Sjögren's Syndrome Patients Research Articles

Exposure to ambient gaseous pollutant and daily hospitalizations for Sjögren's syndrome in Hefei: A time-series study.

Increasing evidence suggested that gaseous pollutants were associated with the development of autoimmune diseases, while there were few studies on the association between gaseous pollutants and Sjögren's syndrome (SS). This study sought to assess the relationship between exposure to several gaseous pollutants and the hospitalizations for SS. The data regarding SS hospitalizations, gaseous pollutants, and meteorological factors in Hefei from 2016 to 2021 were collected. A distributed lag non-linear model combined with a generalized linear model were adopted to analyze the association between gaseous pollutants and SS hospitalizations, and stratified analyses were also conducted. We detected significant associations between gaseous pollutants (NO2, SO2, O3, CO) and SS hospitalizations. Exposure to NO2 was linked with the elevated risk of hospitalizations for SS (RR=1.026, lag1 day). A positive correlation between CO exposure and hospitalizations for SS was found (RR=1.144, lag2 day). In contrast, exposure to SO2, O3 was respectively related to the decreased risk of hospitalizations for SS (SO2: RR=0.897, lag14 day; O3: RR=0.992, lag9 day). Stratified analyses found that female patients were more vulnerable to these gaseous pollutants. SS patients ≥ 65 years were more susceptible to NO2, CO exposure, and younger patients were more vulnerable to O3 exposure. In addition, exposure to O3, CO in cold season were more likely to affect hospitalizations for SS. Our results demonstrated a significant association between exposure to NO2, CO and elevated risk of hospitalizations for SS, and SO2, O3 exposure might be linked to reduced risk of SS hospitalizations.

Alteration of Mitochondrial DNA Copy Number and Increased Expression Levels of Mitochondrial Dynamics-Related Genes in Sjögren's Syndrome.

Sjögren's syndrome (SS) is a chronic autoimmune multifactorial disease characterized by inflammation and lymphocytic infiltration of the exocrine glands. Several studies have highlighted the involvement of oxidative stress in this pathology, suggesting that it could induce mitochondrial dysfunctions. Mitochondria could have a role in inflammatory and immune processes. Since the mitochondrial DNA (mtDNA) copy number could change in response to physiological or environmental stimuli, this study aimed to evaluate possible alterations in the mtDNA copy number in SS. We have analyzed the amount of mtDNA in the peripheral blood of 74 SS patients and 61 healthy controls by qPCR. Then, since mitochondrial fusion and fission play a crucial role in maintaining the number of mitochondria, we investigated the expression variability of the genes most commonly involved in mitochondrial dynamics in a subgroup of SS patients and healthy controls. Interestingly, we observed a highly significant decrease in mtDNA copies in the SS patients compared to healthy controls (p = 1.44 × 10-12). Expression levels of mitochondrial fission factor (MFF), mitofusin-1 (MFN1), and mitochondrial transcription factor A (TFAM) genes were analyzed, showing a statistically significant increase in the expression of MFF (p = 0.003) and TFAM (p = 0.022) in the SS patients compared to healthy controls. These results give further insight into the possible involvement of mitochondrial dysfunctions in SS disease.

Recommendations for evaluation and diagnosis of extra-glandular manifestations of primary Sjögren syndrome: results of an epidemiologic systematic review/meta-analysis and a consensus guideline from the Brazilian society of rheumatology (hepatic, gastrointestinal and pancreatic)

Sjogren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the exocrine glands and other organs, associated with sicca syndrome but also with systemic involvement with varying degrees of severity. Despite their importance, some systemic manifestations, mainly liver, gastrointestinal, and pancreatic are not routinely evaluated. To address these manifestations, the Sjögren's Syndrome Committee of the Brazilian Society of Rheumatology conducted a broad systematic review of the literature on studies investigating prevalence and diagnosis of these symptoms in Sjogren´s patients and made recommendations based on the findings. Agreement between the experts was achieved using the Delphi method. This is the second part of this guideline, providing 6 recommendations for liver, gastrointestinal, and pancreatic care of SS patients.

