia (FM). (2) Methods: Included were all patients of three rheumatology departments having undergone a diagnostic MSGB within 9 years. Next to the examination of histological and immunohistochemical findings, we focused on activity and chronicity parameters of the underlying disease, autoantibodies, presence of systemic and hematologic involvement, as well as chronic pain and SS comorbidities. (3) Results: Among the 678 included patients, 306 (45.1%) had a positive focus score (FS). The remaining patients (n = 372) served as control subjects. There were significant correlations between FS and hypergammaglobulinemia (p < 0.001), ANA and rheumatoid factor positivity (both; p < 0.001), a weak significant correlation with erythrocyte sedimentation rate (rho = 0.235; p < 0.001) and a negative correlation with nicotine use (p = 0.002). Within the primary SS subgroup, FS was associated significantly with glandular enlargement (p = 0.007) and systemic hematologic manifestations (p = 0.002). Next to FS, CD20 cell staining showed an excellent diagnostic performance in the diagnosis of SS by an area under the curve of 0.822 (95%CI 0.780-0.864; p < 0.001). Interestingly, 42.1% of all patients with fibromyalgia (FM) having received an MSGB could be diagnosed with SS. (4) Conclusion: By examining one of the largest cohorts in the literature, we could show that MSGB histological and immunohistochemical findings not only play a key role in the classification and diagnosis of SS but could also provide important information regarding SS phenotype and systemic manifestations. Furthermore, MSGB may help differentiate patients with FM from patients with subclinical SS who suffer primarily from chronic pain.

Combination of ultra-micro angiography and sound touch elastography for diagnosis of primary Sjögren's syndrome: a diagnostic test.

Primary Sjogren's syndrome (PSS) is a prevalent systemic autoimmune disease. However, the current gold standard diagnostic method is invasive, increasing the difficulty of patient acceptance and then delaying treatment. Therefore, a non-invasive, convenient, and effective diagnostic method is required. Although salivary gland ultrasonography (SGUS) is a good choice, previous studies have not found suitable parameters to diagnose PSS. Salivary gland involvement in patients with PSS leads to changes in gland stiffness and vascularization, so we combined sound touch elastography (STE) and ultra-microangiography (UMA) to demonstrate the diagnostic effectiveness of ultrasonography in PSS. This prospective study included 27 patients with PSS and 20 healthy controls, with all participants forming a random series. Major salivary glands were examined with UMA and STE. Color pixel percentage (CPP), shear wave velocity (SWV), and Young's modulus values were investigated, and the combination of these parameters was evaluated by logistic regression analysis. For Young's modulus and SWV in the elasticity index, combined evaluation of both parotid glands and submandibular glands yielded an area under the receiver operating characteristic (ROC) curve (AUC) and confidence interval (CI) of 0.819, 0.699-0.938 and 0.801, 0.677-0.925, respectively. The levels of CPP in the parotid glands were significantly elevated (P<0.003) among patients compared to those in the control group, whereas the CPP values in the submandibular glands were not statistically different (P>0.086). We evaluated the elasticity values of the total 4 glands and the CPP of parotid glands together by logistic regression modeling. The ROC curve yielded an AUC of 0.954 (95% CI: specificity 0.849-0.994) which showed the best accuracy, with 92.6% sensitivity and 85.0% specificity. The use of STE and UMA to examine the salivary glands may aid in the diagnosis of PSS, and their combination may be a promising method. This is good news for patients with PSS who are not suitable or unwilling to undergo labial gland biopsy.

14-3-3η Proteins as a Diagnostic Marker, Disease Activation Indicator, and Lymphoma Predictor in Patients with Primary Sjögren Syndrome.

