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Objective: While the involvement of IL-7/IL-7R axis in pSS has been described in relation to T cells, little is known about the contribution of this pathway in relationship with other immune cells, and its implication in autoimmunity. Using high-content multiomics data, we aimed at characterizing IL-7R expressing cells and the involvement of IL-7/IL-7R pathway in pSS pathophysiology., Methods: An IL-7 signature established using RNA-sequencing of human PBMCs incubated with IL-7 was applied to 304 pSS patients, and on RNA-Seq datasets from tissue biopsies. High-content immunophenotyping using flow and imaging mass cytometry was developed to characterize peripheral and in situ IL-7R expression., Results: We identified a blood 4-gene IL-7 module (IKZF4, KIAA0040, PGAP1 and SOS1) associated with anti-SSA/Ro positiveness in patients as well as disease activity, and a tissue 5-gene IL-7 module (IL7R, PCED1B, TNFSF8, ADAM19, MYBL1) associated with infiltration severity. We confirmed expression of IL-7R on T cells subsets, and further observed upregulation of IL-7R on double-negative (DN) B cells, and especially DN2 B cells. IL-7R expression was increased in pSS compared to sicca patients with variations seen according to the degree of infiltration. When expressed, IL-7R was mainly found on epithelial cells, CD4 + and CD8 + T cells, switched memory B cells, DN B cells and M1 macrophages., Conclusion: This exhaustive characterization of the IL-7/IL-7R pathway in pSS pathophysiology established that two IL-7 gene modules discriminate pSS patients with a high IL-7 axis involvement. Their use could guide the implementation of an anti-IL-7R targeted therapy in a precision medicine approach., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: To develop and validate a web-based ecological momentary assessment (EMA) tool to enhance symptoms monitoring among patients with Sjögren's disease (SjD)., Methods: Consecutive adults with SjD were enrolled in this pilot observational study. Participants used the WebApp over a 3-month period, for the daily collection of individual EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) scales and separate assessment of eyes and mouth dryness, using 0-10 numerical scales. Primary outcome was the measure of the interdaily variability of symptoms. Data collected through the WebApp were compared with those obtained with paper-based questionnaires administered during a final visit, using distinct approaches (predicted error, maximum negative error and maximum positive error). User experience was assessed using the System Usability Scale (SUS) score., Results: Among the 45 participants, 41 (91.1%) were women. Median age was 57 years (IQR: 49-66). Daily variability of symptoms ranged between 0.5 and 0.8 points across the scales. Over the 3-month period, the predicted error ranged between -1.2 and -0.3 points of the numerical scales. The greatest differences were found for fatigue (-1.2 points (IQR: -2.3 to -0.2)) and ESSPRI score (-1.2 points (IQR: -1.7 to -0.3)). Over the last 2 weeks, the predicted error ranged between - 1.2 and 0.0 points. Maximum negative error ranged between -2.0 and -1.0 points, and maximum positive error between -0.3 and 0.0 points. Median SUS score was 90 (IQR: 85-95)., Conclusion: Our results demonstrate the usability and the relevance of our web-based EMA tool for capturing data that closely reflects daily experiences of patients with SjD., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Sjögren's disease is the autoimmune disease with the highest risk of lymphoma development. There is no consensus on the optimal way to manage Sjögren's disease complicated by lymphoma. We aimed to describe characteristics, therapeutic strategies, and outcomes of non-Hodgkin lymphoma associated with Sjögren's disease, and their effect on lymphoma and Sjögren's disease prognoses., Methods: We did a multicentre, retrospective, observational study including patients with Sjögren's disease according to the 2016 American College of Rheumatology-European League Against Rheumatism criteria who did not fulfil diagnostic criteria for other connective tissue diseases. We included patients with a lymphoma diagnosis made before Jan 1, 2020, from two expert centres in Paris (France); from the French, multicentre, prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome cohort; and via practitioners registered with the Club Rhumatismes et Inflammation. Using inverse probability of treatment weighting, the effect of lymphoma treatment was compared in relation to three endpoints: lymphoma progression-free survival, new Sjögren's disease systemic activity, and overall survival. Exploratory analyses also aimed to identify factors associated with lymphoma relapse, new Sjögren's disease systemic activity, and overall survival. People with lived experience were not involved in this research., Findings: 106 patients with Sjögren's disease who developed lymphoma were included in the study. The most frequent histological subtype was mucosa-associated lymphoid tissue lymphoma (68 [64%] of 106 patients), followed by other marginal zone subtypes (14 [13%] of 106 patients) and diffuse large B-cell lymphoma (14 [13%] of 106 patients). Among the 82 patients with marginal zone lymphoma (72 [88%] women and ten (12%) men; mean age at lymphoma diagnosis 57·5 years [SD 14·8]), multivariable analysis showed that pulmonary localisation was associated with mortality (hazard ratio [HR] 7·92 [95% CI 1·70-37·0]). A watch and wait approach was proposed in 19 (23%) of 82 patients with marginal zone lymphoma, 13 (16%) had first-line localised treatment (surgery or radiotherapy), and 50 (61%) had first-line systemic treatment. After a median follow-up of 7 years, 26 patients (32%) had lymphoma relapse, nine (11%) died, and 27 (33%) had new Sjögren's disease systemic activity. After inverse probability of treatment weighting, patients with systemic treatment at lymphoma diagnosis had a reduced risk of new Sjögren's disease activity (HR 0·43 [95% CI 0·21-0·90]). When comparing patients treated with a combination of chemotherapy and anti-CD20 therapy (n=32) with patients treated with monotherapy (n=18) as a first-line therapy for lymphoma, lymphoma-progression-free survival was improved in patients treated with combination therapy (HR 0·36 [95% CI 0·14-0·94]). The were no differences in new Sjögren's disease systemic activity or overall survival according to combination therapy or monotherapy., Interpretation: A systemic treatment strategy for Sjögren's disease-associated lymphoma, rather than localised treatment or a watch and wait strategy, reduces the risk of new Sjögren's disease systemic activity and combination therapy is associated with decreased risk of lymphoma relapse., Funding: None., Competing Interests: Declaration of interests VLG received consulting fees from Novartis; honoraria from Novartis and Bristol Myers Squibb; and travel fees from AstraZeneca and Novartis. MC received honoraria from Lilly and travel fees from Novartis, Janssen, UCB, and Pfizer. XM received consulting fees from AstraZeneca, Bristol Myers Squibb, Galapagos, GSK, Novartis, and Pfizer. RS received consulting fees from GSK, Bristol Myers Squibb, Boehringer, and Janssen; honoraria from GSK, Bristol Myers Squibb, Boehringer, Amgen, Pfizer, and Roche; and travel fees from Amgen and GSK. GN received honoraria from Novartis, Boehringer, AbbVie, and Galapagos SASU and travel fees from Amgen, AbbVie, and UCB. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Sjögren's disease (SjD) is a chronic, systemic autoimmune disease with no approved disease-modifying therapies. Dazodalibep (DAZ), a novel nonantibody fusion protein, is a CD40 ligand antagonist that blocks costimulatory signals between T and B cells and antigen-presenting cells, and therefore may suppress the wide spectrum of cellular and humoral responses that drive autoimmunity in SjD. This study was a phase 2, randomized, double-blinded, placebo (PBO)-controlled trial of DAZ with a crossover stage in two distinct populations of participants with SjD. Population 1 had moderate-to-severe systemic disease activity and population 2 had an unacceptable symptom burden and limited systemic organ involvement. All participants had a diagnosis of SjD, with 21.6% and 10.1% having an associated connective tissue disease (rheumatoid arthritis or systemic lupus erythematosus) in populations 1 and 2, respectively. The remaining participants would be considered as having primary Sjögren's syndrome. The primary endpoint for population 1 (n = 74) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index at day 169. The primary endpoint for population 2 (n = 109) was the change from baseline in the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index at day 169. The primary endpoints (least squares mean ± standard error) were achieved with statistical significance for both population 1 (DAZ, -6.3 ± 0.6; PBO, -4.1 ± 0.6; P = 0.0167) and population 2 (DAZ, -1.8 ± 0.2; PBO, -0.5 ± 0.2; P = 0.0002). DAZ was generally safe and well tolerated. Among the most frequently reported adverse events were COVID-19, diarrhea, headache, nasopharyngitis, upper respiratory tract infection, arthralgia, constipation and urinary tract infection. In summary, DAZ appears to be a potential new therapy for SjD and its efficacy implies an important role for the CD40/CD40 ligand pathway in its pathogenesis. ClinicalTrials.gov identifier: NCT04129164 ., (© 2024. The Author(s).)

