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Background: In patients with psychotic disorders, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the spindle deficit observed in schizophrenia. Methods: An electrophysiological multisite cell-to-network exploration was used to investigate, in pentobarbital-sedated rats, the effects of a single psychotomimetic dose of the NMDA glutamate receptor antagonist ketamine in the sensorimotor and associative/cognitive thalamocortical (TC) systems. Results: Under the control condition, spontaneously-occurring spindles (intra-frequency: 10-16 waves/s) and delta-frequency (1-4Hz) oscillations were recorded in the frontoparietal cortical EEG, in thalamic extracellular recordings, in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons, and in intracellularly recorded TC neurons. The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200-700Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30-80Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity. The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations. Conclusion: The present findings support the hypothesis that NMDA receptor hypofunction is involved in the reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion of ongoing TC-TRN activities may have involved at least both the ascending reticular activating system and the corticothalamic pathway., Schizophrenia Research, Elsevier, In press

Introduction Le nombre croissant de publications dans le domaine de l’immunologie souligne la necessite d’un filtrage automatique des publications afin d’extraire rapidement les informations integrees dans ce corpus de litterature scientifique. Patients et methodes Pour effectuer une revue systematique de la litterature, nous avons utilise BIBOT, un logiciel de traitement du langage naturel developpe autour d’approches d’apprentissage automatique [1] , [2] , pour analyser automatiquement les etudes sur les aspects epigenetiques des maladies auto-immunes. Nous avons fourni les mots-cles suivants a BIBOT : « Mecanisme epigenetique » et « Maladies auto-immunes ». Resultats En utilisant ces mots-cles comme demande d’utilisateur, 307 articles ont ete identifies comme candidats potentiels a partir de la base de donnees PubMed par le programme. Parmi eux, 162 se referaient a des maladies auto-immunes et 240 a differents mecanismes epigenetiques. L’intersection de ces deux ensembles etait composee de 122 articles. Une analyse approfondie des articles selectionnes a revele 211 cibles bien etablies de mecanismes epigenetiques dans les maladies auto-immunes. Nous avons extrait ces cibles, leur maladie associee et leurs mecanismes associes. Parmi notre selection d’articles, nous avons observe une forte proportion d’etudes concernant le lupus, la methylation et les mecanismes d’ARN non codants ( Tableau 1 ). Nous avons ensuite detaille les mecanismes identifies (methylation, miRNA, etc.), par cible (CD40L, CD70, IFN, etc.) et par pathologie (lupus, polyarthrite rhumatoide, etc.). Conclusion Notre traitement du langage naturel a permis de decrire les tendances generales dans les publications et a fourni un fichier de donnees contenant des meta-informations sur chacune des publications selectionnees sur l’epigenetique.

