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Objectives To validate the two recently developed disease activity indexes for assessment of primary Sjögren's syndrome (SS): the European League Against Rheumatism (EULAR) SS Patient Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI). Methods A prospective international 6-month duration validation study was conducted in 15 countries. At each visit, physicians completed ESSDAI, SS disease activity index (SSDAI), Sjögren's Systemic Clinical Activity Index (SCAI) and physician global assessment (PhGA); and patients completed ESSPRI, Sicca Symptoms Inventory (SSI), Profile of Fatigue and Discomfort (PROFAD) and patient global assessment (PGA). Psychometric properties (construct validity, responsiveness and reliability) were evaluated and compared between scores. Results Of the 395 patients included, 145 (37%) and 251 (64%) had currently active or current or past systemic manifestations, respectively. EULAR scores had higher correlation with the gold standard than other scores (ESSDAI with PhGA: r=0.59; ESSRPI with PGA: r=0.70). Correlations between patient and systemic scores were very low (ranging from 0.07 to 0.29). All systemic scores had similar large responsiveness in improved patients. Responsiveness of patient scores was low but was significantly higher for ESSPRI compared with SSI and PROFAD. Reliability was very good for all scores. Conclusions ESSDAI and ESSPRI had good construct validity. All scores were reliable. Systemic scores had a large sensitivity to change in patients whose disease activity improves. Patient scores had a small sensitivity to change, however, significantly better for ESSPRI. Systemic and patient scores poorly correlated, suggesting that they are 2 complementary components that should be both evaluated, but separately.

ObjectivesTo analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis.MethodsThe Big Data Sjögren Project Consortium is an international, multicentre registry designed in 2014. By January 2016, 20 centres from five continents were participating. Multivariable logistic regression analyses were performed.ResultsWe included 7748 women (93%) and 562 men (7%), with a mean age at diagnosis of primary SjS of 53 years. Ethnicity data were available for 7884 patients (95%): 6174 patients (78%) were white, 1066 patients (14%) were Asian, 393 patients (5%) were Hispanic, 104 patients (1%) were black/African-American and 147 patients (2%) were of other ethnicities. SjS was diagnosed a mean of 7 years earlier in black/African-American compared with white patients; the female-to-male ratio was highest in Asian patients (27:1) and lowest in black/African-American patients (7:1); the prevalence of sicca symptoms was lowest in Asian patients; a higher frequency of positive salivary biopsy was found in Hispanic and white patients. A north-south gradient was found with respect to a lower frequency of ocular involvement in northern countries for dry eyes and abnormal ocular tests in Europe (OR 0.46 and 0.44, respectively) and Asia (OR 0.18 and 0.49, respectively) compared with southern countries. Higher frequencies of antinuclear antibodies (ANAs) were reported in northern countries in America (OR=1.48) and Asia (OR=3.80) while, in Europe, northern countries had lowest frequencies of ANAs (OR=0.67) and Ro/La (OR=0.69).ConclusionsThis study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis.

ObjectivesTo evaluate the safety and efficacy of remibrutinib in patients with moderate-to-severe Sjögren’s syndrome (SjS) in a phase 2 randomised, double-blind trial (NCT04035668; LOUiSSE (LOU064 in Sjögren’s Syndrome) study).MethodsEligible patients fulfilling 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria for SjS, positive for anti-Ro/Sjögren’s syndrome-related antigen A antibodies, with moderate-to-severe disease activity (EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) (based on weighted score) ≥ 5, EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) ≥ 5) received remibrutinib (100 mg) either one or two times a day, or placebo for the 24-week study treatment period. The primary endpoint was change from baseline in ESSDAI at week 24. Key secondary endpoints included change from baseline in ESSDAI over time, change from baseline in ESSPRI over time and safety of remibrutinib in SjS. Key exploratory endpoints included changes to the salivary flow rate, soluble biomarkers, blood transcriptomic and serum proteomic profiles.ResultsRemibrutinib significantly improved ESSDAI score in patients with SjS over 24 weeks compared with placebo (ΔESSDAI −2.86, p=0.003). No treatment effect was observed in ESSPRI score (ΔESSPRI 0.17, p=0.663). There was a trend towards improvement of unstimulated salivary flow with remibrutinib compared with placebo over 24 weeks. Remibrutinib had a favourable safety profile in patients with SjS over 24 weeks. Remibrutinib induced significant changes in gene expression in blood, and serum protein abundance compared with placebo.ConclusionsThese data show preliminary efficacy and favourable safety of remibrutinib in a phase 2 trial for SjS.