Objective: The biologic diagnosis of primary Sjögren disease (SjD) mainly relies on anti-Ro60/SSA antibodies, whereas the significance of anti-Ro52/TRIM21 antibodies currently remains unclear. The aim of this study was to characterize the clinical, serological, biologic, transcriptomic, and interferon profiles of patients with SjD according to their anti-Ro52/TRIM21 antibody status., Methods: Patients with SjD from the European PRECISESADS (n = 376) and the Brittany Diagnostic Suspicion of primitive Sjögren's Syndrome (DIApSS); (n = 146) cohorts were divided into four groups: double negative (Ro52 - /Ro60 - ), isolated anti-Ro52/TRIM21 positive (Ro52 + ), isolated anti-Ro60/SSA positive (Ro60 + ), and double-positive (Ro52 + /Ro60 + ) patients. Clinical information; EULAR Sjögren Syndrome Disease Activity Index, a score representing systemic activity; and biologic markers associated with disease severity were evaluated. Transcriptome data obtained from whole blood by RNA sequencing and type I and II interferon signatures were analyzed for PRECISESADS patients., Results: In the DIApSS cohort, Ro52 + /Ro60 + patients showed significantly more parotidomegaly (33.3% vs 0%-11%) along with higher β2-microglobulin (P = 0.0002), total immunoglobulin (P < 0.0001), and erythrocyte sedimentation rate levels (P = 0.002) as well as rheumatoid factor (RF) positivity (66.2% vs 20.8%-25%) compared to other groups. The PRECISESADS cohort corroborated these observations, with increased arthritis (P = 0.046), inflammation (P = 0.005), hypergammaglobulinemia (P < 0.0001), positive RF (P < 0.0001), leukopenia (P = 0.004), and lymphopenia (P = 0.009) in Ro52 + /Ro60 + patients. Cumulative EULAR Sjögren Syndrome Disease Activity Index results further confirmed these disparities (P = 0.002). Transcriptome analysis linked anti-Ro52/TRIM21 antibody positivity to interferon pathway activation as an underlying cause for these clinical correlations., Conclusion: These results suggest that the combination of anti-Ro52/TRIM21 and anti-Ro60/SSA antibodies is associated with a clinical, biologic, and transcriptional profile linked to greater disease severity in SjD through the potentiation of the interferon pathway activation by anti-Ro52/TRIM21 antibodies., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups., Methods: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues., Findings: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only., Interpretation: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials., Funding: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology., Competing Interests: Conflicts of interest GN received honoraria from Boehringer and Novartis and travel fees from Amgen and AbbVie. W-FN received consulting fees from Resolve Therapeutics, Argenx, and Novartis and participated on data safety monitoring boards or advisory boards for Sanofi and Janssen Pharmaceuticals. JM received grants from Bristol Myers Squibb (BMS), Fresenius Kabi, Lilly, Novartis, Pfizer, and Roche-Chugai; received honoraria from AbbVie, Boehringer Ingelheim, Biogen, Lilly, Mylan, Pfizer, Sanofi, BMS, Fresenius Kabi, Galapagos, Medac, Novartis, and Roche-Chugai; received travel fees from BMS, Lilly, and Fresenius Kabi; and participated on advisory boards for AbbVie, Pfizer, and Galapagos. ED received consulting fees from BMS, Celgene, Lilly, Merck Sharp & Dohme (MSD), Novartis, and UCB; honoraria for lectures from AbbVie, BMS, Janssen Pharmaceuticals, Lilly, Medac, MSD, Novartis, Roche-Chugai, Sanofi, UCB, Celgene, Amgen, and Galapagos; and travel fees from AbbVie, BMS, Janssen Pharmaceuticals, Lilly, Medac, MSD, Novartis, Roche-Chugai, Sanofi, UCB, Celgene, Amgen, and Galapagos. PD received grants from Novartis and consulting fees from Pfizer, Roche-Chugai, BMS, AbbVie, and MSD. MC received travel fees from Janssen Pharmaceuticals, UCB, and Pfizer. CS received honoraria from Novartis and Roche-Chugai and travel fees from Novartis, Biogen, and Lilly. VLG received travel fees from AstraZeneca and Novartis. J-EG received grants from Pfizer, AbbVie, and Lilly and consulting fees from AbbVie, AstraZeneca, Sanofi, Lilly, Galapagos, Gilead Sciences, Roche-Chugai, Pfizer, BMS, and MSD. XM received consulting fees from AstraZeneca, BMS, Galapagos, GSK, Novartis, and Pfizer. RS received consulting fees from GSK, BMS, Boehringer Ingelheim, and Janssen Pharmaceuticals; honoraria from GSK, BMS, Boehringer Ingelheim, Amgen, Pfizer, and Roche-Chugai; and travel fees from Amgen and GSK. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity., Competing Interests: Declaration of competing interest Valerie Devauchelle reports receinving funds for consulting to Novartis, Abbvie, Fresenius Kabi. Divi Cornec declares no personal financial competing interests and received research funding from Novartis and GSK. Benjamin A. Fisher has undertaken consultancy for Novartis, BMS, Servier, Galapagos, Roche, UCB, Sanofi and Janssen, and received grant/research support from Janssen, Celgene, Galapagos, Servier. Alberta Hoi reports receiving research funding from AstraZeneca, Bristol-Myers Squibb, Novartis, Janssen. Chiara Baldini reports receiving funds for consulting to GSK, Novartis and Horizon, honoraria for educational events from GSK and Sanofi, support for attending meetings from Abbvie and Bristol-Myers Squibb. WF Ng has consulted for Novartis, GlaxoSmithKline, Abbvie, BMS, Sanofi, MedImmune, Resolves Therapeutics, Janssen and UCB. Simon Bowman receiving funds for consulting from Bristol-Myers Squibb, Iqvia, Janssen, Kiniksa, Novartis, Otsuka-Visterra. His-salary is part funded by the Birmingham Biomedical Research Centre, Birmingham, UK. Karina Torralba reports receiving funds for consulting to Horizon, AstraZeneca, Janssen; for contracted research work with Bioclinica; for clinical trial funding from Novartis, AstraZeneca, GlaxoSmithKline, Amgen. Athena Papas declares grant funding from Novartis and Horizon; advisory board for Novartis. Ionut Pintilie reports receiving funds for consulting to Abbvie, Novartis, Pfizer, Sandoz, Ewopharma, KRKA, Stada, Boehringer Ingelheim, MagnaPharm, MSD. Xavier Mariette declares consulting fee from Astra Zeneca, BMS, Galapagos, GSK, Novartis, and Pfizer. Maria Antonietta D'Agostino, MD, PhD Speakers, or consultant fees from Amgen, Abbvie, BMS, Novartis, Galapagos, UCB, Pfizer, Lily, Janssen. Alan Baer reports receiving funds for consulting to Bristol-Myers Squibb and iCell Gene Therapeutics. Blake M. Warner declares research funding and material transfer agreements with Pfizer, Inc., and Mitobridge, Inc. Soumya D. Chakravarty is an employee of Janssen Scientific Affairs, LLC, and owns stock or stock options in Johnson & Johnson, of which Janssen Scientific Affairs, LLC is a wholly owned subsidiary. Nevsun Inanc reports claims to have received speakers fee from Novartis, Abbvie, Pfizer, UCB, Eli-Lilly and consultancy fee from Abbvie, UCB, Eli-Lilly. Vibeke Strand reports being a founding member of the executive committee of Outcome Measures in Rheumatology (OMERACT) [1992 – present], an international consensus organization that develops and validates outcome measures in rheumatology randomized controlled trials and longitudinal observational studies and has received arms-length funding from as many as 36 sponsors. Md Yuzaiful Md Yusof has received speaker fees from Roche and Novartis and consultancy fees from Aurinia Pharmaceuticals and UCB. Suzanne Arends declares consultancy fees from Argenx and Novartis. Anas Alexis Benyoussef is a consultant for Horus Pharma and Quantel Medical. Sharmila Masli is a consultant for Stellular Bio Inc. and Proteris Biotech. Maureen Rischmueller has undertaken consultancy/speaker engagements for AbbVie, Boehringer Ingelheim, Janssen Global Services, Novartis, Pfizer and Sandoz, and received grant/research support from AbbVie, Amgen, AstraZeneca, BMS, GSK, Janssen, Lilly, Novartis, Pfizer, Servier and UCB. Sara McCoy reports receiving funds for consulting to Bristol-Myers Squibb, Horizon, Novartis, Kiniksa, Targe RWE, Otsuka, Visterra, and iCell. Her time is supported by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant 1KL2TR002374 and NIH/NIDCR R03DE031340. Raphaele Seror reports receiving funds for consulting to Bristol-Myers Squibb, Novartis, GSK, Janssen, Amgen. Hendrika Bootsma declares consultancy fees from Argenx, Novartis, BMS, AztraZeneca, Galapagos.Independent grants from AstraZeneca, Novartis, BMS., (Copyright © 2024. Published by Elsevier Inc.)

