Primary Sjögren's Syndrome Patients Research Articles

Association of Circulating Antibody-Secreting Cell Maturity With Disease Features in Primary Sjögren's Syndrome.

B cell hyperactivity plays an important role in primary Sjögren's syndrome (SS). We undertook this study to better understand the B cell effector branch, namely antibody-secreting cells (ASCs) in primary SS, and to examine the quantity, maturity, and inflammatory properties of ASCs in primary SS patients. Circulating ASCs, defined as CD3-CD14-CD27+CD38++ cells, from 21 primary SS patients and 10 healthy controls were assessed using spectral flow cytometry. Expression levels of relevant ASC markers relating to maturity, survival, and inflammatory status were analyzed using a t-distributed stochastic neighbor embedding approach. Correlation of ASC properties with primary SS disease parameters was assessed. ASCs were more abundant in peripheral blood from primary SS patients than from healthy controls (mean ± SD 3.1 ± 5.1 cells/μl versus 1.1 ± 1.0 cells/μl, respectively; P=0.048) and displayed a more mature phenotype (mean ± SD CD19- ASCs 0.37 ± 1.21 cells/μl versus 0.06 ± 0.11 cells/μl, respectively; P=0.005). An inflammatory CXCR3+ phenotype of ASCs correlated positively with our newly developed ASC maturity index (r=0.568, P=0.007) but correlated negatively with antiinflammatory interleukin-10 expression (r=-0.769, P < 0.001). ASCs with a higher maturity index also demonstrated higher levels of the pro-survival protein myeloid cell leukemia 1 (r=0.567, P=0.007). Frequency and/or maturity of ASCs correlated with several primary SS disease parameters, such as antinuclear antibody and anti-La/SSB titers, salivary gland focus scores, and ocular staining scores. Quantity and maturity of ASCs in primary SS patients are increased and correlate with disease parameters. A higher maturity index of ASCs marks a pro-survival and proinflammatory phenotype. Altogether, B cell hyperactivity in primary SS extends to the peripheral ASC compartment, raising potential for ASCs as future biomarkers or targets for primary SS treatment.

Salivary Flow Rate and Oral Status in Patients with Primary Sjögren's Syndrome and Diffuse Cutaneous Systemic Sclerosis: A Cross-Sectional Study.

Determination of salivary flow rate and oral status in patients with primary Sjögren's Syndrome (pSS) and diffuse cutaneous systemic sclerosis (dcSSc) and comparison with control subjects. Thirty-one pSS patients, 28 dcSSc patients, and 28 control subjects participated in this single-center, cross-sectional study. Unstimulated whole salivary flow rate (UWSFR) and stimulated whole salivary flow rate (SWSFR), salivary pH, DMFT index (D-decayed, M-missing, F-filled tooth), periodontal pocket depth (PPD), clinical attachment level (CAL), interincisal distance, and OHRQoL (oral health-related quality of life) were analyzed in all three groups of subjects. Primary SS and dcSSc patients had statistically significant lower values of UWSFR (0.20; 0.38 vs. 0.91 mL/min) and SWSFR (0.56; 0.70 vs. 1.64 mL/min) compared with control subjects (p < 0.001, Kruskal-Wallis test). Salivary pH values were statistically significantly lower in pSS and dcSSc patients compared with control subjects (6.00; 6.25 vs. 7.00, respectively) (p < 0.001, Kruskal-Wallis test). The DMFT index of dcSSc patients was higher (28.50) and statistically significant compared to control subjects (20.00) (p = 0.01). The prevalence of periodontitis was the same in pSS and dcSSc patients and control subjects (p = 0.384). Primary SS and dcSSc patients had a statistically significant decreased interincisal distance compared to control subjects (43.80; 38.00 vs. 48.00) (p = 0.003 and p < 0.001, respectively). Primary SS and dcSSc patients show decreased UWSFR and SWSFR, salivary pH values closer to an acidic medium, higher DMFT index, higher prevalence of periodontitis, decreased interincisal distance, and poorer OHRQoL, i.e., poor oral and periodontal health.

Biomedical statistics study on the correlation between peripheral blood follicular helper T cell subsets and primary Sjogren's syndrome.