BackgroundPrimary Sjögren’s syndrome (pSS) is a rare systemic autoimmune disease with no specific treatment at present. To better assess patient symptoms, we have developed a web application (WebApp) to collect patient symptom intensity on a regular basis.ObjectivesTo measure the daily variability of symptoms using the WebApp. We also evaluated its ease of use.Methods45 consecutive patients with pSS were included in 3 referral centers. Symptoms were assessed during the baseline and 3 month visits. We collected the VAS relating to fatigue, dryness and pain as well as the ESSPRI score. Patients used the WebApp daily for 3 months. The variability of symptoms over time was assessed by the predicted median error. This value was determined using a linear regression model, in order to predict the value at the 3rd month, then this value was compared to the actual value collected at the 3rd month during the clinical visit. The ease of use of the WebApp was assessed using a satisfaction score (SUS score).ResultsOf the 45 patients included, 91.1% were women with an average age of 57 years, and low systemic disease activity (84.4% had an ESSDAI score below 5). The intensity of the symptoms collected during the clinical visits was similar at baseline and at 3 months. The values ​​of the median error for each measurement are between 0.5 and 0.8. The 3-month predicted median error values ​​ranged from 2 to -3. The patients all used the web application for 3 months with good attendance (80% of data completion) and were satisfied with this tool (median SUS score = 90).ConclusionSymptoms of pSS fluctuate from day to day in the majority of patients, making a point measurement imprecise. The developed WebApp is easy to use, and could allow more sensitive detection of the effect of a therapeutic intervention. This tool will soon be evaluated during prospective interventional clinical trials.AcknowledgementsI would like to thanks all people who have helped and were directly or indirectly involved in this study.Disclosure of InterestsNone declared

BackgroundPrimary Sjögren’s Syndrome (pSS) is a chronic autoimmune disease. Symptoms range from sicca to systemic, potentially life-threatening organ damage. Little is known about the onset of the disease. Anti-Ro antibodies are described to develop years before the first symptoms. In addition, first degree relatives of pSS patients have an 11- to 19- fold increased risk of developing pSS themselves.ObjectivesTo identify and follow-up individuals at risk for pSS in order to study symptoms and immune pathology before and at development of pSS.MethodsIn this ongoing long-term study individuals at risk for developing pSS but not fulfilling the ACR-EULAR classification criteria of pSS were included, defined as: 1.) Anti-SSA positive individuals (Anti-SSA+) without any sicca symptoms or diagnosis of an underlying systemic autoimmune disease; 2.) First degree relatives of patients (relatives) with an established diagnosis of pSS and typical autoantibodies (ANA ≥ 1:160 and/or anti-SSA+ and/or rheumatoid factor+); 3.) Individuals with at least one feature of the ACR-EULAR classification criteria for pSS, but not fulfilling the criteria (incomplete).At baseline and at annual visits, demographic data, blood, saliva and urine samples were collected and stored. Salivary and lacrimal flow, salivary gland ultrasonography (SGUS), and patient-related outcome measures were analysed. A lip salivary gland biopsy was performed at baseline and upon development of symptoms suggestive of pSS. The primary endpoint was the development of definite pSS according to the ACR-EULAR classification criteria.ResultsAfter the first year of recruitment, 50 individuals (Anti-SSA+ n=27, relatives n=21, incomplete n=2) were screened at baseline, of whom 28 were identified as individuals at risk for pSS and were included in the study. Twenty-two individuals were excluded from the study, most of whom were “relatives” with negative autoantibodies. Of these 28 individuals at risk, 89% were female (n=25), they had a median age of 53 years (IQR: 19) and 57% (n=16) had positive antinuclear antibodies. 