Objectives: To estimate prevalence, incidence and mortality rates, and annual healthcare costs of primary Sjögren's syndrome (pSS) and SS associated with other autoimmune disorders (SS+AID) in France., Methods: French national healthcare claims-based study within the prospective Système National des Données de Santé database that includes the majority of the French population. An algorithm was developed to identify patients with SS and SS-related healthcare claims were analysed between 2011 and 2018., Results: Overall, 23 848 patients with pSS and 14 809 with SS+AID were identified. From 2011 to 2018, the prevalence rate increased slightly for pSS (23-32 per 100000) and SS+AID (16-20 per 100 000), with females comprising 90%-91% and 92%-93% of cases, respectively. The incidence rate of SS per 100 000 persons decreased from 2012 (pSS: 4.3; SS+AID: 2.0) to 2017 (pSS: 0.7; SS+AID: 0.3). Mortality rates per 100 000 persons increased from 2012 to 2018 in patients with pSS (0.2-0.8) or SS+AID (0.1-0.5); mean age of death also increased. Artificial tears and hydroxychloroquine were the most common drug reimbursements. Less than half of patients received annual specialist care from a dentist or ophthalmologist. Healthcare costs associated with SS increased from 2011 to 2018 and exceeded the national estimate of expected costs for chronic diseases., Conclusion: In this large French population database study, the low prevalence of pSS confirms that it is an orphan disease. SS is clinically and economically burdensome; these findings may help clinicians better understand routine healthcare received by patients., Competing Interests: Competing interests: RS is a consultant for Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Fresenius Kabi, GlaxoSmithKline, Janssen, Pfizer and Roche. LC is a consultant for Bristol Myers Squibb. GD is a consultant for Bristol Myers Squibb and a consultant with no fees for Roche. JZ and VV-M are employees of and shareholders in Bristol Myers Squibb. VD-P is a consultant for AbbVie, Bristol Myers Squibb and Novartis, and has received grant/research support from Bristol Myers Squibb, Eli Lilly and Roche-Chugai. MB declares no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes., Method: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST., Results: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6., Conclusions: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes., Competing Interests: Competing interests: VD-P has undertaken clinical trials and provided consultancy or expert advice in the area of Sjogren’s disease to the following companies: MedImmune, UCB, Abbvie, Sanofi, Novartis and BMS. BF has undertaken consultancy for Novartis, BMS, Servier, Galapagos, Roche, Sanofi and Janssen and received research funding from Janssen, Galapagos, Servier and Celgene. SJB has undertaken consultancy for Novartis, BMS, Iqvia and Janssen and accepted hospitality from Novartis to attend a working dinner at the BSR conference regarding secukinumab in inflammatory arthritis in the last year. MB has received consultancy and/or advisory board fees and/or grant support from GSK, Janssen, Ono Pharmaceutical, Horizon Therapeutics in the last two years. W-FN has undertaken clinical trials and provided consultancy or expert advice in the area of Sjogren’s syndrome to the following companies: GlaxoSmithKline, MedImmune, UCB, Abbvie, Roche, Eli Lilly, Takeda, Resolves Therapeutics, Sanofi, Novartis and BMS. No other potential conflict of interest relevant to this article was reported., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: We undertook this study to analyze whole blood gene expression and to investigate the role of B cell genes in primary Sjögren's syndrome-related non-Hodgkin lymphoma (primary SS-NHL)., Methods: Peripheral whole blood samples were collected from 345 well-phenotyped patients with primary SS enrolled in the prospective Assessment of Systemic Signs and Evolution in Sjögren's Syndrome (ASSESS) cohort. Transcriptomic analysis was performed using human Clariom S Arrays (Affymetrix). In our primary analysis, we considered patients with incident lymphoma (i-primary SS-NHL) as the case group and all patients without lymphoma as the comparison group. In our sensitivity analyses, we considered all patients with primary SS-NHL, including those with a history of lymphoma (h-primary SS-NHL), as the case group and primary SS patients without lymphoma, stratified on their risk factors of lymphoma, as the comparison group., Results: Twenty-one patients with primary SS-NHL (including 8 with i-primary SS-NHL and 13 h-primary SS-NHL) were eligible for transcriptomic analysis; we compared these patients to 324 primary SS controls without lymphoma, including 110 with moderate to severe disease activity and 61 with no risk factor of lymphoma. Functional clustering analyses revealed an enrichment of genes related to innate and adaptive immunity, including B cell-related genes. Bruton's tyrosine kinase (BTK) and a proliferation-inducing ligand (APRIL) genes were overexpressed before the occurrence of lymphoma in patients with incident lymphoma compared with patients without lymphoma. In sensitivity analyses, BTK was consistently up-regulated across all comparisons performed. BTK expression was associated with risk of lymphoma on multivariate analyses, which considered 9 validated predictors of lymphoma in primary SS., Conclusion: BTK and APRIL were overexpressed in the peripheral blood of primary SS patients prior to lymphoma. The association between BTK, APRIL, and primary SS-NHL requires confirmation in other prospective cohorts., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Sjögren's disease (SD), also known as Sjögren's syndrome (SS) or Gougerot-Sjögren's syndrome in France, is a rare systemic autoimmune disease in its primary form and is characterised by tropism for the exocrine glandular epithelia, particularly the salivary and lacrimal glands. The lymphocytic infiltration of these epithelia will clinically translate into a dry syndrome which, associated with fatigue and pain, constitutes the symptom triad of the disease. In about one third of patients, SD is associated with systemic complications that can affect the joints, skin, lungs, kidneys, central or peripheral nervous system, and lymphoid organs with an increased risk of B-cell lymphoma. SD affects women more frequently than men (9/1). The peak frequency is around the age of 50. However, the disease can occur at any age, with paediatric forms occurring even though they remain rare. SD can occur alone or in association with other systemic autoimmune diseases. In its isolated or primary form, the prevalence of SD is estimated to be between 1 per 1000 and 1 per 10,000 inhabitants. The most recent classification criteria were developed in 2016 by EULAR and ACR. The course and prognosis of the disease are highly variable and depend on the presence of systemic involvement and the severity of the dryness of the eyes and mouth. The current approach is therefore to identify at an early stage those patients most at risk of systemic complications or lymphoma, who require close follow-up. On the other hand, regular monitoring of the ophthalmological damage and of the dental status should be ensured to reduce the consequences., (Copyright © 2023. Published by Elsevier Masson SAS.)