Strong Association of Combined Genetic Deficiencies in the Classical Complement Pathway With Risk of Systemic Lupus Erythematosus and Primary Sjögren's Syndrome.

Complete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (SS) has not been studied systematically. This study was undertaken to investigate potential associations of heterozygous C2 deficiency and C4 copy number variation with clinical manifestations in patients with SLE and patients with primary SS. The presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients who had received a diagnosis of SLE (n=958) or primary SS (n=911) and in 2,262 healthy controls through the use of DNA sequencing. The concentration of complement proteins in plasma and classical complement function were analyzed in a subgroup of SLE patients. Heterozygous C2 deficiency-when present in combination with a low C4A copy number-substantially increased the risk of SLE (odds ratio [OR] 10.2 [95% confidence interval (95% CI) 3.5-37.0]) and the risk of primary SS (OR 13.0 [95% CI 4.5-48.4]) when compared to individuals with 2 C4A copies and normal C2. For patients heterozygous for rs9332736 with 1 C4A copy, the median age at diagnosis was 7 years earlier in patients with SLE and 12 years earlier in patients with primary SS when compared to patients with normal C2. Reduced C2 levels in plasma (P=2 × 10-9 ) and impaired function of the classical complement pathway (P=0.03) were detected in SLE patients with heterozygous C2 deficiency. Finally, in a primary SS patient homozygous for C2 deficiency, we observed low levels of anti-Scl-70, which suggests a risk of developing systemic sclerosis or potential overlap between primary SS and other systemic autoimmune diseases. We demonstrate that a genetic pattern involving partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and for primary SS. Our results emphasize the central role of the complement system in the pathogenesis of both SLE and primary SS.

Short-term results of a pulsed therapy with hydrocortisone eye drops to treat moderate to severe dry eye in primary Sjögren syndrome patients.

We investigated the safety and efficacy of short-term treatment with topical low-dose hydrocortisone sodium phosphate 0.335% (PFH) in patients with moderate to severe primary Sjögren syndrome (SS)-related dry eye disease (DED). A retrospective single-centre interventional study. All patients received PFH for 6days with a pulsed posology: three times daily for 2days, twice daily for 2days, and once daily for 2days. This scheme was repeated for 3 consecutive months and then alternated for 3months. Data were collected at baseline, 3months, and 6months of follow-up. A total of 40 SS patients were enrolled. Conjunctival hyperaemia and corneal-conjunctival stain significantly improved (p < 0.001). Ocular Surface Disease Index score reduced significantly between baseline and 3months and between baseline and 6months (p < 0.001). The tear film osmolarity lowered significantly in each eye from baseline to 3months and from baseline to 6months (p = 0.002 and p = 0.037, respectively). Comparing results at 3 and 6months, the Ocular Surface Disease Index score (p = 1.000), the frequency of lacrimal substitutes installation (p = 0.632), and tear film osmolarity (right eye p = 0.518, left eye p = 1.000) did not change significantly. Intraocular pressure did not change during the study period. PFH eye drops with a pulsed posology improve signs and symptoms, not affecting the intraocular pressure in SS-related DED. Therefore, this pulsed treatment is safe and efficacious.

Clinical significance of T cell receptor repertoire in primary Sjogren's syndrome.