To study the expressions of follicular helper T cell (Tfh) subsets--Tfh1, Tfh2, and Tfh17, in peripheral blood (PB) of primary Sjogren's syndrome (PSS) patients in the active phase and remission period after treatment, and to analyze the pathogenic effects of Tfh subsets in PSS patients. The proportions of Tfh1, Tfh2, and Tfh17 were measured by flow cytometry in the healthy group, PSS patients group, active phase group, and remission phase group. Enzyme-linked immunosorbent assay was used to detect IL-21 expression in SS patients in active and remission stages. Biomedical statistics was used to analyze the correlation between Tfh subsets and SS disease activity index; and analyze the correlation between the proportions of Tfh subsets in the healthy group, primary group, active stage, and remission stage In contrast with the healthy group, the levels of Tfh1, Tfh2, and Tfh17 in CD4+ T cells of PSS patients were prominently reduced. PSS patients in the active phase had significantly lower Tfh1, Tfh2, and Tfh17 levels but remarkably higher IL-21 levels than in the remission phase. The contents of Tfh1, Tfh2, and Tfh17 are negatively correlated with the severity of PSS.

FDG-PET/CT discriminates between patients with and without lymphomas in primary Sjögren's syndrome.

To assess the usefulness of [18F]-fluorodeoxyglucose (FDG)-PET/CT (i) to discriminate between primary SS (pSS) patients with and without lymphomas and (ii) to evaluate systemic disease activity in pSS. ACR-EULAR-positive pSS patients who underwent FDG-PET/CT were included. Scans were visually evaluated and quantitative analysis was performed by measuring standardized uptake values (SUV) of salivary and lacrimal glands and systemic regions. Receiver operating characteristic curve analyses were performed to find SUV cut-off values to discriminate between lymphoma and non-lymphoma. Of the 70 included patients, 26 were diagnosed with a pSS-associated lymphoma, mostly of the mucosa-associated lymphoid tissue type (23/26). Lymphoma patients showed higher FDG uptake in the parotid and submandibular glands, and more frequently showed presence of nodular lung lesions, compared with non-lymphoma patients. The accuracy of the maximum SUV (SUVmax) in the parotid and submandibular gland to predict lymphoma diagnosis was good, with optimal cut-off points of 3.1 and 2.9. After combining these three visual and quantitative findings (nodular lung lesions, parotid SUVmax > 3.1 and submandibular SUVmax > 2.9), sensitivity was 92% when at least one of the three features were present, and specificity was 91% in case at least two features were present. Furthermore, FDG-PET/CT was able to detect systemic manifestations in pSS patients, mostly involving lymph nodes, entheses and lungs. FDG-PET/CT can assist in excluding pSS-associated lymphomas in patients without PET abnormalities, possibly leading to a decrease of invasive biopsies in suspected lymphoma patients. Furthermore, FDG-PET/CT is able to detect systemic manifestations in pSS and can guide to the best biopsy location.

Analysis of clinical features and risk factors of peripheral neuropathy in patients with primary Sjögren's syndrome

ObjectiveTo observe the clinical features and efficacy of immunosuppressive therapy in patients with primary Sjögren's syndrome (PSS) combined with peripheral neuropathy (PN) syndrome and to explore the risk factors for PN in patients with PSS.MethodsSixty consecutive patients with PSS admitted to the Department of Rheumatology and Immunology, Wuhan No. 1 Hospital, from January 2014 to June 2020 were analysed retrospectively. Patients were divided into a PN group (N = 15) and a non-PN group (N = 45). The clinical characteristics of the two groups were compared, and the independent risk factors for PN combined with PSS were analysed by multivariate logistic regression. The patients with PSS combined with PN were followed up to observe the effect of immunosuppressive therapy.ResultsThe patients with PN had a longer course of disease than those without PN (z = − 3.225, P = 0.001), and the incidence of Raynaud's phenomenon, anti-SSB antibody, rheumatoid factor and hyperglobulinaemia was higher (all P < 0.05) in patients with PN than in those without PN. Multivariate logistic regression analysis showed that hyperglobulinaemia, RF and anti-SSB antibodies were independent risk factors for PN with PSS (P < 0.05). Fourteen patients with PSS-PN were treated with immunosuppressants. The clinical symptoms of 10 patients were relieved, and mRS scores of 10 patients were decreased.ConclusionPN is a common complication in PSS patients. Patients with PSS combined with PN have a longer course of disease and a significantly higher percentage of Raynaud's phenomenon, positive anti-SSB antibody, positive RF and hyperglobulinaemia. Immunosuppressive therapy was effective for partial remission of PN with PSS.