86 percent were positive for anti-SSA and 14% were positive for anti-SSB. Decreased complement C3 and C4 were found in 18% and 4%, respectively. Serum IgG concentration was elevated in 29% of individuals. A reduction of lacrimal flow was found in 29% and stimulated whole salivary flow was reduced in 29%. The median of the ESSPRI was 1.6 (3.0). Eight-teen percent of the investigated individuals had a pathological ultrasound [Hocevar score median 4,5 (9,0)] and in 9% a focus score ≥ 1 [median 0.15 (0.57)] was found in the lip salivary gland biopsies. Four patients (14%) met the primary endpoint and were diagnosed with pSS within the first year.ConclusionThe design of the PRESTIGE study allows us to follow individuals at risk for pSS and will help to unveil symptoms and immune pathology as pSS develops. We suggest to establish a larger international pre-pSS cohort to increase statistical power.Disclosure of InterestsNone declared

BackgroundThe prevalence of salivary glands ultrasound (SGUS) abnormalities in Sjögren’s syndrom (SS) is well described(2). However, the prevalence is still unknown in rheumatic inflammatory conditions such as rheumatoid arthritis (RA).ObjectivesThe main objective of this study was to describe the prevalence of SGUS parenchymal structural abnormalites in patients with RA. Secondary objectives were: i) to study correlation between disease duration and the SGUS OMERACT score and ii) to study correlation between duration of sicca syndrome and the SGUS OMERACT score.Methods561 patients with RA satisfying ACR/EULAR 2010 classification criterias were included in 10 french centers in the prospective cohort BCD, comparing joint ultrasonography to clinical follow-up. Cross sectionnal SGUS examination (parotid and submandibular) was performed in a substudy of this cohort. The new OMERACT-SGUS scoring system(1) was used and clinical, biological, immunological and radiological data were collected.Results100 patients agreed to be included in this substudy of BCD cohort, and a total of 98 SGUS patients data were evaluated (lack of SGUS data for 2 patients). Most patients were women (81%), mean age 59 years, with time from RA diagnosis of 11 years on average. The mean CRP-DAS-28 at baseline was at 3.2 with a third of patients in remission at inclusion. Anti-CCP antibodies or RF was positive in 92 patients (92%). 27 patients (27%) complained of eye dryness and 20 (20%) of mouth dryness. 12 (12%) suffered from both. The levels of self-reported fatigue was higher than in the general group of RA included in the study. Two thirds of patients benefited from csDMARD, with a third treated with bDMARDS. 33 (33%) also benefited from a corticosteroid treatment. Among 98 patients, 22 (22.5%) had at least one salivary gland scored grade 1 or more, this number was reduced to 18 patients (18.4%) when considering only the parotid glands. 7 patients (7.1%) had at least one salivary gland scored grade 2 or more, with a number reduced to 4 patients (4.1%) when considering only the parotids. Only one patient (1%) had a parotid gland scored 3. In the 7 patients presenting significant abnormalities in SGUS (grade 2 or more), 5 patients had either dry eye or dry mouth symptoms (71,4%).ConclusionOur findings suggest that 7% of RA patients present significant SGUS abnormalities according to OMERACT scoring system, associated with clinical sicca syndrome in 71% of cases. There was no significant association between the duration of rheumatoid arthritis and the OMERACT score (Spearman coefficient for correlation -0,028, p = 0,99). There was also no significant association found between the duration of sicca symptoms and the OMERACT score (Spearman coefficient for correlation 0,025, p = 0,89). This study highlights the importance of SGUS assessment in RA sicca patients to improve monitoring and follow-up in routine clinical practice.References[1]Jousse-Joulin S, D’Agostino MA, Nicolas C, Naredo E, Ohrndorf S, Backhaus M, Tamborrini G, Chary-Valckenaere I, Terslev L, Iagnocco A, Collado P, Hernández-Díaz C, Gandjbakhch F, Schmidt WA, Filippou G, Dejaco C, Stradner MH, Mortada MA, Hočevar A, Chrysidis S, El Mardenly G, de Agustín JJ, Thiele R, MacCarter DK, Finzel S, Hanova P, Zabotti A, Glaser C, Alavi Z, Hammenfors DS, Gatineau F, Bruyn GA. Video clip assessment of a salivary gland ultrasound scoring system in Sjögren’s syndrome using consensual definitions: an OMERACT ultrasound working group reliability exercise. Ann Rheum Dis. 2019 Jul;78(7):967-973.[2]Zhang X, Feng R, Zhao J, Wang Y, He J, Liu L, Cheng Y, Yao H, Tang S, Chen J, Zhang S, Zhang Z, Wang Q, He J, Li Z. Salivary gland ultrasonography in primary Sjögren’s syndrome from diagnosis to clinical stratification: a multicentre study. Arthritis Res Ther. 2021 Dec 20;23(1):305.Disclosure of InterestsNone declared