SummaryBackgroundPrimary Sjogren's syndrome (SS) is a chronic inflammatory disease with unknown aetiology. Although clonal expansion of autoreactive T cells has been identified in patients with SS, the clinical correlation of T-cell receptor (TCR) variance in SS remains unclear.MethodsTCRβ repertoire sequencing was performed on 260 SS patients with 3-6 months of follow-up in a cohort study to dynamically assess the characteristics of TCR diversity and their clinical significance.FindingsWe found that SS patients had lower TCR diversity, but higher frequency of public clones than healthy controls (HCs). Significant differences were identified in the usage of the variable (V) gene, joining (J) gene, and V-J pairing between SS and HCs. Eighteen SS-associated clones were identified, showing a high sensitivity and specificity for disease classification. TCR diversity was correlated with the presence of dental caries, thrombocytopenia, hepatocholangeitis, antinuclear antibody, anti-SSA/SSB, and hypergammaglobulinemia but not with disease course, number of relapses, arthritis, rheumatoid factor, hypocomplementemia or disease activity defined by SSDAI. During follow-up, the TCR abnormalities remained, represented by more altered V/J usage and higher frequencies of SS-associated clones. Among SS patients, the sensitive subgroup had increased TCR diversity after treatment. Eighty-five SS-sensitivity associated TCRs were identified and used for sensitivity classification by cross validation with high specificity and sensitivity.InterpretationThese results demonstrate that the TCR repertoire could provide insights into the disease status and prognosis in SS and other autoimmune diseases.FundingThis study was funded by the National Key Research and Development Program of China (2016YFC0906201), Sichuan Science and Technology Program (2020YJ0223), and the 1·3·5 project for disciplines of excellence, West China Hospital, Sichuan University (ZYGD18015).

Clinical significance of autoantibodies against ubiquitin carboxyl hydrolase L1 epitopes in the screening and diagnosis of Sjögren syndrome

Objective: To study the clinical significance of autoantibodies against different ubiquitin carboxyl hydrolase L1 (UCH-L1) epitopes in Sjogren syndrome (SS). Methods: The serum levels of different UCH-L1 epitope autoantibodies in 98 SS patients [SS group, 17 males and 81 females, aged (49.1±12.3) years] in the Fifth Affiliated Hospital of Zhengzhou University and Peking University People's Hospital from January 2017 to January 2020 and 37 healthy controls [control group, 6 males and 31 females, aged (46.3±5.8) years] were determined by enzyme-linked immunosorbent assay (ELISA). Three potential epitopes of UCH-L1 protein were analyzed and synthesized and anti-UCH-L1203-214 and anti-UCH-L158-69 antibodies were studied between the two groups. The levels of the two anti-UCH-L1 antibodies in the two groups were compared. The correlation between the levels of UCH-L1 antibodies and clinical data of SS patients were analyzed by Pearson correlation analysis. Results: The serum levels of anti-UCH-L1203-214 and anti-UCH-L158-69 antibody in SS patients were significantly higher than those in healthy controls (HCs) (anti-UCH-L1203-214: 108.2±54.3 vs 78.9±25.8, P<0.001, anti-UCH-L158-69: 86.8±33.3 vs 60.4±21.5, P<0.001). The positive rates of anti-UCH-L1203-214 and anti-UCH-L158-69 antibodies in serums of SS patients were 27.6 % (27/98) and 25.5% (25/98), and those in HCs were 2.7%(1/37) and 5.4 %(2/37), respectively. In SS patients with positive serum anti-UCH-L158-69 antibody, the levels of IgG, γ globulin and rheumatoid factor (RF) and anti-SS-related antigen B (anti-SSB) antibody positive rate were all significantly higher than those in patients with negative antibody (all P<0.05). In SS patients with negative antinuclear antibody (ANA), anti-RNA binding protein (anti-RNP) antibody, anti-SS-related antigen A (anti-SSA) antibody and anti-SSB antibody, the positive rates of anti-UCH-L1203-214 antibody was 32.1%(9/28), 27.2%(25/92), 36.4%(12/33), 28.6%(18/63), respectively; and the positive rates of anti-UCH-L158-69 antibody was 21.4%(6/28), 30.4%(28/92), 30.3%(10/33), 20.6%(13/63), respectively. The level of serum anti-UCH-L1203-214 antibody in SS patients was positively correlated with the IgA level (r=0.21, P=0.024). The level of anti-UCH-L158-69 antibody in SS patients was positively correlated with the levels of γ-globulin, IgG and RF (r=0.35, 0.33, 0.32, all P<0.01). Conclusion: Autoantibodies against UCH-L1 epitopes are correlated with some clinical parameters of SS patients, which is of promising significance in the screening and diagnosis of SS.

Corneal subbasal nerve analysis in patients with primary Sjogren's syndrome: a novel objective grading method and clinical correlations.