Development of Clinical Decision Models for the Prediction of Systemic Lupus Erythematosus and Sjogren's Syndrome Overlap.

To explore the clinical features of patients with systemic lupus erythematosus and Sjögren's syndrome overlap (SLE-SS) compared to concurrent SLE or primary SS (pSS) patients, we utilized a predictive machine learning-based tool to study SLE-SS. This study included SLE, pSS, and SLE-SS patients hospitalized at Nanjing Drum Hospital from December 2018 to December 2020. To compare SLE versus SLE-SS patients, the patients were randomly assigned to discovery cohorts or validation cohorts by a computer program at a ratio of 7:3. To compare SS versus SLE-SS patients, computer programs were used to randomly assign patients to the discovery cohort or the validation cohort at a ratio of 7:3. In the discovery cohort, the best predictive features were determined using a least absolute shrinkage and selection operator (LASSO) logistic regression model among the candidate clinical and laboratory parameters. Based on these factors, the SLE-SS prediction tools were constructed and visualized as a nomogram. The results were validated in a validation cohort, and AUC, calibration plots, and decision curve analysis were used to assess the discrimination, calibration, and clinical utility of the predictive models. This study of SLE versus SLE-SS included 290 patients, divided into a discovery cohort (n = 203) and a validation cohort (n = 87). The five best characteristics were selected by LASSO logistic regression in the discovery cohort of SLE versus SLE-SS and were used to construct the predictive tool, including dry mouth, dry eye, anti-Ro52 positive, anti-SSB positive, and RF positive. This study of SS versus SLE-SS included 266 patients, divided into a discovery cohort (n = 187) and a validation cohort (n = 79). In the discovery cohort of SS versus SLE-SS, by using LASSO logistic regression, the eleven best features were selected to build the predictive tool, which included age at diagnosis (years), fever, dry mouth, photosensitivity, skin lesions, arthritis, proteinuria, hematuria, hypoalbuminemia, anti-dsDNA positive, and anti-Sm positive. The prediction model showed good discrimination, good calibration, and fair clinical usefulness in the discovery cohort. The results were validated in a validation cohort of patients. The models are simple and accessible predictors, with good discrimination and calibration, and can be used as a routine tool to screen for SLE-SS.

Quantitative Texture Analysis of Parotid Gland Ultrasound Images Yield Higher Correlation with Scintigraphy than Semiquantitative Scoring in Primary Sjögren's Syndrome Patients.

Ultrasound (US) can detect salivary gland abnormalities in primary Sjögren's syndrome (SS). This study aimed to compare the correlation among the semiquantitative US scores, texture features, and the quantitative salivary gland scintigraphy (SGS) results. This retrospective study included 11 patients who were diagnosed with primary SS and underwent US examinations of the parotid glands and SGS simultaneously. We evaluated SGS quantitatively based on the calculation of maximum accumulation ratio (MAR) and stimulated excretion fraction (EF). The US findings were accessed through the semiquantitative Outcome Measures in Rheumatology scoring system and by gray-level co-occurrence matrix (GLCM) texture analysis. Spearman's rank correlation tests were performed. A significant moderate negative correlation was noted between the semiquantitative US score and MAR (rho = -0.57, P = 0.006), but not with EF (rho = -0.11, P = 0.613). The GLCM texture metrics, including contrast, dissimilarity, and homogeneity, were all determined to be significantly associated with both MAR and EF. The GLCM contrast correlated moderately to MAR (rho = -0.66, P = 0.001). The GLCM homogeneity highly correlated to EF (rho = 0.74, P < 0.001). The contrast and homogeneity can still discriminate the changes in MAR and EF in the subgroups with the same semiquantitative US scores. US findings on parotid gland can correlate with SGS results when analyzed based on GLCM texture features. With the GLCM texture metrics, US appears to be an excellent imaging tool for the assessment of the parotid glands in primary SS patients.

Depression is the most significant independent predictor of fatigue in patients with primary Sjögren's syndrome.

