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Sjögren’s syndrome (SS) is an autoimmune disease affecting the salivary and lacrimal glands. Symptoms range from dryness to severe extra-glandular disease involving manifestations in the skin, lungs, nervous system, and kidney. Fatigue occurs in 70% of patients, characterizing primary SS (pSS) and significantly impacting the patient’s quality of life. There are some generic and specific instruments used to measure fatigue in SS. The mechanisms involved with fatigue in SS are still poorly understood, but it appears fatigue signaling pathways are more associated with cell protection and defense than with pro-inflammatory pathways. There are no established pharmacological treatment options for fatigue in pSS. So far, exercise and neuromodulation techniques have shown positive effects on fatigue in pSS. This study briefly reviews fatigue in pSS, with special attention to outcome measures, biomarkers, and possible treatment options.

ObjectivesUltrasonography (US) is sensitive for detecting echostructural abnormalities of the major salivary glands (SGs) in primary Sjögren’s syndrome (pSS). Our objectives were to define selected US-SG echostructural abnormalities in pSS, set up a preliminary atlas of these definitions and evaluate the consensual definitions reliability in both static and acquisition US-SG images.MethodsInternational experts in SG US in pSS participated in consensus meetings to select and define echostructural abnormalities in pSS. The US reliability of detecting these abnormalities was assessed using a two-step method. First 12 experts used a web-based standardised form to evaluate 60 static US-SG images. Intra observer and interobserver reliabilities were expressed in κ values. Second, five experts, who participated all throughout the study, evaluated US-SG acquisition interobserver reliability in pSS patients.ResultsParotid glands (PGs) and submandibular glands (SMGs) intra observer US reliability on static images was substantial (κ > 0.60) for the two main reliable items (echogenicity and homogeneity) and for the advised pSS diagnosis. PG inter observer reliability was substantial for homogeneity. SMGs interobserver reliability was moderate for homogeneity (κ = 0.46) and fair for echogenicity (κ = 0.38). On acquisition images, PGs interobserver reliability was substantial (κ = 0.62) for echogenicity and moderate (κ = 0.52) for homogeneity. The advised pSS diagnosis reliability was substantial (κ = 0.66). SMGs interobserver reliability was fair (0.20< κ ≤ 0.40) for echogenicity and homogeneity and either slight or poor for all other US core items.ConclusionThis work identified two most reliable US-SG items (echogenicity and homogeneity) to be used by US-SG trained experts. US-PG interobserver reliability result for echogenicity is in line with diagnosis of pSS.

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are members of the tumour necrosis factor superfamily. We have examined circulating BAFF and APRIL in relation to serological deviations and lymphoid organization in the salivary glands of the chronic, autoimmune disorder Sjögren's syndrome. Lymphoid organization in the shape of ectopic germinal centers were detected in 33 of 130 consecutive minor salivary gland biopsies and coincided with increased focus score and elevated levels of serum IgG. Follicular dendritic cell networks, proliferation of mononuclear cells and altered B/T cell ratio also separated the two subgroups. Serum levels of sBAFF and sAPRIL were increased in Sjögren's syndrome compared to healthy blood donors, especially in anti-Ro/La+ patients. Though the differences could not be related to germinal center formation, positive correlations between serum levels of sBAFF and sAPRIL, focus score and IgG denotes their possible role in the disease progression of primary Sjögren's syndrome.

Objectives: Salivary gland ultrasonography (SGUS) is increasingly applied for the management of primary Sjögren's syndrome (pSS). This study aims to: (i) compare the reliability between two SGUS scores; (ii) test the reliability among sonographers with different levels of experience. Methods: In the reliability exercise, two four-grade semi-quantitative SGUS scoring systems, namely De Vita et al. and OMERACT, were tested. The sonographers involved in work-package 7 of the HarmonicSS project from nine countries in Europe were invited to participate. Different levels of sonographers were identified on the basis of their SGUS experience and of the knowledge of the tested scores. A dedicated atlas was used as support for SGUS scoring. Results: Twenty sonographers participated in the two rounds of the reliability exercise. The intra-rater reliability for both scores was almost perfect, with a Light's kappa of 0.86 for the De Vita et al. score and 0.87 for the OMERACT score. The inter-rater reliability for the De Vita et al. and the OMERACT score was substantial with Light's Kappa of 0.75 and 0.77, respectively. Furthermore, no significant difference was noticed among sonographers with different levels of experience. Conclusion: The two tested SGUS scores are reliable for the evaluation of major salivary glands in pSS, and even less-expert sonographers could be reliable if adequately instructed.