To investigate corneal sub-basal nerve morphology changes in primary Sjogren's syndrome (SS) dry eye (SSDE) patients and determine the association with disease severity at microstructural level. Twenty-eight eyes of 17 SSDE and 82 eyes of 47 age- and sex-matched non-SS dry eye (NSSDE) patients were included. The Ocular Surface Disease Index questionnaire (OSDI), Schirmer's test (ST), tear meniscus height (TMH), non-invasive breakup time (NIBUT), meibomian gland (MG) morphology, and ocular staining score (OSS) were assessed. In vivo confocal microscopy was performed to observe corneal sub-basal nerve morphology (length, reflectivity, width, and tortuosity). Associations between clinical features and nerve parameters were analysed. SSDE patients more frequently had increased nerve reflectivity (151.12 ± 17.07 vs. 139.37 ± 14.31 grey value), width (4.45 ± 0.87 vs. 3.92 ± 0.81μm), tortuosity (132.90 ± 8.04 vs. 129.50 ± 7.33 degree), and higher reflectivity, width, and total nerve grades than NSSDE individuals (all P < 0.05). Significant associations were found between nerve reflectivity/width and anti-SSA [OR = 1.139 (1.013-1.281)/1.802 (1.013-4.465)]/labial gland biopsy [OR = 1.046 (1.002-1.161)/1.616 (1.020-3.243)]. Higher nerve width was associated with increased OSDI [β = 0.284 (0.187-0.455)], MG score [β = 0.185 (0.109-0.300)] and OSS [β = 0.163 (0.020-0.345)], but decreased NIBUT [β = - 0.247 (- 0.548 ~ - 0.154)]. Higher nerve total grade was associated with increased OSDI [β = 0.418 (0.157-0.793)] and OSS [β = 0.287 (0.027-0.547)], but decreased ST [β = - 0.410 (-0.857 ~ - 0.138)]. Corneal nerve morphology changes associated with clinical features in SS patients. These changes may facilitate severity evaluation and management of the disease.

The inflammatory signature in monocytes of Sjögren's syndrome and systemic lupus erythematosus, revealed by the integrated Reactome and drug target analysis.

The innate immune regulation, especially by thetype I IFN signature in the CD14+ monocytes, is known to be critical in the pathogenesis of autoimmune Sjögren's syndrome (SjS) and systemic lupus erythematosus (SLE). Since patients with one condition can be overlapped with another, this study is to identify shared differentially expressed genes (DEGs) in SjS and SLE compared to healthy controls (HCs) and refine transcriptomic profiles with the integrated Reactome and gene-drug network analysis for an anti-inflammation therapy. CD14+ monocytes were purified from whole blood of SjS and SLE patients (females, ages from 32 to 62) and subject to bulk RNA-sequencing, followed by data analyses for comparison with HC monocytes (females, ages 30 and 33). Functional categorizations, using Gene Ontology (GO) and the Reactome pathway analysis, were performed and DEGs associated with therapeutic drugs were identified from the Drug Repurposing Hub (DHUB) database. The GO analysis revealed that DEGs in the inflammatory response and the cellular response to cytokine were highly enriched in both conditions. A propensity toward M1 macrophage differentiation appears to be prominent in SjS while the Response to Virus was significant in SLE monocytes. Through the Reactome pathway analysis, DEGs in the IFN signaling and the cytokine signaling in immune system were most significantly enriched in both. Upregulation of NGF-induced transcription activity in SjS and the complement cascade activity in SLE were also noted. Multiple anti-inflammatory drugs, such as prostaglandin-endoperoxide synthase and angiotensin-I-converting- enzyme were associated with the DEGs in these conditions. Taken together, our analysis indicates distinct inflammatory transcriptomic profiles shared in SjS and SLE monocytes. Comprehensive characterizations of the data from these conditions will ultimately allow differential diagnosis of each condition and identification of therapeutic targets.

Assessment of semaphorin 3A and semaphorin 7A levels in primary Sjogren's syndrome.