The study aimed to evaluate the level of fatigue and the relationship between mood, pain, fibromyalgia, insomnia, disease activity, and dryness with fatigue in primary Sjögren's syndrome (PSS) patients. In this case-control study, the participants were recruited between January 2021 and July 2021. Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), pain DETECT questionnaire, Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Insomnia Severity Index (ISI) were administered to 50 PSS patients (48 females, 2 males; mean age: 48.9±10.8 years; median age: 47 years; range, 29 to 71 years) and 60 healthy controls (HCs; 57 females, 3 males; mean age: 49.8±8.4 years, median age: 52 years; range, 32 to 72 years). In addition, EULAR Sjögren's syndrome disease activity index (ESSPRI), EULAR Sjögren's Syndrome Patient Reported Index (ESSDAI), pain thresholds, Schirmer tests, and whole unstimulated salivary flow rate measurements were determined in PSS patients. Independent predictors of fatigue (fatigue subscale scores <30.5) were investigated by logistic regression analysis. The frequency of fatigue in PSS patients and HCs was 54.0% and 8.3%, respectively. The rates of mood disturbance (BDI ≥11) in PSS patients with and without fatigue were 70.4% and 13.1%, respectively. BDI (Rho=-0.804), BAI (Rho=-0.586), ISI (Rho=-0.483), and ESSDAI (Rho=-0.345) were negatively correlated with the fatigue subscale score. Depression [Odds ratio (OR): 1.214, confidence interval (CI): 1.007-1.463], fibromyalgia (OR: 21.674, CI: 1.470-319.469), disease activity (OR: 1.440; CI: 1.005-2.065), and insomnia (OR: 1.223, CI: 1.003-1.4922) were identified as independent predictors of fatigue in PSS patients. It was determined that BD alone could predict fatigue by 84% in PSS patients. Depression can be a prominent predictor of fatigue in PSS patients. There is a need for studies evaluating the effect of antidepressant treatment approaches on fatigue accompanied by mood disturbance in PSS patients.

Scleroderma specific autoantibodies in rheumatoid arthritis and Sjögren's syndrome patients with interstitial lung disease: Prevalence and associations

Systemic sclerosis (SSc) has been classically linked to interstitial lung disease (ILD) development, often in association with specific SSc autoantibodies. In the present report, we aimed to estimate the prevalence of SSc autoantibodies in 60 seropositive RA and 41 primary SS patients complicated or not by ILD. SSc autoantibodies were determined in patients’ sera by a commercial immunoblot assay. RA ILD patients displayed higher frequency of SSc-specific antibodies at strong titers compared to RA-with no lung involvement (25% vs 3.1%, p = 0.01)[OR 95% CI:10.9 (1.2–94.5)], with no differences detected between primary SS groups. These data indicate that many seropositive RA ILD patients probably represent an overlap RA/SSc entity, requiring tailored diagnostic and therapeutic approach.

Long-term risk of heart failure and other adverse cardiovascular outcomes in primary Sjögren's syndrome.

Data on long-term cardiovascular outcomes in primary Sjögren's syndrome (PSS) are scarce. We aim to investigate the long-term rate of incident heart failure (HF) and other adverse cardiovascular endpoints in patients with PSS compared with the general population and to investigate mortality in individuals with incident HF with or without a history of PSS. Using Danish nationwide registries, PSS patients (diagnosed 1996-2018) without a history of other autoimmune diseases were each matched with four individuals from the general population by sex, age, and comorbidities. Multivariable Cox regression was used to estimate the rate of cardiovascular outcomes. In addition, the rate of death from any cause was compared between PSS patients with incident HF and four age- and sex-matched HF patients without PSS. In total, 5092 patients with newly diagnosed PSS were matched with 20,368 individuals from the general population (median age 57 years, 87.3% women, median follow-up 7.4 years). The cumulative incidence of HF at 10 years was 4.0% for PSS patients and 2.8% for matched individuals. After adjustment, patients with PSS had a higher associated rate of incident HF (hazard ratios [HR] 1.42 [95% CI, 1.20-1.68]) and other cardiovascular outcomes, compared with the background population. PSS patients with incident HF had a similar rate of death from all-cause mortality compared with HF patients without PSS (HR 0.94 [0.74-1.19]). Patients with PSS had a higher associated rate of incident HF and other cardiovascular outcomes compared with the general population. In individuals with incident HF, a history of PSS was not associated with increased mortality.