Objective: To determine whether repeated minor salivary gland biopsy (MSGB) has a clinical diagnostic utility in patients with suspicion of Sjögren's syndrome (SS)., Methods: Clinical, biological, pathological data and physician's diagnosis after each MSGB from patients with suspected primary or secondary SS who had benefited from 2 MSGB at Brest University Hospital between January 1st, 1990 and January 14th, 2015, were retrospectively collected. We compared the characteristics of patients with and without first positive MSGB, concordance between the MSGB, and analyzed the modifications of diagnosis after the second MSGB., Results: Ninety-three patients were included, first MSGB was positive for 23 and negative for 70. Patients with first positive MSGB had more often renal involvement (P<0.05) and hypergammaglobulinemia (P=0.01), anti-SSA antibodies (P<0.05) and positive second biopsy with focus score ≥ 1 or Chisholm>2 (P<0.01). The mean time between the 2 MSGB was 5.7±4.3 years. The concordance between the results of the 2 biopsies was low (κ = 0.34). MSGB influenced diagnostic's change in 10 cases where the second MSGB was always guided by new specific clinical manifestations., Conclusion: We observed a low concordance between 2 MSGB in patients with suspected pSS in our study. Despite this variability, performing a second MSGB changed the initial diagnosis in only a minority of the patients and was particularly useful when clinical manifestations had deeply evolved., (Copyright © 2022 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: To investigate the safety and efficacy of SARS-Cov-2 vaccination in patients with primary Sjögren syndrome (pSS) due to scarcity of data in this population., Methods: By the first week of May 2021, all Big Data SS Consortium centres patients who had received at least one dose of any SARS-CoV-2 vaccine were included in the study. The in-charge physician asked patients about local and systemic reactogenicity to collect SARS-CoV-2 vaccination data., Results: The vaccination data of 1237 patients were received. A total of 835 patients (67%) reported any adverse events (AEs), including local (53%) and systemic (50%) AEs. Subjective symptoms (63%) were the most common local AEs, followed by objective signs at the injection site (16%), and general symptoms were the most commonly reported systemic AEs (46%), followed by musculoskeletal (25%), gastrointestinal (9%), cardiopulmonary (3%), and neurological (2%). In addition, 141 (11%) patients reported a significant worsening/exacerbation of their pre-vaccination sicca symptoms and fifteen (1.2%) patients reported active involvement in the glandular (n=7), articular (n=7), cutaneous (n=6), pulmonary (n=2), and peripheral nervous system (n=1) domains due to post-vaccination SS flares. In terms of vaccination efficacy, breakthrough SARS-CoV-2 infection was confirmed after vaccination in three (0.24 %) patients, and positive anti-SARS-Cov-2 antibodies were detected in approximately 95% of vaccinated SS patients, according to data available., Conclusions: Our data suggest that patients with pSS develop adequate humoral response and no severe AEs after SARS-CoV-2 vaccination and therefore raise no concerns about the vaccine's efficacy or safety profile in this population.

Objectives: To characterise the key epidemiological, clinical, immunological, imaging, and pathological features of the coexistence between sarcoidosis and Sjögren's syndrome (SS)., Methods: All centres included in two large multicentre registries (the Sjögren Syndrome Big Data Consortium and the Sarco-GEAS-SEMI Registry) were contacted searching for potential cases of coexistence between SS and sarcoidosis seen in daily practice. Inclusion criteria were the fulfilment of the current classification criteria both for SS (2016 ACR/EULAR) and sarcoidosis (WASOG). The following features were considered for evaluating a coexisting immunopathological scenario between the two diseases: non-caseating granulomas (NCG), focal lymphocytic sialadenitis (FLS) and positive anti-Ro antibodies., Results: We identified 43 patients who fulfilled the inclusion criteria (38 women, with a mean age of 53 years at diagnosis of SS and of 52 years at diagnosis of sarcoidosis). In 28 (65%) cases, sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of patients with an already diagnosed SS, while in the remaining 15 (35%), SS was diagnosed during the follow-up of an already diagnosed sarcoidosis. Patients in whom sarcoidosis was diagnosed first showed a lower mean age (43.88 vs. 55.67 years, p=0.005) and were less frequently women (73% vs. 96%, p=0.04) in comparison with those in whom sarcoidosis was diagnosed concomitantly with SS, or during the follow-up of an already diagnosed SS. We identified the following immunopathological scenarios: a combination of NCG involving extrasalivary tissues and anti-Ro antibodies in 55% of patients, a coexistence of both pathological scenarios (extrasalivary NCG and FLS in MSGB) in 42% (with positive anti-Ro antibodies in two thirds of cases), and NCG involving salivary glands and anti-Ro antibodies in 3% of cases., Conclusions: We have characterised the largest reported series of patients who fulfilled the current classification criteria for both SS and sarcoidosis. This implies that sarcoidosis (and not just the presence of isolated NCG on salivary gland biopsy) may, like other systemic autoimmune diseases, coexist with SS, and that a sarcoidosis diagnosis does not preclude the development of SS in the future.

Objective: To develop a composite responder index in primary Sjögren's syndrome (pSS): the Sjögren's Tool for Assessing Response (STAR)., Methods: To develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren's syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed., Results: The Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options combining these domains were selected to be tested for sensitivity to change. After two Delphi rounds, a meta-analysis of the 20 remaining options was performed. The candidate STAR was then selected by a final vote based on metrological properties and clinical relevance., Conclusion: The candidate STAR is a composite responder index that includes all main disease features in a single tool and is designed for use as a primary endpoint in pSS RCTs. The rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity to change and will be prospectively validated by the NECESSITY consortium in a dedicated RCT., Competing Interests: Competing interests: RS has received consulting fees from GlaxoSmithKline, Boehringer, Janssen and Novartis, participated in an advisory board for Janssen, and received support for attending meeting from GlaxoSmithKline and Amgen. DC has received consulting fees from GlaxoSmithKline, Bristol Myers Squibb, Janssen, Amgen, Pfizer and Roche. J-EG has received honoraria from AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, Sanofi, Novartis, MSD, CSL Behring and Genzyme and received grant from Bristol Myers Squibb. SJB and BF receive funding from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK. SJB has provided consultancy services in the field of clinical trial design for Sjögren’s syndrome for AbbVie, AstraZeneca, Galapagos and Novartis Pharmaceuticals in 2018–2021. BF has received grants from Servier, Galapagos and Janssen, provided consultancy services for Novartis, Bristol Myers Squibb, Janssen and Servier, and received honoraria from Bristol Myers Squibb and Novartis. MB has received grants from Amgen/MedImmune, Janssen and GlaxoSmithKline, and personal fees from UCB, Amgen/MedImmune, Janssen and GlaxoSmithKline. HB has received grants from Bristol Myers Squibb and Roche, and consulting fees from Bristol Myers Squibb, Roche, Novartis, MedImmune and Union Chimique Belge. WH and PG are employees of Novartis Pharma and recipients of Novartis stocks. XM has received a grant from Ose Pharmaceuticals and consultancy fees from Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer and UCB. GB, MC, EP, JAvR, VD-P and RP declare no competing interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To analyse the frequency and characteristics of post-COVID-19 syndrome in patients with primary Sjögren's syndrome (pSS) affected by acute SARS-CoV-2 infection., Methods: By the first week of April 2021, all centres included in the Big Data Sjögren Consortium were contacted asking for patients included in the Registry diagnosed with SARSCoV-2 infection according to the ECDC guidelines. According to the NICE definitions, symptoms related to COVID-19 were classified as acute COVID-19 (signs and symptoms for up to 4 weeks), ongoing symptomatic COVID-19 (presence of signs and symptoms from 4 to 12 weeks) and post-COVID-19 syndrome (signs and symptoms that continue for > 12 weeks not explained by an alternative diagnosis after a protocolized study)., Results: We identified 132 patients who were followed a mean follow-up of 137.8 days (ranging from 5 days to 388 days) after being diagnosed with COVID-19. In the last visit, 75 (57%) patients remained symptomatic: 68 (52%) remained symptomatic for more than 4 weeks fulfilling the NICE definition for ongoing symptomatic post-COVID-19, and 38 (29%) remained symptomatic for more than 12 weeks fulfilling the definition of post-COVID-19 syndrome. More than 40% of pSS patients reported the persistence of four symptoms or more, including anxiety/depression (59%), arthralgias (56%), sleep disorder (44%), fatigue (40%), anosmia (34%) and myalgias (32%). Age-sex adjusted multivariate analysis identified raised LDH levels (OR 10.36), raised CRP levels (OR 7.33), use of hydroxychloroquine (OR 3.51) and antiviral agents (OR 3.38), hospital admission (OR 8.29), mean length of hospital admission (OR 1.1) and requirement of supplemental oxygen (OR 6.94) as factors associated with a higher risk of developing post-COVID-19 syndrome. A sensitivity analysis including hospital admission in the adjusted model confirmed raised CRP levels (OR 8.6, 95% CI 1.33-104.44) and use of hydroxychloroquine (OR 2.52, 95% CI 1.00-6.47) as the key independent factors associated with an enhanced risk of developing post-COVID-19 syndrome., Conclusions: This is the first study that analyses the frequency and characteristics of post-COVID-19 syndrome in patients affected by a systemic autoimmune disease. We found that 57% of patients with pSS affected by COVID-19 remain symptomatic after a mean follow-up of 5 months. The risk of developing post-COVID-19 syndrome in patients who required hospitalisation was 8-times higher than in non-hospitalised patients, with baseline raised CRP levels and the use of hydroxychloroquine being independent risk factors for post-COVID-19.