Sjogren's syndrome (SS) is a chronic autoimmune connective tissue disease. Varying rates of system involvements may be seen in the course of the disease. Semaphorins has multifunctions in several physiological and pathological processes such as immune system regulation. The association of Semaphorin 3A (Sema3A) and Semaphorin 7A (Sema7A), which are immune semaphorins, with autoimmune diseases is interesting for researchers. We aimed to compare serum Sema3A and Sema7A levels between primary SS and control subjects, and investigated Sema3A and Sema7A levels in disease subgroups and associated system involvements. 50 consecutive primary SS patients and 40 healthy subjects followed in the Rheumatology clinic of Cumhuriyet University Medical Faculty between 2017 and 2018 were included in the study. Inclusion criteria of patients were diagnosis of primary SS according to the 2016 ACR/EULAR classification criteria. Serum Sema3A and Sema7A levels were measured by commercial ELISA kit. Both groups were similar in terms of age, gender, and body mass index. Serum Sema3A and Sema7A levels were significantly lower in SS than in the controls (p = 0.001 and p = 0.005, respectively). Serum Sema3A levels were significantly lower in patients with renal involvement than in patients without (p = 0.03). Sema3A and Sema7A may play a role in the etiopathogenesis of SS and may be a potential serological marker for the diagnosis of SS and may be a target for treatment.

Mesenchymal stem cell transplantation alleviates Sjögren's syndrome symptoms by modulating Tim-3 expression

Mesenchymal stem cell (MSC) transplantation has been proven to be an effective treatment for Sjögren’s syndrome (SS) to improve salivary gland pathology and exocrine function, but the mechanism remains unclear. A recently reported inhibitory receptor, Tim-3, also appears to be closely related to autoimmune diseases. Here, we aimed to explore the roles of Tim-3 in the pathogenesis of SS and MSC treatment. The results showed that Tim-3 was downregulated in T cells of SS patients and nonobese diabetic (NOD) mice, which is correlated with SS pathogenesis. MSC transplantation ameliorated SS-like symptoms and pathological changes in the submandibular glands with modulated Tim-3 expression, resulting in attenuation of localized inflammation, fibrosis, and epithelial-mesenchymal transition. Furthermore, Tim-3 is crucial for the inhibitory effect of MSCs on PBMC proliferation in vitro. Therefore, our work has demonstrated that MSC transplantation effectively mitigates the pathological changes of SS by regulating Tim-3 expression, which provides a novel mechanism of MSC treatment and indicates a brand-new perspective of the combination of inhibitory-receptor-targeted treatment and MSC therapy in SS.

Infectious Keratitis in Patients with Ocular Sjögren's Syndrome.

PurposeTo investigate the incidence, characteristics, risk factors, and treatment outcomes for infectious keratitis in patients with ocular Sjögren’s syndrome (SS).MethodsWe performed a retrospective chart review of patients who had been followed up for ocular SS in Seoul National University Hospital from 2010 to 2020 and identified cases where infectious keratitis developed. The incidence, demographical and clinical characteristics, risk factors, microbiological profiles, and treatment outcome were investigated, some of which were compared with infectious keratitis cases in the non-SS group.ResultsOut of 929 patients with ocular SS, infectious keratitis occurred in 18 eyes (1.94%). All 18 patients were female in the ocular SS group, while 48 out of 100 infectious keratitis patients (48%) were female in the non-SS group (p < 0.01). The mean age at diagnosis of infectious keratitis was 66.1 years in the ocular SS group, which was not different from the non-SS group (57.2 years, p = 0.12). Of risk factors analyzed, the use of therapeutic contact lens was more frequently used in the ocular SS patients, compared to the non-SS patients (67% vs. 11%, p < 0.01). Culture-positivity rate was 50% in the ocular SS group. All culture-proven cases were bacterial infection, one of which was bacterial-fungal coinfection. Infection resolved in all eyes after the mean 29 days of medical treatment, except one that additionally required penetrating keratoplasty with vitrectomy. The visual acuity improved in 15 eyes (83%) after resolution. Infectious keratitis recurred in three patients (17%) during the mean 55.7 months of follow-up.ConclusionsThe incidence of infectious keratitis was 1.94% in patients with ocular SS. Most were bacterial infections and resolved by medical treatment. Therapeutic and visual outcomes were favorable, but recurrence occurred in 17%.