Tear Proteomics Approach to Distinguishing Primary from Secondary Sjögren’s Syndrome for Dry Eye Patients with Long-Term Instillation of Eyedrops

The diagnosis and monitoring of Sjögren syndrome (SS) is often difficult, requiring a multidisciplinary approach with invasive procedures. Our aim is to elucidate the tear protein alterations of dry eye disease (DED) with primary SS (pSS) and secondary SS (sSS) with the long-term instillation of eyedrops. We collected clinical demographics and tear fluid (TF) samples from DED patients with no autoimmune diseases (non-SS-DED), pSS-DED, and sSS-DED patients, followed by TF screening with tandem mass tagging-labeling gel-free proteomics assay. Bioinformatic analysis via Ingenuity Pathway Analysis was used to identify functional pathways and interacting networks. Validation of candidate proteins with enzyme-linked immunosorbent assay on the tear samples was done. The top functional pathways of the two comparisons (sSS-DED vs. pSS-DED and sSS-DED vs. non-SS-DED) were both associated with inflammation and stress-related signaling. After constructing an interaction network model with the selected candidate proteins, five proteins were identified. A Disintegrin and Metalloproteinase domain-containing protein 10 (ADAM10) was found to be an important candidate biomarker in all groups, followed by epidermal growth factor (EGF) in TF. This study revealed novel DED markers, ADAM10 and EGF, in differentiating between primary and secondary SS patients from tears by in-depth proteomic analysis.

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.

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.

Primary Sjögren's syndrome is not associated with poor outcomes after total hip arthroplasty: a retrospective case-control study with a matched cohort of osteoarthritis patients.

IntroductionThe number of patients with primary Sjögren’s syndrome (PSS) requiring total hip arthroplasty (THA) is expected to increase, but few studies have detailed their outcomes. The purpose of this study was to evaluate a THA cohort of patients with avascular necrosis of the femoral head (ANFH) who had PSS and to compare their outcomes with those of matched patients with osteoarthritis.MethodA case–control study using data from a single-institution arthroplasty registry was performed. Forty-two THAs in 32 patients undergoing THA with a diagnosis of PSS were identified and were matched with 84 THAs in 64 patients with osteoarthritis (1:2 ratio). Functional and health-related quality of life (QoL) evaluations were performed, and complications were recorded at the last follow-up. Logistic regression was used to determine factors associated with reaching the transfusion trigger of hemoglobin < 8 g/dL (TT8) in PSS patients.ResultsAfter a mean 5-year follow-up, both cohorts had similar hip function and health-related QoL outcomes. The incision complications and reaching TT8 were greater in the PSS group. No differences were observed in the rate of 90-day readmission, reoperation, or overall revision. By multivariate analysis, the influencing factors for reaching TT8 in PSS patients were lower preoperative hemoglobin (OR = 0.842, 95% CI [0.741–0.958], P < 0.05).ConclusionOur study demonstrated PSS patients who received THA due to ANFH could achieve clinical outcomes similar to those of non-PSS patients. Improving preoperative Hb level can reduce the risk of transfusion.Key Points• THA significantly improved hip function and health-related quality of life in PSS patients with osteonecrosis of the femoral head.• Patients with PSS were more likely to reach the transfusion trigger and higher rates of incision complications after THA.• Improving preoperative Hb level can reduce the risk of transfusion for PSS patients who underwent THA.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10067-022-06256-2.

Subclinical atherosclerosis profiles in rheumatoid arthritis and primary Sjögren's syndrome: the impact of BAFF genetic variations.

RA and primary SS carry increased atherosclerotic risk, while B-cell activating factor holds a vital role in disease pathogenesis and atherosclerosis. We aimed to compare subclinical atherosclerosis profiles between the two clinical entities and define whether BAFF genetic variants alter atherosclerotic risk. DNA from 166 RA, 148 primary SS patients and 200 healthy controls of similar age and sex distribution was subjected to PCR-based assay for the detection of five single nucleotide polymorphisms of the BAFF gene (rs1224141, rs12583006, rs9514828, rs1041569 and rs9514827). Genotype and haplotype frequencies were determined by SNPStats software and statistical analysis was performed by SPSS and Graphpad Software. Subclinical atherosclerosis was defined by the presence of carotid/femoral plaque formation and arterial wall thickening. Atherosclerotic plaque formation was more frequently detected in the RA vs primary SS group (80.7% vs 62.2%, P-value <0.001), along with higher rates of family CVD history, current steroid dose and serum inflammatory markers. The TT genotype of the rs1224141 variant was more prevalent in RA but not primary SS patients with plaque and arterial wall thickening vs their counterparts without. Regarding the rs1014569 variant, among RA patients the TT genotype increased the risk for plaque formation while in primary SS patients the AT genotype conferred increased risk. Haplotype GTTTT was protective in the RA cohort, while TATTT and TTCTT haplotypes increased susceptibility for arterial wall thickening in the primary SS cohort. Increased inflammatory burden, higher steroid doses and distinct BAFF gene variations imply chronic inflammation and B-cell hyperactivity as key contributors for the augmented atherosclerotic risk among autoimmune patients.