Objective The development of non-Hodgkin's lymphoma (NHL) confers a high risk of mortality in primary Sjögren's syndrome (pSS) patients, but the sensitivity and specificity of proposed lymphoma predictors are insufficient for practical use. The performance of lymphoid organisation in the form of germinal centre (GC)-like lesions was evaluated in labial salivary gland biopsies taken at pSS diagnosis as a potential lymphoma-predicting biomarker. Methods Labial salivary gland tissue biopsies available from two Swedish pSS research cohorts (n=175) were re-evaluated by light microscopy in a blind study in order to identify GC-like structures as a sign of ectopic lymphoid tissue formation and organisation. A linkage study was performed with the Swedish Cancer Registry for lymphoma identification. The risk of developing NHL in GC-positive patients in comparison with GC-negative patients was evaluated using Kaplan–Meier statistics and log-rank test. Associations between GC-like structures and clinical and/or laboratory disease markers were also determined using χ2 or Fisher's exact tests. Results At diagnosis, 25% of pSS patients had GC-like structures in their salivary glands. Seven of the 175 patients studied (14% GC+ and 0.8% GC−) developed NHL during 1855 patient-years at risk, with a median onset of 7 years following the initial diagnostic salivary gland biopsy. Six of the seven patients had GC-like structures at diagnosis; the remaining patient was GC negative at the time of diagnosis (p=0.001). Conclusions The detection of GC-like structures by light microscopy in pSS diagnostic salivary biopsies is proposed as a highly predictive and easy-to-obtain marker for NHL development. This allows for risk stratification of patients and the possibility to initiate preventive B-cell-directed therapy.

Sjögren’s disease is a complex autoimmune disease with twelve established susceptibility loci. This genome-wide association study (GWAS) identifies ten novel genome-wide significant (GWS) regions in Sjögren’s cases of European ancestry: CD247 , NAB1 , PTTG1-MIR146A , PRDM1-ATG5 , TNFAIP3 , XKR6 , MAPT- CRHR1 , RPTOR-CHMP6-BAIAP6 , TYK2 , SYNGR1 . Polygenic risk scores yield predictability (AUROC = 0.71) and relative risk of 12.08. Interrogation of bioinformatics databases refine the associations, define local regulatory networks of GWS SNPs from the 95% credible set, and expand the implicated gene list to >40. Many GWS SNPs are eQTLs for genes within topologically associated domains in immune cells and/or eQTLs in the main target tissue, salivary glands. The genetic architecture underlying Sjögren’s syndrome is not fully understood. Here, the authors perform a genome-wide association study to identify 10 new genetic risk regions, implicating genes involved in immune and salivary gland function.

ObjectivesHerein, we investigate the presence and prognostic value of autoantibodies against carbamylated proteins (anti-CarP) in the serum of patients with primary Sjögren's syndrome (pSS).Patients and methodsSerum levels of anti-CarP antibodies were measured in Norwegian patients with pSS (n=78) and corresponding controls (n=74) using ELISA and analysed in relation with exocrine gland function, degree of salivary gland inflammation, signs of ectopic germinal centre (GC) formation and immunological markers. For univariate comparisons, the Mann–Whitney U test and χ2 or Fisher's exact tests were used. Correlations were assessed with Spearman's rank testing. Multivariate regression analyses were used to assess the effect of anti-CarP positivity on clinical manifestations.ResultsOf the patients with pSS, 27% were positive for anti-CarP IgG antibodies. Levels of anti-CarP correlated positively with total IgG, IgM, rheumatoid factor and β2-microglobulin. Importantly, after adjusting for confounding factors, patients positive for anti-CarP had significantly higher focus score. Furthermore, positive anti-CarP status coincided with 9.2-fold higher odds of having developed GC-like structures in the minor salivary glands. As a patient group considered having worse disease outcome, individuals with ectopic GC-like structures also presented with significantly higher levels of anti-CarP antibodies.ConclusionsPresence of anti-CarP in patients with pSS is strongly associated with increased focal lymphocytic infiltration, formation of ectopic GC-like structures in minor salivary glands, and diminished salivary gland function. Even taking into consideration our relatively small cohort we believe that anti-CarP antibodies offer new possibilities for identifying patients with more active disease and at risk of developing additional comorbidity.

Background Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to investigate differences in the clinical presentation of primary Sjögren’s syndrome (pSS) between the sexes and establish whether male sex is associated with a more severe form of long-term pSS. Methods Our study population included 967 patients with pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 ± 7.6 for women and 8.5 ± 6.2 for men (ns). Clinical data including serological and hematological parameters and glandular and extraglandular manifestations were compared between men and women. Results Male patient serology was characterized by more frequent positivity for anti-Ro/SSA and anti-La/SSB ( p  = 0.02), and ANA ( p  = 0.02). Further, men with pSS were more frequently diagnosed with interstitial lung disease ( p  = 0.008), lymphadenopathy ( p  = 0.04) and lymphoma ( p  = 0.007). Conversely, concomitant hypothyroidism was more common among female patients ( p  = 0.009). Conclusions We observe enhanced serological responses and higher frequencies of lymphoma-related extraglandular manifestations in men with pSS. Notably, lymphoma itself was also significantly more common in men. These observations may reflect an aggravated immune activation and a more severe pathophysiological state in male patients with pSS and indicate a personalized managing of the disease due to the influence of the sex of patients with pSS.