Objectives: To analyse how the main components of the disease phenotype (sicca symptoms, diagnostic tests, immunological markers and systemic disease) can be driven by the age at diagnosis of primary Sjögren's syndrome (pSS)., Methods: By January 2021, the participant centres had included 12,753 patients from 25 countries that fulfilled the 2002/2016 classification criteria for pSS. The age at diagnosis was defined as the time when the attending physician confirmed fulfilment of the criteria. Patients were clustered according to age at diagnosis. 50 clusters with more than 100 observations (from 27 to 76 years) were used to study the influence of the age at diagnosis in the disease expression., Results: There was a consistent increase in the frequency of oral dryness according to the age at diagnosis, with a frequency of <90% in patients diagnosed at the youngest ages and >95% in those diagnosed at the oldest ages. The smooth curves that best fitted a linear model were the frequency of dry mouth (adjusted R2 0.87) and the frequency of abnormal oral tests (adjusted R2 0.72). Therefore, for each 1-year increase in the age at diagnosis, the frequency of dry mouth increased by 0.13%, and the frequency of abnormal oral diagnostic tests by 0.11%. There was a consistent year-by-year decrease in the frequency of all autoantibodies and immunological markers except for cryoglobulins. According to the linear models, for each 1-year increase in the age at diagnosis, the frequency of a positive result decreased by 0.57% (for anti-Ro antibodies), 0.47% (for RF) and 0.42% (for anti-La antibodies). The ESSDAI domains which showed a more consistent decrease were glandular and lymph node involvement (for each 1-year increase in the age at diagnosis, the frequency of activity decreased by 0.18%), and constitutional, cutaneous, and haematological involvements (the frequency decreased by 0.09% for each 1-year increase). In contrast, other domains showed an ascending pattern, especially pulmonary involvement (for each 1-year increase in the age at diagnosis, the frequency of activity increased by 0.22%), and peripheral nerve involvement (the frequency increased by 0.09% for each 1-year increase)., Conclusions: The influence of the age at diagnosis on the key phenotypic features of pSS is strong, and should be considered critical not only for designing a personalised diagnostic approach, but also to be carefully considered when analysing the results of diagnostic tests and immunological parameters, and when internal organ involvement is suspected at diagnosis.

Objective: To determine the prevalence and significance of dermatological disorders in primary Sjögren syndrome (pSS)., Methods: We used 2 pSS French cohorts (ASSESS, in which prevalence of skin disorders in 395 patients was evaluated; and diapSS, in which 76 on 139 pSS patients had an examination by a dermatologist) and baseline data of the TEARS randomized trial (110 patients with recent or active pSS treated with rituximab or placebo and evaluated for skin dryness using a visual analogue scale (VAS) out of 100)., Results: Skin manifestations included in the EULAR Sjögren syndrome disease activity index (ESSDAI) were rare in the ASSESS cohort (n=16/395, 4.1%, mainly purpuras; only 3 had high activity), but they were associated with activity in the other ESSDAI domains (peripheral neurological (P<0.001), muscular (P<0.01), haematological (P<0.05), biological (P<0.05), history of arthritis (P<0.01), splenomegaly (P<0.05) and higher gamma globulin levels (P<0.01)). In the diapSS cohort, compared to pSS patients not receiving a dermatological consultation, the pSS patients who had a dermatological consultation had significantly more dermatological involvement outside the ESSDAI score [38.2% (29/76) versus 15.9% (10/63); P<0.01]. The TEARS study showed a high prevalence of cutaneous dryness (VAS>50; 48.2%) and found that patients with dry skin had higher VAS pain (P<0.01) and drought (P<0.01) scores., Conclusion: ESSDAI skin activity is rare and associated with hypergammaglobulinemia and ESSDAI activity. Systematic dermatological examination is informative for non-specific lesions. The most common skin disorder is skin dryness, which is associated with a higher pain and overall subjective dryness., (Copyright © 2021 Société française de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.)

There is currently no approved treatment for primary Sjögren's syndrome, a disease that primarily affects adult women. The difficulty in developing effective therapies is -in part- because of the heterogeneity in the clinical manifestation and pathophysiology of the disease. Finding common molecular signatures among patient subgroups could improve our understanding of disease etiology, and facilitate the development of targeted therapeutics. Here, we report, in a cross-sectional cohort, a molecular classification scheme for Sjögren's syndrome patients based on the multi-omic profiling of whole blood samples from a European cohort of over 300 patients, and a similar number of age and gender-matched healthy volunteers. Using transcriptomic, genomic, epigenetic, cytokine expression and flow cytometry data, combined with clinical parameters, we identify four groups of patients with distinct patterns of immune dysregulation. The biomarkers we identify can be used by machine learning classifiers to sort future patients into subgroups, allowing the re-evaluation of response to treatments in clinical trials.

Objectives: This phase 2 proof-of-concept study (NCT02610543) assessed efficacy, safety and effects on salivary gland inflammation of seletalisib, a potent and selective PI3Kδ inhibitor, in patients with moderate-to-severe primary Sjögren's syndrome (PSS)., Methods: Adults with PSS were randomized 1:1 to seletalisib 45 mg/day or placebo, in addition to current PSS therapy. Primary end points were safety and tolerability and change from baseline in EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score at week 12. Secondary end points included change from baseline at week 12 in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score and histological features in salivary gland biopsies., Results: Twenty-seven patients were randomized (seletalisib n = 13, placebo n = 14); 20 completed the study. Enrolment challenges led to early study termination with loss of statistical power (36% vs 80% planned). Nonetheless, a trend for improvement in ESSDAI and ESSPRI [difference vs placebo: -2.59 (95% CI: -7.30, 2.11; P=0.266) and -1.55 (95% CI: -3.39, 0.28), respectively] was observed at week 12. No significant changes were seen in saliva and tear flow. Serious adverse events (AEs) were reported in 3/13 of patients receiving seletalisib vs 1/14 for placebo and 5/13 vs 1/14 discontinued due to AEs, respectively. Serum IgM and IgG concentrations decreased in the seletalisib group vs placebo. Seletalisib demonstrated efficacy in reducing size and organisation of salivary gland inflammatory foci and in target engagement, thus reducing PI3K-mTOR signalling compared with placebo., Conclusion: Despite enrolment challenges, seletalisib demonstrated a trend towards clinical improvement in patients with PSS. Histological analyses demonstrated encouraging effects of seletalisib on salivary gland inflammation and organisation., Trial Registration: https://clinicaltrials.gov, NCT02610543., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: No immunomodulatory drug has been approved for primary Sjögren's syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren's syndrome-related systemic complications., Methods: Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren's syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren's Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician's global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment., Results: 110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of -11.4% (95% credible interval -30.6 to 9.0) (Pr[Toc >Pla]=0.14)., Conclusion: Among patients with primary Sjögren's syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo., Trial Registration Number: NCT01782235., Competing Interests: Competing interests: J-EG received honoraries and research grants from BMS and Pfizer, and honoraries from CSL Behring, Lilly, Janssen, UCB, Roche. All other authors declare no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years, no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To characterize the systemic phenotype of primary Sjögren's syndrome at diagnosis by analysing the EULAR-SS disease activity index (ESSDAI) scores., Methods: The Sjögren Big Data Consortium is an international, multicentre registry based on worldwide data-sharing cooperative merging of pre-existing databases from leading centres in clinical research in Sjögren's syndrome from the five continents., Results: The cohort included 10 007 patients (9352 female, mean 53 years) with recorded ESSDAI scores available. At diagnosis, the mean total ESSDAI score was 6.1; 81.8% of patients had systemic activity (ESSDAI score ≥1). Males had a higher mean ESSDAI (8.1 vs 6.0, P < 0.001) compared with females, as did patients diagnosed at <35 years (6.7 vs 5.6 in patients diagnosed at >65 years, P < 0.001). The highest global ESSDAI score was reported in Black/African Americans, followed by White, Asian and Hispanic patients (6.7, 6.5, 5.4 and 4.8, respectively; P < 0.001). The frequency of involvement of each systemic organ also differed between ethnic groups, with Black/African American patients showing the highest frequencies in the lymphadenopathy, articular, peripheral nervous system, CNS and biological domains, White patients in the glandular, cutaneous and muscular domains, Asian patients in the pulmonary, renal and haematological domains and Hispanic patients in the constitutional domain. Systemic activity measured by the ESSDAI, clinical ESSDAI (clinESSDAI) and disease activity states was higher in patients from southern countries (P < 0.001)., Conclusion: The systemic phenotype of primary Sjögren's syndrome is strongly influenced by personal determinants such as age, gender, ethnicity and place of residence, which are key geoepidemiological players in driving the expression of systemic disease at diagnosis., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To evaluate the systemic phenotype associated with the presence of isolated anti-La/SSB antibodies in a large international registry of patients with primary Sjögren's syndrome (pSS) fulfilling the 2002 classification criteria., Methods: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. Baseline clinical information from leading centres on clinical research in SS of the 5 continents was collected. Combination patterns of anti-Ro/SSA-La/SSB antibodies at the time of diagnosis defined the following four immunological phenotypes: double positive (combined Ro/SSA and La/SSB,) isolated anti-Ro/SSA, isolated anti-La/SSB, and immunonegative., Results: The cohort included 12,084 patients (11,293 females, mean 52.4 years) with recorded ESSDAI scores available. Among them, 279 (2.3%) had isolated anti-La/SSB antibodies. The mean total ESSDAI score at diagnosis of patients with pSS carrying isolated anti-La/SSB was 6.0, and 80.4% of patients had systemic activity (global ESSDAI score ≥1) at diagnosis. The domains with the highest frequency of active patients were the biological (42.8%), glandular (36.8%) and articular (31.2%) domains. Patients with isolated anti-La/SSB showed a higher frequency of active patients in all ESSDAI domains but two (articular and peripheral nerve) in comparison with immune-negative patients, and even a higher absolute frequency in six clinical ESSDAI domains in comparison with patients with isolated anti-Ro/SSA. In addition, patients with isolated anti-La/SSB showed a higher frequency of active patients in two ESSDAI domains (pulmonary and glandular) with respect to the most active immunological subset (double-positive antibodies). Meanwhile, systemic activity detected in patients with isolated anti-La/SSB was overwhelmingly low. Even in ESSDAI domains where patients with isolated anti-La/SSB had the highest frequencies of systemic activity (lymphadenopathy and muscular), the percentage of patients with moderate or high activity was lower in comparison with the combined Ro/SSA and La/SSB group., Conclusions: Patients carrying isolated La/SSB antibodies represent a very small subset of patients with a systemic SS phenotype characterised by a significant frequency of active patients in most clinical ESSDAI domains but with a relative low frequency of the highest severe organ-specific involvements. Primary SS still remains the best clinical diagnosis for this subset of patients.