Hematologic parameters and disease activity in patients with primary Sjögren's syndrome

Aim of the workTo evaluate hematologic parameters in patients with primary Sjögren's syndrome (PSS) and their association with disease activity. Patients and methodsSixty-five PSS patients and 65 age and sex matched control were studied. Neutrophil to lymphocyte ratio (NLR), mean platelet volume (MPV), red blood cells distribution width (RDW), platelet to lymphocyte ratio (PLR) and platelet count were evaluated. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured. The European league against rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI) was assessed. ResultsThe mean age of patients was 47.8 ± 12.1 years and disease duration 5.71 ± 1.2 years and they were 63 females and 2 males. The mean ESSDAI was 6.4 ± 7.9 (3–25). 11 had neurological involvement. 92.3% of patients received low-dose prednisolone (<10 mg/day) and hydroxychloroquine (HCQ). The mean NLR (1.83 ± 0.8), PLR (131.9 ± 32.5) and MPV (8.82 ± 1.4) in patients was significantly higher than in control (NLR 1.57 ± 0.56, PLR 109.9 ± 24.7 and MPV 7.71 ± 1.3; p = 0.036, p < 0.001 and p < 0.001 respectively). The RDW tended to be higher in patients (13 ± 1.56) compared to control (12.83 ± 1.13) (p = 0.46). There was a significant correlation between ESSDAI with NLR (r = 0.29, p = 0.02), RDW (r = 0.37, p = 0.002), ESR (r = 0.32, p = 0.01) and CRP (r = 0.33, p = 0.007) and between MPV with CRP (r = 0.27, p = 0.03) and between RDW and ESR (r = 0.36, p = 0.003).On regression analysis, NLR and RDW were significant predictors of disease activity (p = 0.01 and p = 0.02 respectively). ConclusionThe MPV, PLR and NLR, were significantly increased in PSS. NLR and RDW can be used as indicators of disease activity.

Prevalence and clinical significance of serum anti-cyclic citrullinated peptide antibodies in primary Sjögren's syndrome

Objectives: Although anti-cyclic citrullinated peptide (anti-CCP) antibody is a specific marker for rheumatoid arthritis (RA), it is also detected positively in some other rheumatological diseases including Sjögren's syndrome (SS) and even in healthy people. Studies have shown that anti-CCP guides the early diagnosis, prognosis and treatment of RA patients. SS and RA overlap syndrome are common. This study was conducted to determine the prevalence and clinical significance of serum anti-CCP in primary SS patients followed in our outpatient clinic. Methods: Eighty-two primary SS, 100 RA patients and 100 healthy controls applied to rheumatology outpatient clinic were examined. Patients and control groups were compared in terms of demographic characteristics, laboratory results and anti-CCP. Results: In the present study, anti-CCP was positive in 4 (4.9%) of 82 primary SS patients. In the SS group, among other autoantibodies, ANA was found to be positive at 88.8%, RF 45%, SS-A 64.6%, and SS-B 36.7%. There was no relationship between anti-CCP and joint involvement in patients with SS. Conclusions: Anti-CCP antibody positivity can be found in SS patients. Acute phase proteins may be higher in primary SS patients with positive anti-CCP antibody. However, studies have found conflicting findings about the prevalence of erosive arthritis and the future development of RA in these patient groups.

Digital image analysis of intraepithelial B-lymphocytes to assess lymphoepithelial lesions in salivary glands of Sjögren's syndrome patients.