Depression-like behaviors in mouse model of Sjögren's syndrome: A role of gut–microbiota–brain axis

Depression is a common psychiatric symptom in patients with Sjögren's syndrome (SS). Prevalence of depression in SS patients is significantly higher than that in the general population. Increasing evidence suggests a crucial role of gut–microbiota–brain axis in depression. In this study, we investigated whether non-obese diabetic (NOD) mice, a widely used animal model of SS, exhibit depression-like phenotypes and abnormal composition of gut microbiota. Eleven-week-old NOD mice spontaneously exhibited SS-related symptoms without pancreatic destruction. NOD mice displayed depression-like behaviors, decreased expression of synaptic proteins in the prefrontal cortex (PFC), and abnormal composition of gut microbiota. Interestingly, SS-related proinflammatory factors in the submandibular gland (SMG) and autoantibodies (anti-SSA and anti-SSB) in the plasma were correlated with the expression of synaptic proteins in the PFC or depression-like behaviors. In addition, there were correlations between the relative abundance of microbiota and SS-related symptoms (or depression-related phenotypes). These data suggest that SS-related symptoms and abnormal composition of gut microbiota may play a role in depression-like phenotypes in NOD mice through gut–microbiota–brain axis.

The effect of air pollution exposure on risk of outpatient visits for Sjogren's syndrome: A time-series study

BackgroundEmerging evidence showed that air pollutants are associated with development and recurrence of autoimmune disorders, but there is scarce evidence regarding the relationship between air pollutants and Sjogren's syndrome (SS). We sought to investigate whether air pollutants affect the risk of outpatient visits for SS and to quantify the burden of SS visits attributable to air pollution exposure in Hefei, China. MethodsDaily data on outpatient visits for SS, air pollutants and meteorological data in Hefei, China, from January 1, 2015 to December 31, 2020 were obtained. A distributed lag non-linear model in conjunction with a generalized linear model were employed to assess the relationship between air pollution and SS outpatient visits. Stratified analyses were further performed by gender, age and season. Attributable fraction (AF) and attributable number (AN) were used to reflect disease burden. ResultsThere were 4501 records of outpatient visits for SS. Exposure to PM2.5 was associated with increased risk of SS outpatient visits (relative risk (RR) = 1.218, 95% confidence interval (CI): 1.017–1.458, lag 0–14 day). An increase of 24 μg/m3 (interquartile range) in NO2 concentration was associated with 26.3% increase in the risk of SS outpatient visits (RR = 1.263, 95%CI: 1.105–1.445, lag 0–10 day). In contrast, exposure to O3 was associated with decreased risk of SS outpatient visits (RR = 0.692, 95%CI: 0.510–0.939, per 63 μg/m3 in O3 exposure, lag 0–27 day). Stratified analyses showed that females (vs. males) was more vulnerable to SS outpatient visits associated with NO2 and O3 exposure. SS patients aged ≥65 years (vs. aged <65 years) were susceptible to PM2.5 exposure. Exposure to PM2.5 or NO2 in the cold season was associated with higher risk of SS outpatient visits than that in the warm season. In addition, the AN (232, 95%CI: 119, 324) and AF (5.16%, 95%CI: 2.55%, 7.21%) of NO2 exposure were higher than those of PM2.5 exposure. ConclusionPM2.5 and NO2 exposure are associated with increased risk of SS outpatient visits, while O3 exposure appears to be associated with decreased risk of SS outpatient visits. The effect of air pollutants exposure on risk of SS outpatients can be modified by age, gender and season. The burden of SS outpatient visits attributable to NO2 exposure is higher than those attributable to PM2.5 exposure.

Suspect recurrent transient ischemic attack ec Sjogren’s Syndrome

Sjogren's Syndrome is a chronic systemic autoimmune disorder that is usually accompanied by dry eyes and mouth due to inflammation and abnormalities in the lacrimal and salivary glands. This disease can cause a decrease in the production of secretions in other organs that need moisture, such as the nose, throat, respiratory tract, and skin. The prevalence in the general population is not yet known, but the prevalence in the Americas is 0.05-4.8% of the population. Sixty percent of Sjogren's Syndrome patients have disease secondary to accompanying autoimmune disorders such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), or systemic sclerosis.