Objectives: Manual systematic literature reviews are becoming increasingly challenging due to the sharp rise in publications. The primary objective of this literature review was to compare manual and computer software using artificial intelligence retrieval of publications on the cutaneous manifestations of primary SS, but we also evaluated the prevalence of cutaneous manifestations in primary SS., Methods: We compared manual searching and searching with the in-house computer software BIbliography BOT (BIBOT) designed for article retrieval and analysis. Both methods were used for a systematic literature review on a complex topic, i.e. the cutaneous manifestations of primary SS. Reproducibility was estimated by computing Cohen's κ coefficients and was interpreted as follows: slight, 0-0.20; fair, 0.21-0.40; moderate, 0.41-0.60; substantial, 0.61-0.80; and almost perfect, 0.81-1., Results: The manual search retrieved 855 articles and BIBOT 1042 articles. In all, 202 articles were then selected by applying exclusion criteria. Among them, 155 were retrieved by both methods, 33 by manual search only, and 14 by BIBOT only. Reliability (κ = 0.84) was almost perfect. Further selection was performed by reading the 202 articles. Cohort sizes and the nature and prevalence of cutaneous manifestations varied across publications. In all, we found 52 cutaneous manifestations reported in primary SS patients. The most described ones were cutaneous vasculitis (561 patients), xerosis (651 patients) and annular erythema (215 patients)., Conclusion: Among the final selection of 202 articles, 155/202 (77%) were found by the two methods but BIBOT was faster and automatically classified the articles in a chart. Combining the two methods retrieved the largest number of publications., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: To assess the presence of a seasonal effect on fatigue, pain and dryness in primary Sjögren's syndrome (pSS)., Methods: Data (date; visual analogue scales (VAS) for pain, fatigue and dryness) were extracted from three randomised placebo-controlled trials (RCTs) evaluating infliximab (TRIPSS; n = 103 patients), hydroxychloroquine (JOQUER; n = 120 patients) and rituximab (TEARS; n = 120 patients) and from the 5-year follow-up of the ASSESS prospective cohort (n = 395 patients). Data were analysed at each visit for each patient, according to the day, the month of the year and the season. Linear mixed models were used to take into account the repeated structure of the data and to analyse a potential cyclic effect., Results: A total of 744, 584, 848 and 682 pain, fatigue and dryness VASs were collected on 632 subjects in spring, summer, fall and winter, respectively. No significant difference was observed in pain, fatigue and dryness, according to the month of the year or the season (all p values > 0.05)., Conclusion: In pSS, seasonality does not affect patient-reported outcomes (PROs) on fatigue, pain and dryness.

Objective: Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion., Methods: A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS., Results: A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%., Conclusion: SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria., (© 2019 The Association for the Publication of the Journal of Internal Medicine.)

Primary Sjögren's syndrome (SjS) is a chronic and systemic autoimmune epithelitis with predominant female incidence, which is characterized by exocrine gland dysfunction. Incompletely understood, the etiology of SjS is multi-factorial and evidence is growing to consider that epigenetic factors are playing a crucial role in its development. Independent from DNA sequence mutations, epigenetics is described as inheritable and reversible processes that modify gene expression. Epigenetic modifications reported in minor salivary gland and lymphocytes from SjS patients are related to (i) an abnormal DNA methylation process inducing in turn defective control of normally repressed genes involving such matters as autoantigens, retrotransposons, and the X chromosome in women; (ii) altered nucleosome positioning associated with autoantibody production; and (iii) altered control of microRNA. Results from epigenome-wide association studies have further revealed the importance of the interferon pathway in disease progression, the calcium signaling pathway for controlling fluid secretions, and a cell-specific cross talk with risk factors associated with SjS. Importantly, epigenetic modifications are reversible thus opening opportunities for therapeutic procedures in this currently incurable disease.

Objective: Parotidomegaly is a criterion of the EULAR Primary Sjögren Syndrome Disease Activity Index (ESSDAI). The cut-off value was set at 3 cm in length for the parotid gland, 2 cm for the submandibular glands. However, clinical appreciation of salivary glands size remains hazardous. The objective is to evaluate inter-observer reproducibility of parotid gland measurement by palpation, and to secondary evaluate its reliability compared to US assessment., Methods: Outpatients with primary Sjögren Syndrome (pSS) or with a diagnostic suspicion, in a single reference centre, were included. They underwent clinical examination by two independent investigators (VDP and DC), evaluating: parotid gland swelling, parotid gland size (direct measurement with a decameter under the mandibular angle), and pain. Cohen's kappa coefficient was calculated to determine inter-observer concordance for parotid gland swelling, and intraclass correlation coefficient to determine inter-observer agreement of gland size measurement., Results: Thirty-four patients (33 women, 1 man) were included. Clinical data were complete for 33 patients. Inter-observer concordance Kappa coefficient was 0.90 [0.76-1.00] for detection of parotidomegaly over 66 parotid glands. It was of 0.60 [0.42-0.73] for gland length measurement. For one observer, the median cut-off for defining parotidomegaly was 4.15 cm; for the second observer, it was of 4.92 cm. For submandibular glands palpation, no correlation was found between investigators. A significant association between clinical parotidomegaly and a larger echographic surface was found., Conclusion: Clinical measurement of parotidomegaly was concordant between two observers on a binary mode (presence/absence). However, concordance on direct measurement was weak. US could be a complementary examination., (Copyright © 2019. Published by Elsevier Masson SAS.)