Salivary glands of primary SS (pSS) patients characteristically harbour periductal infiltrates, in which lymphoepithelial lesions (LELs) can develop. LELs are composed of hyperplastic ductal epithelium with infiltrating lymphocytes and may assist in the challenging diagnostic process of pSS. As manual identification of LELs remains difficult, we aimed to identify LELs by using an objective digital image analysis (DIA) algorithm that detects intraepithelial lymphocytes. A virtual triple-staining technique developed for this study was used to count intraepithelial lymphocytes in consecutive slides stained for CD3 (T-lymphocytes), high-molecular-weight cytokeratin (hmwCK) (striated ducts) and CD20 (B-lymphocytes) in labial and parotid gland biopsies in a diagnostic cohort of 109 sicca patients. Patients were classified as having pSS or non-SS according to the ACR-EULAR classification criteria. T-lymphocytes were detected in almost all analysed ducts of pSS and non-SS sicca patients, whereas intraepithelial B-lymphocytes were present in 59-68% of labial and parotid gland biopsies of pSS patients, against only 2-3% of patients classified as non-SS. Intraepithelial B-lymphocytes were found in almost all striated ducts with hyperplasia (LELs). Remarkably, ∼25% of analysed striated ducts without hyperplasia of pSS patients also contained B-lymphocytes (precursor-LELs). Furthermore, presence of intraepithelial B-lymphocytes was associated with clinical parameters of pSS (i.e. serology). The presence of intraepithelial B-lymphocytes in salivary gland biopsies of sicca patients is a clear indicator of pSS and can be used as an objective alternative to LEL scoring. Therefore, identification of B-lymphocyte-containing ducts should be added to the diagnostic histopathological work-up of patients suspected of pSS.

Maladaptive Autophagy in the Pathogenesis of Autoimmune Epithelitis in Sjögren's Syndrome.

Salivary gland epithelial cells (SGECs) are key cellular drivers in the pathogenesis of primary Sjögren's syndrome (SS); however, the mechanisms sustaining SGEC activation in primary SS remain unclear. We undertook this study to determine the role of autophagy in the survival and activation of SGECs in primary SS. Primary SGECs isolated from the minor SGs of patients with primary SS or sicca syndrome were evaluated by flow cytometry, immunoblotting, and immunofluorescence to assess autophagy (autophagic flux, light chain 3 IIB [LC3-IIB], p62, LC3-IIB+/lysosome-associated membrane protein 1 [LAMP-1] staining), apoptosis (annexin V/propidium iodide [PI], caspase 3), and activation (intercellular adhesion molecule, vascular cell adhesion molecule). Focus score and germinal center presence were assessed in the SGs from the same patients to assess correlation with histologic severity. Human SG (HSG) cells were stimulated in vitro with peripheral blood mononuclear cells (PBMCs) and serum from primary SS patients in the presence or absence of autophagy inhibitors to determine changes in autophagy and epithelial cell activation. SGECs from primary SS patients (n=24) exhibited increased autophagy (autophagic flux [P=0.001]; LC3-IIB [P=0.02]; p62 [P=0.064]; and as indicated by LC3-IIB/LAMP-1+ staining), increased expression of antiapoptotic molecules (Bcl-2 [P=0.006]), and reduced apoptosis (annexin V/PI [P=0.002]; caspase 3 [P=0.057]), compared to samples from patients with sicca syndrome (n=16). Autophagy correlated with histologic disease severity. In vitro experiments on HSG cells stimulated with serum and PBMCs from primary SS patients confirmed activation of autophagy and expression of adhesion molecules, which was reverted upon pharmacologic inhibition of autophagy. In primary SS SGECs, inflammation induces autophagy and prosurvival mechanisms, which promote SGEC activation and mirror histologic severity. These findings indicate that autophagy is a central contributor to the pathogenesis of primary SS and a new therapeutic target.

Milk Fat Globule Epidermal Growth Factor 8 (MFGE8) Gene Variants in Rheumatoid Arthritis and Sjögren's Syndrome.

Milk Fat Globule Epidermal Growth Factor 8 (MFGE8) deficiency and gene polymorphisms have been previously linked to systemic lupus erythematosus (SLE)-like and SLE development. Our aim was to explore whether four MFGE8 variants and MFGE8 serum levels are associated with autoimmunity susceptibility and autoimmune related atherosclerosis. DNA from 107 primary Sjogren’s syndrome (SS), 116 rheumatoid arthritis (RA) and 123 SLE patients as well as 199 HC were genotyped for the MFGE8 rs2271715, rs1878326, rs4945, rs3743388 variants by RFLP-PCR. MFGE8 serum levels were measured by ELISA. The CA genotype of rs4945 variant exhibited a protective effect against RA development, a finding not confirmed in the SS and SLE populations. The CACG haplotype exhibited a protective effect in both RA and SS patients compared to HC. Primary SS patients with IMT ≤ 0.9 mm displayed higher MGFE8 serum levels compared to those with ˃0.9 mm. Here, we report a novel association of MFGE8 variants in SS and RA susceptibility, as well as reduced MFGE8 serum levels in SS patients with heightened atherosclerotic risk.