Background Autoimmune diseases have been associated with changes in the gut microbiome. In this study, the gut microbiome was evaluated in individuals with dry eye and bacterial compositions were correlated to dry eye (DE) measures. We prospectively included 13 individuals with who met full criteria for Sjögren’s (SDE) and 8 individuals with features of Sjögren’s but who did not meet full criteria (NDE) for a total of 21 cases as compared to 21 healthy controls. Stool was analyzed by 16S pyrosequencing, and associations between bacterial classes and DE symptoms and signs were examined. Results Results showed that Firmicutes was the dominant phylum in the gut, comprising 40–60% of all phyla. On a phyla level, subjects with DE (SDE and NDE) had depletion of Firmicutes (1.1-fold) and an expansion of Proteobacteria (3.0-fold), Actinobacteria (1.7-fold), and Bacteroidetes (1.3-fold) compared to controls. Shannon’s diversity index showed no differences between groups with respect to the numbers of different operational taxonomic units (OTUs) encountered (diversity) and the instances these unique OTUs were sampled (evenness). On the other hand, Faith’s phylogenetic diversity showed increased diversity in cases vs controls, which reached significance when comparing SDE and controls (13.57 ± 0.89 and 10.96 ± 0.76, p = 0.02). Using Principle Co-ordinate Analysis, qualitative differences in microbial composition were noted with differential clustering of cases and controls. Dimensionality reduction and clustering of complex microbial data further showed differences between the three groups, with regard to microbial composition, association and clustering. Finally, differences in certain classes of bacteria were associated with DE symptoms and signs. Conclusions In conclusion, individuals with DE had gut microbiome alterations as compared to healthy controls. Certain classes of bacteria were associated with DE measures.

Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) may coexist, and they are chronic complex disorders, with an autoimmune background, multifactorial etiology, multiple circulating autoantibodies, and variable prognosis. The prominent feature of SS is the impairment of the lacrimal and salivary glands leading to sicca symptoms. This disease may be classified as primary Sjögren's syndrome (pSS), or secondary Sjögren's syndrome (sSS) since it is often associated to other autoimmune disorders, principally SLE, rheumatoid arthritis, and systemic sclerosis. Systematic reviews and meta-analyses show an sSS prevalence in SLE patients of about 14%-17.8%. Herein, we updated important aspects of the clinical association between SLE and sSS through a narrative review of the PubMed database in the last 5 years (from July 2013 to October 2018) with the terms \"Sjogren syndrome and systemic lupus erythematosus\". The following aspects are addressed: the classification criteria for sSS; differences and similarities between SLE and pSS regarding demographic, clinical, and serological characteristics (including new autoantibodies), as well as comorbidities; the etiopathogenic links between SLE and pSS (including genetic and environmental factors, B-cell activation, and autoantibodies); the predictive factors for sSS onset in SLE patients; the ocular and oral involvements due to sSS in SLE; and the main distinctive demographic, clinical, and serological features of SLE with and without associated SS.

Background Juvenile Sjögren’s Syndrome (jSS) is a rare phenomenon that may appear as primary jSS or associated with mixed connective tissue disease (MCTD) and other autoimmune diseases as secondary jSS. With currently no standard diagnostic procedures available, jSS in MCTD seems to be underdiagnosed. We intended to describe and identify similar distinct salivary gland ultrasound (SGUS) findings in a cohort of primary and secondary jSS patients, focusing on sicca like symptoms and glandular pain/swelling in the patients‘history. Methods We present a single-center study with chart data collection. B-mode examinations of salivary glands were obtained with a linear high-frequency transducer and evaluated using the scoring-system of Hocevar . Inclusion criteria were: (i) primary or secondary jSS and/or (ii) diagnosis of MCTD and additionally (iii) any presence of sicca like symptoms or glandular pain/swelling. Results Twenty five patients with primary (pjSS) and secondary jSS (sjSS) were included in the study ( n  = 25, 21 female, 4 male), with a median age of 15.3 years at the time of first visit and a mean disease duration of 4.9 years. Pathologic SGUS findings were observed in 24 of 25 patients, with inhomogeneous parenchymal appearances with hypoechoic lesions present in 96% of patients. At least one submandibular gland was affected in 88.5% of the whole group, and all patients in the MCTD-group. Twenty of twenty five patients were scanned and scored on a second visit. Pre-malignancies or mucosa-associated lymphoid tissue (MALT) were detected in biopsies of three patients (Hocevar scoring of 40, 33, and 28). Conclusion SGUS in patients with pjSS and sjSS is a helpful first-line tool to detect and score salivary gland involvement, in particular when keratoconjunctivitis sicca, xerostomia, or glandular swelling occurs. Juvenile MCTD patients have a significant risk of developing secondary jSS. We propose SGUS as a method in the diagnostic workup and screening for inflammatory changes. Further studies have to determine the predictive value of SGUS for follow up.