Objectives: Onset of primary SS is usually between 40 and 60 years of age, with severe systemic complications in 15% of cases. We sought to determine whether early-onset disease is related to a specific phenotype and if it is predictive of a poor outcome., Methods: Biological and clinical data from 393 patients recruited in the ASSESS cohort, a French multicentre prospective cohort, were compared according to age at diagnosis., Results: Fifty-five patients had early-onset disease, defined as age ⩽35 years at diagnosis, and presented a significantly higher frequency of salivary gland enlargement (47.2% vs 33.3%, P = 0.045), adenopathy (25.5% vs 11.8%, P = 0.006), purpura (23.6% vs 9.2%, P = 0.002) and renal involvement (16.4% vs 4.4%, P = 0.003). They had a higher frequency of hypergammaglobulinaemia (60.8% vs 26.6%, P < 0.001), RF positivity (41.5% vs 20.2%, P < 0.001), low C3 level (18.9% vs 9.1%, P = 0.032), low C4 level (54.7% vs 40.2%, P = 0.048) and autoantibodies [84.6% with anti-SSA vs 54.4% (P < 0.001) and 57.7% with anti-SSB vs 29.7% (P < 0.001)]. The change in ESSDAI scores between baseline and the 5-year follow-up was significantly different (P = 0.005) with a trend for worsening in the early-onset group (0.72, P = 0.27) and a significant improvement in the later onset group (-1.27, P < 0.0001)., Conclusion: Early-onset primary SS is associated with a specific phenotype defined by clinical and biological features known to be predictive factors of severe systemic disease. Interestingly, we showed a different evolution of the ESSDAI score depending on the age at disease onset, patients with early-onset disease tending to worsen over time., (© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To analyse the frequency and characterise the systemic presentation of primary Sjögren's syndrome (SS) out of the ESSDAI classification in a large international, multi-ethnic cohort of patients., Methods: The Big Data Sjögren Project Consortium is an international, multicentre registry based on world-wide data-sharing and cooperative merging of pre-existing clinical SS databases from leading centres in clinical research in SS from the five continents. A list of 26 organ-by-organ systemic features not currently included in the ESSDAI classification was defined according to previous studies; these features were retrospectively recorded., Results: Information about non-ESSDAI features was available in 6331 patients [5,917 female, mean age at diagnosis 52 years, mainly White (86.3%)]. A total of 1641 (26%) patients had at least one of the ESSDAI systemic features. Cardiovascular manifestations were the most frequent organ-specific group of non-ESSDAI features reported in our patients (17% of the total cohort), with Raynaud's phenomenon being reported in 15%. Patients with systemic disease due to non-ESSDAI features had a lower frequency of dry mouth (90.7% vs. 94.1%, p<0.001) and positive minor salivary gland biopsy (86.7% vs. 89%, p=0.033), a higher frequency of anti-Ro/SSA (74.7% vs. 68.7%, p<0.001), anti-La/SSB antibodies (44.5% vs. 40.4%, p=0.004), ANA (82.7% vs. 79.5%, p=0.006), low C3 levels (17.4% vs. 9.7%, p<0.001), low C4 levels (14.4% vs. 9.6%, p<0.001), and positive serum cryoglobulins (8.6% vs. 5.5%, p=0.001). Systemic activity measured by the ESSDAI, clinESSDAI and DAS was higher in patients with systemic disease out of the ESSDAI in comparison with those without these features (p<0.001 for all comparisons)., Conclusions: More than a quarter of patients with primary SS may have systemic manifestations not currently included in the ESSDAI classification, with a wide variety of cardiovascular, digestive, pulmonary, neurological, ocular, ENT (ear, nose, and throat), cutaneous and urological features that increase the scope of the systemic phenotype of the disease. However, the individual frequency of each of these non-ESSDAI features was very low, except for Raynaud's phenomenon.

Objectives: To evaluate the influence of the main immunological markers on the disease phenotype at diagnosis in a large international cohort of patients with primary Sjögren's syndrome (SjS)., Methods: The Big Data Sjögren Project Consortium is an international, multicentre registry created in 2014. As a first step, baseline clinical information from leading centres on clinical research in SjS of the 5 continents was collected. The centres shared a harmonised data architecture and conducted cooperative online efforts in order to refine collected data under the coordination of a big data statistical team. Inclusion criteria were the fulfillment of the 2002 classification criteria. Immunological tests were carried out using standard commercial assays., Results: By January 2018, the participant centres had included 10,500 valid patients from 22 countries. The cohort included 9,806 (93%) women and 694 (7%) men, with a mean age at diagnosis of primary SjS of 53 years, mainly White (78%) and included from European countries (71%). The frequency of positive immunological markers at diagnosis was 79.3% for ANA, 73.2% for anti-Ro, 48.6% for RF, 45.1% for anti- La, 13.4% for low C3 levels, 14.5% for low C4 levels and 7.3% for cryoglobulins. Positive autoantibodies (ANA, Ro, La) correlated with a positive result in salivary gland biopsy, while hypocomplementaemia and especially cryoglo-bulinaemia correlated with systemic activity (mean ESSDAI score of 17.7 for cryoglobulins, 11.3 for low C3 and 9.2 for low C4, in comparison with 3.8 for negative markers). The immunological markers with a great number of statistically-significant associations (p<0.001) in the organ-by-organ ESS- DAI evaluation were cryoglobulins (9 domains), low C3 (8 domains), anti-La (7 domains) and low C4 (6 domains)., Conclusions: We confirm the strong influence of immunological markers on the phenotype of primary SjS at diagnosis in the largest multi-ethnic international cohort ever analysed, with a greater influence for cryoglobulinaemic-related markers in comparison with Ro/La autoantibodies and ANA. Immunological patterns play a central role in the phenotypic expression of the disease already at the time of diagnosis, and may guide physicians to design a specific personalised management during the follow-up of patients with primary SjS.

Objective: EMBODY 1 (ClinicalTrials.gov identifier: NCT01262365) and EMBODY 2 (ClinicalTrials.gov identifier: NCT01261793) investigated the efficacy and safety of epratuzumab, a CD22-targeted humanized monoclonal IgG antibody, in patients with systemic lupus erythematosus (SLE). The studies showed no significant difference from placebo in primary or secondary clinical outcome measures but did demonstrate B cell-specific immunologic activity. The aim of this post hoc analysis was to determine whether epratuzumab had a different clinical efficacy profile in SLE patients with versus those without an associated diagnosis of Sjögren's syndrome (SS)., Methods: The efficacy and safety of epratuzumab were compared between 2 patient subpopulations randomized in EMBODY 1 and 2: SLE patients with and those without a diagnosis of associated SS. British Isles Lupus Assessment Group (BILAG) total score, BILAG-based Combined Lupus Assessment (BICLA) clinical response to treatment, biologic markers (including B cells, IgG, IgM, and IgA), and safety were assessed., Results: A total of 1,584 patients were randomized in the EMBODY 1 and EMBODY 2 trials; 113 patients were anti-SSA positive and had a diagnosis of associated SS, and 1,375 patients (86.8%) had no diagnosis of associated SS (918 patients were randomized to receive epratuzumab and 457 to receive placebo). For patients with associated SS, but not those without associated SS, a higher proportion of patients receiving epratuzumab achieved a BICLA response and a reduction from baseline in BILAG total score. B cell reduction was faster in patients with associated SS. The sensitivity of B cells to epratuzumab as measured by the mean concentration producing 50% of the maximum B cell count depletion was lower for patients with associated SS (9.5 μg/ml) versus the total EMBODY population (87.1 μg/ml). No difference in the frequency of adverse events in those receiving placebo was reported., Conclusion: Patients with SLE and associated SS treated with epratuzumab showed improvement in SLE disease activity, which was associated with bioactivity, such as decreases in B cell number and IgM level., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Objective: To evaluate whether major salivary-gland ultrasonography (SGUS) abnormalities change over time in patients with suspected primary Sjögren's syndrome (pSS) during the natural course of the disease., Methods: We studied patients with suspected pSS who were included in the Brittany cohort of suspected pSS and underwent SGUS at least twice, as part of the routine diagnostic workup done at baseline then at least 1 year later as an additional investigation deemed appropriate by the physician. The evaluation criteria were the semi-quantitative SGUS score (0-4) for each parotid and submandibular gland, the highest SGUS score among the four glands, and the sum of SGUS scores for the four glands. These scores were compared in patients with and without pSS according to the workup at baseline, and their changes over time were assessed., Results: Of 49 included patients, 29 received a diagnosis of pSS at baseline; none of the remaining 20 patients was diagnosed with pSS at either evaluation. The mean (SD) sum of SGUS scores at baseline was 8.9 (5.6) in patients with and 2.1 (2.9) in those without pSS (P<0.01). Mean time between SGUSs was 1.9 (1.6) years. None of the evaluation criteria changed between the two SGUSs in the overall population, pSS group, or group without pSS. Similar results were found in the subgroup with recent-onset symptoms., Conclusion: SGUS abnormalities assessed using a semi-quantitative score did not change significantly during a follow-up of nearly 2 years after an initial evaluation for suspected pSS., (Copyright © 2017 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Background: The objective was to evaluate concordance between 2002 American-European Consensus Group (AECG) and 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for primary Sjögren's syndrome (pSS) and to assess how salivary gland ultrasonography (SGUS) might improve the classification of patients., Methods: Patients with suspected pSS underwent a standardised evaluation, including SGUS, at inclusion into the single-centre Brittany DIApSS cohort. Agreement between the two criteria sets was assessed using Cohen's κ coefficient. Characteristics of discordantly categorised patients were detailed., Results: We prospectively included 290 patients between 2006 and 2016, among whom 125 (43%) met ACR/EULAR criteria and 114 (39%) also met AECG criteria; thus, 11 (4%) patients fulfilled only ACR/EULAR, no patients AECG only, and 165 (57%) patients neither criteria set. Concordance was excellent (κ = 0.92). Compared to patients fulfilling both criteria sets, the 11 patients fulfilling only ACR/EULAR criteria had similar age and symptom duration but lower frequencies of xerophthalmia and xerostomia (p < 0.01 for each) and salivary gland dysfunction (p < 0.01); most had systemic involvement (91%), including three (27%) with no sicca symptoms; 91% had abnormal salivary gland biopsy and 46% anti-Sjögren's-syndrome-related antigen A (anti-SSA); 64% were diagnosed with pSS by the physician. SGUS was abnormal in 12% of the 165 patients fulfilling no criteria set. Including SGUS among the ACR/EULAR criteria increased sensitivity from 87.4% to 91.1% when physician diagnosis was the reference standard., Conclusions: Agreement between AECG and ACR/EULAR criteria sets is excellent. ACR/EULAR criteria are slightly more sensitive and classified some patients without sicca symptoms as having pSS. Including SGUS in the ACR/EULAR criteria may further improve their sensitivity.