Primary Sjögren syndrome (PSS) is a chronic, autoimmune, and lymphoproliferative disease of the connective tissue. In patients with PSS, the risk of developing B-cell non-Hodgkin lymphoma (NHL) increases dramatically, with a prevalence of approximately 5%. The 14-3-3 protein isoforms are phospho-serin/phospho-threonine binding proteins associated with many malignant diseases. This study aimed to evaluate the relationship between disease activity parameters and markers predicting lymphoma development in patients with PSS and 14-3-3η proteins. This study was designed as an analytical case-control study. A total of 57 PSS patients and 54 healthy volunteers were included in the study. The European League Against Rheumatism (EULAR) Sjögren syndrome disease activity index (ESSDAI) was used to assess systemic disease activity in PSS. Receiver operating characteristic (ROC) analysis was used to test the diagnostic accuracy measures of the analytical results. Multivariable linear regression analysis was used to evaluate the effects of independent variables on the 14-3-3η protein. The 14-3-3η protein serum levels were found to be significantly higher in PSS (2.72 [2.04-4.07]) than healthy controls (1.73 [1.41-2.43]) (P<0.0001). A significant relationship was found between 14-3-3η protein levels and ESSDAI group (β=0.385, 95%CI=0.318-1.651, P=0.005), hypocomplementemia (C3 or C4) (β=0.223, 95% CI=0.09-1.983, P=0.048) and purpura (β=0.252, 95% CI=0.335-4.903, P=0.022), which are accepted as lymphoma predictors. A significant correlation was found between PSS disease activity score ESSDAI and 14-33η protein (β=0.496, 95% CI=0.079-0.244, P=0.0002). 14-3-3η proteins are potential candidates for diagnostic marker, marker of disease activity, and predictor of lymphoma in 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.

Clinical significance of the expression levels of serum transforming growth factor-β and CXC type chemokine ligand 13 in primary Sjogren's syndrome patients.

The aim of this study was to investigate the expression levels of the serum transforming growth factor-β1 (TGF-β1) CXC type chemokine ligand 13 (CXCL13) in primary Sjogren's syndrome (pSS) patients and its correlation with disease severity. Thirty patients with pSS admitted to Nanjing Traditional Chinese Medicine Affiliated Hospital of Nanjing University of Traditional Chinese Medicine from January 2021 to December 2022 were included as the pSS group, while 30 patients who underwent physical examination during the same period were included as the control group. The levels of TGF-β1 and CXCL13 were detected. The diagnostic value of TGF-β1 and CXCL13 for pSS was analyzed. Detection of serum TGF-β1 and CXCL13 levels in pSS patients with different disease activities and lip gland pathological grading of pSS was done. We compared the correlation between TGF-β1 and CXCL13 levels and disease activity and labial gland pathological grading in pSS patients. The TGF-β1 and CXCL13 levels in the pSS group were higher than those in the control group. The area under the receiver operating characteristic (ROC) curve (AUC) for TGF-β1 and CXCL13 diagnosis of pSS was 0.790 (95% confidence interval (CI): 0.720~0.861) and 0.838 (95% CI: 0.778~0.898), respectively. The serum TGF-β1 and CXCL13 levels of pSS patients significantly increase with the increase of disease activity and lip gland pathological grading. The TGF-β1 and CXCL13 levels in pSS patients were positively correlated with disease activity and lip gland pathological grading. The levels of TGF-β1 and CXCL13 in pSS patients were increased, and it was closely related to disease activity and lip gland pathological grading, which can be used as an effective indicator for the diagnosis of pSS. Key Points • The TGF-β1 and CXCL13 levels in the pSS group were higher than those in the control group. • The TGF-β1 and CXCL13 levels in pSS patients were positively correlated with disease activity and lip gland pathological grading. • TGF-β1 and CXCL13 can be used as an effective indicator for the diagnosis of pSS.

Oral Disorders in Sjögren’s Syndrome

Abstract Sjögren’s syndrome (SS) is a complex, chronic, systemic, autoimmune disease that mainly affects the exocrine glands, especially the salivary and lacrimal glands, leading to the dryness of the mouth and eyes, along with fatigue, joint and muscle pain. The prevalence of SS is estimated to be between 0.05% and 1% in European population. Diagnosis of SS is based on the revised criteria of the American-European consensus group (AECG). Sjögren’s syndrome can be subclassified into primary disease (primary Sjögren syndrome, pSS) and a secondary disease (secondary Sjögren syndrome, sSS) when present with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and systemic sclerosis. The decrease in salivary flow and qualitative alterations in saliva could explain many of the oral manifestations frequently present in patients with SS. Low salivary flow may affect chewing, swallowing, speech and sleeping in pSS patients. Oral manifestations include dental erosion, dental caries, mucosal infection, ulcers and oral candidiasis. Recent studies reveal that pSS patients experience impaired olfactory and gustatory functions and have higher occurrence of oral complications such as dysgeusia, burning sensation in the tongue (BST) and halitosis. The exocrine manifestations and systemic involvement in SS significantly impact the patient’s perception of oral healthrelated quality of life (OHRQoL).