BackgroundSeveral adverse events (AEs) occurring during immune checkpoint inhibitors (ICIs) therapy are clearly related to their mechanisms of action, and in this case they are indicated as immune-related AEs (irAEs). Every organ may be affected, including the musculoskeletal system; myositis, polymyalgia rheumatica, arthritis or arthritis have been reported in several retrospective and prospective case series and cohorts, with an incidence between 1.5% and 22%. While arthritis, vasculitis, myositis, and polymyalgia rheumatica are usually defined as “irAE” in RCTs, other rheumatic musculoskeletal conditions such as arthralgia, myalgia, back pain and muscular pain are often reported under the umbrella of “general” AEs.ObjectivesWe aimed to analyze rheumatic irAE and non-irAE due to immune-checkpoint inhibitors (ICIs) targeting programmed cell death-1 or its ligand PD-(L)1 in lung cancer patients from the available literature.MethodsWe performed a systematic review and meta-analysis of phase III randomized clinical trials (RCTs) assessing PD-(L)1 -ICIs in lung cancer patients, from inception until January 12th, 2021. We extracted data of each trial to estimate odds ratio (OR) for rheumatic ir or non-irAE as classified in RCTs safety data. Sensitivity analyses (by ICI, treatment group and histology) were performed.ResultsEighteen RCTs met the inclusion criteria (n=12172 subjects). The OR [95%IC] for rheumatic irAE in ICIs versus controls (either placebo or chemotherapy) was 2.20 [0.85,5.72].Among rheumatic non-irAEs, both overall (any grade, Figure 1A) and severe (grade≥3, Figure 1B) back pain were significantly more frequent in ICIs versus controls (2.01 [1.09;3.73] and 2.90 [1.18;7.08], respectively).Figure 1.Forest plot showing pooled odds ratio (OR) for back pain (5 phase III trials) (A) and severe back pain (4 phase III trials) (B), respectively.The overall frequency of arthralgia and severe arthralgia was similar between ICIs and controls (1.13 [0.86, 1.47] and 1.69 [0.68, 4.20], respectively). By sensitivity analysis RCTs assessing ICIs in combination with chemotherapy versus chemotherapy alone showed a significant association with arthralgia (1.55 [1.15;2.10]). Similarly, the frequency of myalgia did not differ between ICIs and controls, but was significantly lower in RCTs assessing ICIs alone versus chemotherapy (OR 0.32 [0.24;0.42]). Muscular pain was not significantly increased with ICI.ConclusionRheumatic irAEs are not increased in RCTs assessing PD-(L)1 inhibitors, not reflecting the real-life incidence, therefore likely underreported or misclassified. Back pain is significantly associated with PD-(L)1-ICIs regardless its severity, suggesting a possible implication of the PD-(L)1 axis in the development of inflammatory back pain in some patients.In addition, PD-(L)1-ICIs added on conventional chemotherapy are associated with a significantly higher frequency of arthralgia than ICI alone. This trend was seen in the other rheumatic AEs, suggesting that conventional chemotherapy might be a confounder in the interpretation of the occurrence of rheumatic AEs.Disclosure of InterestsAntonello Veccia: None declared, Marie Kostine: None declared, Alice Tison: None declared, Mariachiara Dipasquale: None declared, Stefania Kingspergher: None declared, Guido Grandi: None declared, Orazio Caffo: None declared, Sandro Inchiostro: None declared, Giuseppe Paolazzi: None declared, Roberto Bortolotti: None declared, Divi Cornec: None declared, Alvise Berti Consultant of: GSK