Imaging Activated-T-Lymphocytes in the Salivary Glands of Patients with Sjögren's Syndrome by 99mTc-Interleukin-2: Diagnostic and Therapeutic Implications.

Background: Sjögren’s syndrome (SS) is a progressive autoimmune disease characterized by local mononuclear cell infiltration of the salivary and lachrymal glands. Labial biopsy demonstrates local infiltration by Th1 cells that produce pro-inflammatory cytokines, such as interleukin-2 (IL2). The aim of this study was to assess the utility of 99mTc-labelled-IL2 (99mTc-IL2) in evaluating in vivo the extent and severity of lympho-mononuclear cell infiltration in the salivary glands of patients with SS. Methods: We investigated 48 patients with primary SS and 27 control subjects using 99mTc-IL2 scintigraphy. Furthermore, in a subgroup of 30 patients, we also performed 99mTc-pertechnetate scintigraphy (99mTcO4−) for evaluation of the salivary gland function. Results: 99mTc-IL2 uptake in the salivary glands of SS patients was higher than in the control subjects (1.30 ± 0.16 vs. 0.83 ± 0.08 for parotids and 1.36 ± 0.15 vs. 1.16 ± 0.07 for submandibular glands; p < 0.0001). The salivary gland uptake of 99mTc-IL2 in patients with a longer history of disease was lower compared with the recently diagnosed patients. A significant direct correlation was found between the uptake of 99mTc-IL2 and histology. Conclusions: 99mTc-IL2 scintigraphy showed that the degree of lymphocytic infiltration of major salivary glands is variable in patients with different disease durations. Patients with a high 99mTc-IL2 uptake could be efficiently treated with immuno-modulatory drugs and the efficacy of treatment could be followed-up by 99mTc-IL2 scintigraphy.

Risk of Cancer in Connective Tissue Diseases in Northeastern Italy over 15 Years.

Objective: To evaluate cancer risk among individuals with connective tissue disease (CTD) in Friuli Venezia Giulia, northern Italy. Methods: A population-based cohort study was conducted based on data from health records available in the regional healthcare database. Demographic characteristics, hospital discharges, exemption from medical charges, drug prescriptions, were individually matched with data from the population-based cancer registry. Cancer risk was assessed in people diagnosed with the following diseases: systemic lupus erythematosus (SLE), Sjögren’s syndrome (SS), systemic sclerosis (SSc), polymyositis (PM), and dermatomyositis (DM). Results: In all, 2504 patients were followed for a total of 18,006 person-years (median follow-up: 6.8 years). After 5 and 10 years of follow-up, the cumulative cancer incidence was 2.6% and 8.5%, respectively. The most common cancers were breast (n = 34), lung (n = 24), colon–rectum–anus (n = 20), and non-Hodgkin lymphomas (NHL) (n = 20). Overall, no excess cancer risk was noted (SIR = 0.87), whereas the number of observed NHL cases was more than two-fold significantly higher than expected (SIR = 2.52). The subgroup analysis showed a higher risk of NHL among SS patients (SIR = 3.84) and SLE patients (SIR = 2.69). Conversely, the study population showed a decreased risk for breast cancers (SIR = 0.61) and corpus uteri (SIR = 0.21). Conclusions: The incidence of NHL was higher among patients with SS and SLE. Careful surveillance for hematological malignancies in these patients is recommended.

Multi-Omic Biomarkers for Patient Stratification in Sjogren's Syndrome-A Review of the Literature.