Recommendations for the diagnosis and treatment of Sjögren's syndrome in China

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease characterized by lymphocyte proliferation and progressive exocrine gland damage. In addition to the impairment of salivary and lacrimal gland function, SS can present with multi-system and multi-organ involvement, accompanied by autoantibodies in serum and hyperimmunoglobulinemia. SS can be divided into primary and secondary forms based on the absence or presence, respectively, of concurrent connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis. Based on evidence and guidelines from China and other countries, the Chinese Rheumatology Association drafted standardized criteria for the diagnosis and treatment of primary SS. The objectives were to standardize the detection and interpretation of key indicators for the diagnosis of SS, including serum anti-SSA antibody and labial gland pathology, suggest the use of the widely accepted European League Against Rheumatism (EULAR)-SS disease activity index for the evaluation of the disease, and standardize the rational management of SS patients with topical and systemic therapies.

Environmental Effects on Dry Eyes in Primary Sjogren&amp;apos;s Syndrome

Purpose: To investigate the effects of humidity, temperature, and fine particulate matter (PM&lt;sub&gt;2.5&lt;/sub&gt;) on dry eye disease (DED) parameters in primary Sjogren's syndrome patients.Methods: We retrospectively analyzed the medical records of 18 primary Sjogren's syndrome patients who underwent DED treatment and had more than two follow-up visits. Symptom Assessment in Dry Eye (SANDE) scores, tear secretion, tear film breakup times, ocular surface staining scores, and tear osmolarity were assessed. Temperature, humidity, and PM&lt;sub&gt;2.5&lt;/sub&gt; concentrations during the week before the patient visits were calculated using public data and their relationships with DED parameters were analyzed.Results: All patients were females, with an average age of 57.6 ± 12.4 years. High temperature was significantly correlated with humidity and PM&lt;sub&gt;2.5&lt;/sub&gt; concentration (&lt;i&gt;p&lt;/i&gt; = 0.004 and = 0.006, respectively). The high humidity, high temperature, and low PM&lt;sub&gt;2.5&lt;/sub&gt; groups had lower SANDE scores (&lt;i&gt;p&lt;/i&gt; = 0.017, = 0.063, and = 0.049, respectively) and tear osmolarity (&lt;i&gt;p&lt;/i&gt; &lt; 0.001, = 0.009, and &lt; 0.001, respectively). Multiple regression analysis showed that temperature and humidity had stronger correlations with tear osmolarity (&lt;i&gt;p&lt;/i&gt; = 0.005 and = 0.012, respectively) compared to PM&lt;sub&gt;2.5&lt;/sub&gt; concentrations.Conclusions: Ocular discomfort and tear osmolarity were correlated with temperature, humidity, and PM&lt;sub&gt;2.5&lt;/sub&gt; concentrations. Among the DED parameters, tear osmolarity was the most sensitive indicator of exposure to environmental factors.

Multiple Eruptive Dermatofibromas in a Patient with Primary Sjögren’s Syndrome

Multiple eruptive dermatofibromas (MEDF) are rare tumors and thought to be associated with the disturbances in the immune system. In our 40-year-old case, 5 nodules have developed in a 4-month period. The patient was diagnosed by a dermatologist to have MEDF, and referred to rheumatology outpatient clinic because of the symptoms such as dry mouth, and polyarthralgia. After clinical and laboratory evaluation, the diagnosis of primary Sjögren’s syndrome (SS) was made. According to the best of our knowledge, this case is the first reported association between MEDF and primary SS. Therefore, when the diagnosis of MEDF is made, SS should also been included in the comprehensive evaluation of associated diseases.

Unraveling the transcriptome-based network of tfh cells in primary sjogren syndrome: insights from a systems biology approach.

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. 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. 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 (CD4+CXCR5+ICOS+) 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. 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.