The objective of this study was to explore the expression profile of the Interleukin (IL)-37/IL-18/IL-18BP/IL-18R axis in patients with primary Sjögren’s syndrome (pSS). This study included 36 patients diagnosed with pSS, 13 patients presenting with sicca symptoms without confirmed pSS, and 14 healthy controls. Serum concentrations of IL-37, IL-18, IL-18BP, and IL-18R were measured using a sandwich ELISA. These levels were then correlated with relevant clinical and biological parameters. Furthermore, expression of the same cytokines was assessed in salivary gland biopsies via immunohistochemistry. No significant difference in serum IL-37 levels was observed among the three groups (p = 0.1695). However, serum levels of IL-18 and IL-18BP were significantly elevated in pSS patients compared to healthy controls (p < 0.0001), and these levels were strongly correlated. Immunohistochemical analysis revealed significantly higher expression of IL-37 in both the excretory ducts and inflammatory infiltrates of salivary glands in pSS patients compared to sicca patients. No correlation was found between IL-37 expression and the histological severity of glandular infiltration as assessed by the Chisholm score. In addition, an enhanced expression of IL-18, IL-18BP, and IL-18Rα was observed in the salivary glands of pSS patients. These findings suggest the potential contribution of the IL-37/IL-18/IL-18BP/IL-18R signaling axis in the pathogenesis of Sjögren’s syndrome, particularly through its increased expression in salivary glands and correlation with disease-specific inflammatory markers. These findings may contribute to a better understanding of pSS immunopathology and suggest new avenues for biomarker development or therapeutic targeting.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by lymphoplasmacytic infiltration of exocrine glands, leading to dry eyes and mouth. Renal involvement, particularly glomerulonephritis, occurs in approximately 5% of pSS patients. Membranous nephropathy (MN) is one of the less common forms of renal involvement in pSS. A 48-year-old female with a history of oral and ocular dryness for several years and bilateral symmetrical lower extremity edema for three months was admitted to our hospital. Laboratory findings revealed moderate anemia, hypoalbuminemia, and nephrotic-range proteinuria. Schirmer's test, tear break-up time, and lip biopsy confirmed the diagnosis of pSS. Renal biopsy demonstrated widespread mesangial hypercellularity and mesangial matrix expansion, thickening of the glomerular basement membrane(GBM) with prominent spikes, and subepithelial, intramembranous and mesangial electron-dense deposits under electron microscopy. Immunofluorescence showed diffuse fine granular deposits of IgG (predominantly IgG1 and IgG2). Based on these findings, secondary membranous nephropathy due to pSS was diagnosed. The patient was treated with prednisone (30 mg/day) and two infusions of rituximab (1 g each, administered 2 weeks apart). After treatment, her 24-hour urinary protein level decreased from 8.5 g to 2.2 g. The dose of glucocorticoids was gradually tapered off. During follow-up, an additional 1 g of rituximab was administered six months later, resulting in a further reduction of proteinuria to 1.3 g/24 hours. This case highlights the effectiveness of rituximab in managing secondary membranous nephropathy associated with pSS. Further studies are needed to clarify the underlying mechanisms and optimize treatment strategies for this condition.

Background Prevalence of anxiety and depression is high in people with Primary Sjögren’s syndrome (pSS). However, there are currently no known reported studies about anxiety/depression in pSS patients from China. Our aim was to compare anxiety/depression in pSS patients and healthy controls; to investigate the prevalence of anxiety and/or depression among pSS patients in China; to evaluate its relationship with the disease activity, fatigue, pain, education, ocular surface disease, oral health, swallowing disorders, employment status, European League Against Rheumatism Sjögren’s Syndrome Patient Reported Index(ESSPRI) as well as to analyze potential determinants of anxiety and depression. Methods In this study, 160 pSS patients and 170 age- and sex- matched healthy controls were included. Participants completed self-administered questionnaires, Hospital Anxiety and Depression Scale (HADS) and so on. Independent samples t-tests, χ 2 analyses and multivariable stepwise logistic regression modeling were used to analyze the data. Results We found 33.8% pSS patients were anxiety, and 36.9% had depression, which were significantly higher than controls. And there were significant correlations among education, employment status, disease activity, fatigue, ocular surface disease, ESSPRI, oral health, swallowing disorders and anxiety/depression. Meanwhile, logistic regression analysis revealed that oral health and swallowing disorders were significantly associated with anxiety in pSS patients; as well as fatigue was significantly associated with depression. Conclusions The prevalence of depression and anxiety was high in adult pSS patients. Interestingly, oral health and swallowing disorders were the most important predictors of anxiety in pSS patients. Therefore, rheumatologists should pay attention to the potential mental comorbidities while managing patients with pSS and provide the basis for mental health providers in order to identify effective strategies for preventing and treating depression and anxiety among adult pSS patients. Simultaneously, rheumatologists should also focus on the oral health and swallowing disorders in pSS patients.

ObjectivesTo evaluate the efficacy and safety of ianalumab (VAY736), a B cell-depleting, B cell activating factor receptor-blocking, monoclonal antibody, in patients with active primary Sjögren’s syndrome (pSS) in a double-blind, placebo-controlled, phase II, single-centre study.MethodsPatients with pSS, EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) ≥6, were randomised to ianalumab single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12) or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B cell numbers had recovered. Clinical outcomes included ESSDAI, EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI), salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity.ResultsA similar trend showing positive therapeutic effect by ianalumab was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, Multidimensional Fatigue Inventory, Short Form-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B cell depletion of long-lasting duration occurred after a single infusion of ianalumab at either dose. Serum Ig light chains decreased, with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild to moderate infusion reactions within 24 hours of ianalumab administration.ConclusionsOverall results in this single-dose study suggest potent and sustained B cell depletion by ianalumab could provide therapeutic benefits in patients with pSS without major side effects.