BackgroundThe low prevalence of systemic autoimmune diseases and the diversity of their clinical manifestations make complex to conduct randomised clinical trials to assess the potential efficacy of targeted treatments.ObjectivesTo assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory autoimmune diseases.MethodsThe TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age > 18 years; rare systemic autoimmune disease (systemic lupus erythematosus, Sjögren’s syndrome, systemic scleroderma, inflammatory myopathy, vasculitis) or other refractory rheumatism treated with off-label drugs started after 1st January 2019.ResultsHundred (100) patients (79 females) were enrolled. The median age was 52.5 years [49;56], the median disease duration before enrolment was 5 years [3;7]. The targeted therapies at enrolment were as follows: JAK/STAT inhibitors (44%), anti-IL6R (22%), anti-IL12/23, anti-IL23 and anti-IL17 (9%), anti-BAFF (5%), abatacept (5%), other targeted treatments (9%), and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months [8;10].Safety: 11 serious infections (incidence rate of 14.8 /100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).Efficacy: The targeted treatment was considered effective by the clinician in 56% of patients and allowed in responders a median reduction of oral corticosteroids of 15 [9-21] mg/day.ConclusionThese initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.References[1]B. Terrier et al., Safety and efficacy of rituximab in systemic lupus erythematosus: results from 136 patients from the French AutoImmunity and Rituximab registry. Arthritis Rheum 62, 2458-2466 (2010).[2]J. E. Gottenberg et al., Efficacy of rituximab in systemic manifestations of primary Sjogren’s syndrome: results in 78 patients of the AutoImmune and Rituximab registry. Ann Rheum Dis 72, 1026-1031 (2013).[3]J. E. Gottenberg et al., Risk factors for severe infections in patients with rheumatoid arthritis treated with rituximab in the autoimmunity and rituximab registry. Arthritis Rheum 62, 2625-2632 (2010).[4]F. R. S. S. S. C. I. consortium, contributors, Severity of COVID-19 and survival in patients with rheumatic and inflammatory diseases: data from the French RMD COVID-19 cohort of 694 patients. Ann Rheum Dis, (2020).[5]R. Felten et al., B-cell targeted therapy is associated with severe COVID-19 among patients with inflammatory arthritides: a 1-year multicentre study in 1116 successive patients receiving intravenous biologics. Ann Rheum Dis 81, 143-145 (2022).[6]D. J. Wallace et al., Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 392, 222-231 (2018).[7]J. J. Paik et al., Study of Tofacitinib in Refractory Dermatomyositis: An Open-Label Pilot Study of Ten Patients. Arthritis Rheumatol 73, 858-865 (2021).[8]S. Cole et al., Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus. Arthritis Res Ther 20, 85 (2018).[9]S. J. Bowman et al., Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjogren’s syndrome: a randomised, double-blind, placebo-controlled, phase 2b dose-finding trial. Lancet 399, 161-171 (2022).AcknowledgementsFrench networks (FAI2R, CRI, IMIDIATE, SFR, SNFMI) focused on rare systemic autoimmune diseases contributed this work by the contribution of network-affiliated physicians.Disclosure of InterestsJacques-Eric Gottenberg Consultant of: Abbvie, BMS, Gilead, Galapagos, Novartis, Lilly Roche Chugai, Sanofi, Janssen, Pfizer, Grant/research support from: BMS.Lilly and Pfizer for this register (with no access to data)., Aurore Chaudier: None declared, Yves Allenbach: None declared, Arsene Mekinian: None declared, Zahir Amoura: None declared, Patrice cacoub: None declared, Divi Cornec: None declared, Eric Hachulla: None declared, Pierre Quartier: None declared, isabelle melki: None declared, Christophe Richez: None declared, Raphaèle Seror: None declared, Benjamin Terrier: None declared, Valerie Devauchelle-Pensec: None declared, Julien Henry: None declared, MARC GATFOSSE: None declared, LAURENCE BOUILLET: None declared, Emeline GAIGNEUX: None declared, Vincent ANDRE: None declared, Gildas BAULIER: None declared, Aurélie SAUNIER: None declared, Marie Desmurs: None declared, Antoine POULET: None declared, Mathieu ETE: None declared, Marie-Elise Truchetet: None declared, Martin Michaud: None declared, Claire Larroche: None declared, AZEDDINE DELLAL: None declared, Amelie LEURS: None declared, Sebastien Ottaviani: None declared, Hubert NIELLY: None declared, Guillaume VIAL: None declared, Roland JAUSSAUD: None declared, Benedicte ROUVIERE: None declared, Pierre-Yves JEANDEL: None declared, Aurelien GUFFROY: None declared, Anne-Sophie Korganow: None declared, Mathieu JOUVRAY: None declared, alain meyer: None declared, Emmanuel Chatelus: None declared, Christelle Sordet: None declared, Renaud FELTEN: None declared, Jean Sibilia: None declared, Samira AHMED YAHIA: None declared, Jean François Kleinmann: None declared, Xavier Mariette Consultant of: BMS, Galapagos, GSK, Janssen, Novartis, Pfizer, Sanofi, UCB