Sjögren’s syndrome (SS) is a heterogeneous autoimmune rheumatic disease (ARD) characterised by dryness due to the chronic lymphocytic infiltration of the exocrine glands. Patients can also present other extra glandular manifestations, such as arthritis, anaemia and fatigue or various types of organ involvement. Due to its heterogenicity, along with the lack of effective treatments, the diagnosis and management of this disease is challenging. The objective of this review is to summarize recent multi-omic publications aiming to identify biomarkers in tears, saliva and peripheral blood from SS patients that could be relevant for their better stratification aiming at improved treatment selection and hopefully better outcomes. We highlight the relevance of pro-inflammatory cytokines and interferon (IFN) as biomarkers identified in higher concentrations in serum, saliva and tears. Transcriptomic studies confirmed the upregulation of IFN and interleukin signalling in patients with SS, whereas immunophenotyping studies have shown dysregulation in the immune cell population frequencies, specifically CD4+and C8+T activated cells, and their correlations with clinical parameters, such as disease activity scores. Lastly, we discussed emerging findings derived from different omic technologies which can provide integrated knowledge about SS pathogenesis and facilitate personalised medicine approaches leading to better patient outcomes in the future.

Targeting EZH2 prevents the occurrence and mitigates the development of Sjögren's syndrome in mice

ObjectiveWe analyzed RNA-SEQ data and found that EZH2 gene expression in salivary glands (SGs) of Sjögren's syndrome (SS) patients was up-regulated and correlated with pathological injury. In this study, we sought to determine if inhibiting EZH2 would ameliorate SS-like disease in NOD/Ltj (NOD) mice. MethodsWe analyzed RNA-SEQ data of SGs of patients with SS from data obtained from the GEO database to explore the correlation between EZH2 gene expression and the progression of SS. Inhibition of EZH2 in the NOD mice was achieved by intraperitoneal administration of GSK343 using both a preventative and a therapeutic model. The effects of GSK343 on SGs secretion and pathological damage, as well as the levels and functions of T cells, B cells, Myeloid-derived suppressor cells (MDSCs), and other immune cells were evaluated. ResultsThe expression levels of the gene encoding EZH2 in the SGs of SS patients were significantly higher than the non-SS sicca patients, and the expression levels were positively correlated with the severity of the SGs pathological damage. GSK343 treatment significantly increased the salivary flow rate and pathological damage of the SGs in the NOD mice compared to the control mice. In addition, GSK343 significantly inhibited the number and pro-inflammatory-factor secretion of CD4+ and CD8+ T cells and inhibited the increase in the Th1/Th2 cell ratio caused by SS. RNA-SEQ data also showed that EZH2 inhibited several inflammatory pathways during the pathogenesis of SS. ConclusionsEZH2 expression was up-regulated in the submandibular gland tissue of SS patients.Inhibition of EZH2 alleviated SS-like disease in NOD mice, suggesting that EZH2 might be a potential target for the clinical treatment of SS.

High-throughput sequencing of IgH gene in minor salivary glands from Sjögren's syndrome patients reveals dynamic B cell recirculation between ectopic lymphoid structures.

B cells play a central role in Sjögren's syndrome (SS) whereby autoreactive B-cells populate ectopic germinal centres (GC) in SS salivary glands (SG) and undergo somatic hypermutation (SHM) and class-switch recombination of the immunoglobulin genes. However, the capacity of specific B cell clones to seed ectopic GC in different SG and undergo clonal diversification is unclear. To unravel the dynamics of B cell recirculation among minor SG biopsies, we investigated the immunoglobulin heavy chain (IgH) gene usage and the pattern of SHM using a high-throughput sequencing approach. We generated ~166,000 reads longer than 350bp and detected 1631 clonotypes across eight samples from four different SS patients, all characterised by the presence of functional ectopic GC as demonstrated by the expression of activation-induced cytidine deaminase. A large number of shared clonotypes were observed among paired mSG biopsies from each patient but not across different patients. Lineage tree analysis revealed significant clonal expansion within the mSG with the identification of shared dominant B cell clones suggestive of extensive recirculation across different SG. Several shared clonotypes with high proliferating capacity displayed IgH-VH gene usage common in autoreactive B cells, including VH1-69, which is typical of rheumatoid factor+ B cells representing potential lymphoma precursors. The complex dynamic recirculation of B cells that we observed within ectopic GC responses linked with their ability to independently proliferate, undergo ongoing SHM and Ig class-switching within individual glands may explain the difficulty in achieving consistent eradication of ectopic GCs following B cell depleting agents reported in different studies.