Labial salivary gland (LSG) biopsy is used in the classification of primary Sjögren's syndrome (PSS) and in patient stratification in clinical trials. It may also function as a biomarker. The acquisition of tissue and histological interpretation is variable and needs to be standardised for use in clinical trials. A modified European League Against Rheumatism consensus guideline development strategy was used. The steering committee of the ad hoc working group identified key outstanding points of variability in LSG acquisition and analysis. A 2-day workshop was held to develop consensus where possible and identify points where further discussion/data was needed. These points were reviewed by a subgroup of experts on PSS histopathology and then circulated via an online survey to 50 stakeholder experts consisting of rheumatologists, histopathologists and oral medicine specialists, to assess level of agreement (0-10 scale) and comments. Criteria for agreement were a mean score ≥6/10 and 75% of respondents scoring ≥6/10. Thirty-nine (78%) experts responded and 16 points met criteria for agreement. These points are focused on tissue requirements, identification of the characteristic focal lymphocytic sialadenitis, calculation of the focus score, identification of germinal centres, assessment of the area of leucocyte infiltration, reporting standards and use of prestudy samples for clinical trials. We provide standardised consensus guidance for the use of labial salivary gland histopathology in the classification of PSS and in clinical trials and identify areas where further research is required to achieve evidence-based consensus., Competing Interests: Competing interests: SJB has received honoraria/consultancy fees in the field of Sjögren's syndrome in 2015–2016 for AstraZeneca, Celgene, Glenmark, Eli Lilly, Novartis, Ono and UCB Pharmaceuticals. Roche provided rituximab for the TRACTISS study. BAF has received honoraria/consultancy fees from Novartis, Roche and Medimmune. FB has received honoraria/consultancy fees from Roche, GlaxoSmithKline, Glenmark and Medimmune, and research funding from UCB. Other authors have declared no competing interests., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objectives: To analyse the influence of geolocation and ethnicity on the clinical presentation of primary Sjögren's syndrome (SjS) at diagnosis., Methods: The 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., Results: We 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)., Conclusions: This study provides the first evidence of a strong influence of geolocation and ethnicity on the phenotype of primary SjS at diagnosis., Competing Interests: Competing interests: None declared., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: To identify the principal determinants of health-related quality of life (HRQOL) impairment in patients with active primary Sjögren's syndrome (SS) participating in a large therapeutic trial, Tolerance and Efficacy of Rituximab in Primary Sjögren's Syndrome (TEARS)., Methods: At the inclusion visit for the TEARS trial, 120 patients with active primary SS completed the Short Form 36 health survey (SF-36), a validated HRQOL assessment tool. Univariate then multivariate linear regression analyses were used to assess associations linking SF-36 physical and mental components to demographic data, patient-reported outcomes (symptom intensity assessments for dryness, pain, and fatigue, including the European League Against Rheumatism [EULAR] Sjögren's Syndrome Patient Reported Index [ESSPRI]), objective measures of dryness and autoimmunity, and physician evaluation of systemic activity (using the EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI])., Results: SF-36 scores indicated marked HRQOL impairments in our population with active primary SS. Approximately one-third of the patients had low, moderate, and high systemic activity according to the ESSDAI. ESSPRI and ESSDAI scores were moderately but significantly correlated. The factors most strongly associated with HRQOL impairment were patient-reported symptoms, best assessed using the ESSPRI, with pain and ocular dryness intensity showing independent associations with HRQOL. Conversely, systemic activity level was not associated with HRQOL impairment in multivariate analyses, even in the patient subset with ESSDAI values indicating moderate-to-high systemic activity., Conclusion: The cardinal symptoms of primary SS (dryness, pain, and fatigue, best assessed using the ESSPRI) are stronger predictors of HRQOL impairment than systemic involvement (assessed by the ESSDAI) and should be used as end points in future therapeutic trials focusing on patients' well-being. New consensual and data-driven response criteria are needed for primary SS studies., (© 2016, American College of Rheumatology.)

Objective: To compare quality of life (QoL), depression, anxiety, and fatigue in prospectively included patients with primary Sjögren's syndrome (pSS) or with sicca but no diagnosis of Sjögren's syndrome., Methods: Patients undergoing a multidisciplinary evaluation at a single university center in Brest, France, for suspected pSS and having sicca symptoms were included prospectively between November 2006 and December 2013. The same standardized investigations were performed in all patients. pSS and sicca not due to pSS diagnoses were based on evaluating physician opinion. Each patient completed three validated questionnaires on QoL (SF-36), fatigue (MFI), depression and anxiety (HADS)., Results: Of the 95 included patients, 55 (57.9%) had pSS and 40 (42.1%) had sicca without pSS. Gender distribution, age, disease duration, and sicca symptoms were similar in the two groups. The pSS group had a significantly higher proportion of patients with abnormal objective tests for dryness (Schirmer's test and salivary flow rate). The SF-36, HADS, and MFI scores were similarly altered in the two groups. Anxiety was more common than depression in both groups. The most affected domains were vitality in the SF-36 and general/physical fatigue in the MFI. Extraglandular systemic involvement was not a major determinant of QoL alteration in patients with pSS., Conclusions: Sicca symptoms are associated with severe alterations in SF-36, HADS, and MFI scores regardless of objective test abnormalities and pSS diagnosis. Anxiety is more common than depression and should be taken into account when managing all patients with sicca symptoms., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Primary Sjögren syndrome (pSS) is a progressive autoimmune disease characterized by sicca and systemic manifestations. In this Review, we summarize the available data on topical and systemic medications, according to clinical signs and disease activity, and we describe the ongoing studies using biologic drugs in the treatment of pSS. Expanding knowledge about the epidemiology, classification criteria, systemic activity scoring (ESSDAI) and patient-reported outcomes (ESSPRI) is driving active research. Treatment decisions are based on the evaluation of symptoms and extraglandular manifestations. Symptomatic treatment is usually appropriate, whereas systemic treatment is reserved for systemic manifestations. Sicca is managed by education, environment modification, elimination of contingent offending drugs, artificial tears, secretagogues and treatments for complications. Mild systemic signs such as fatigue are treated by exercise. Pain can require short-term moderate-dose glucocorticoid therapy and, in some cases, disease-modifying drugs. Severe and acute systemic manifestations indicate treatment with glucocorticoids and/or immunosuppressant drugs. The role for biologic agents is promising, but no double-blind randomized controlled trials (RCTs) proving the efficacy of these drugs are available. Targets for new treatments directed against the immunopathological mechanisms of pSS include epithelial cells, T cells, B-cell overactivity, the interferon signature, proinflammatory cytokines, ectopic germinal centre formation, chemokines involved in lymphoid cell homing, and epigenetic modifications.