BackgroundToday, there are still no DMARDs licensed for primary Sjögren Syndrome (pSS) patients. Among the explanations, are the limitations of current outcome measures used as primary endpoints: e.g; high placebo response rate, evaluation of either symptoms or systemic activity, and important features not being assessed. The NECESSITY consortium (https://www.necessity-h2020.eu/), including pSS experts from academia, pharmaceutical industry and patient groups formed to develop a new composite responder index, the Sjögren’s Tool for Assessing Response (STAR) that solve the issues of current outcome measures in pSS and is intended for use in clinical trials as an efficacy endpoint.ObjectivesTo develop a composite responder index in primary Sjögren’s syndrome (pSS): the STAR.MethodsTo develop the STAR, the NECESSITY consortium used data-driven methods, based on 9 randomized controlled trials (RCTs), and consensus techniques, involving 78 experts and 20 patients. Based on reanalysis of rituximab trials (TRACTISS and TEARS) and literature review, the Delphi panel identified a core set of domains to include in the STAR, with their respective outcome measures. STAR options combining these domains were designed and proposed to the panel to select and improve them. For each STAR option, sensitivity to change was estimated by the C-index (derived from Effect size) in all 9 RCTs. Delphi rounds were run for selecting STAR among these options. The Delphi panel also voted to classify trials as positive, negative or “in between” in regards to primary but also key secondary endpoints. For the options remaining before the final vote, meta-analyses of the RCTs were performed separately for positive and “in between” trials together, and for negative trials.ResultsThe Delphi panel identified 5 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, meta-analyses of the 20 remaining options were performed. The candidate STAR was selected by a final vote based on metrological properties and clinical relevance. In positive/in between trials, candidate STAR detected a difference between arms (OR 3.29, 95%-CI [2.07;5.22], whereas it did not in negative trials (OR 1.53, 95%-CI [0.81;2.91]).ConclusionThe candidate STAR is a composite responder index, including in a single tool all main disease features, and is designed for use as a primary endpoint in pSS RCTs. Its rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity and specificity to change. The candidate STAR will be prospectively validated in a dedicated three arms RCT of the NECESSITY consortium that will evaluate combination of synthetic DMARDs (hydroxychloroquine + lefunomide or hydroxychloroquine + mycophenolate vs placebo). We encourage the use of STAR in any ongoing and future trials.Table 1.Candidate STARDomainPointDefinition of responseSystemic activity3Decrease of clinESSDAI ≥ 3Patient reported outcome3Decrease of ESSPRI ≥ 1 point or ≥ 15%Lachrymal gland function1Schirmer:If abnormal score at baseline: increase ≥ 5 mm from baselineIf normal score at baseline: no change to abnormalOrOcular Staining Score:If abnormal score at baseline: decrease ≥ 2 points from baselineIf normal score at baseline: no change to abnormalSalivary gland function1Unstimulated Whole Salivary Flow:If score > 0 at baseline: increase ≥ 25% from baselineIf score is 0 at baseline: any increase from baselineorUltrasound:Decrease ≥ 25% in total Hocevar score from baselineBiological1Serum IgG levels: decrease ≥ 10%orRheumatoid Factor levels: decrease ≥ 25%Candidate STAR responder≥ 5 pointsESSDAI: EULAR Sjögren syndrome disease activity index; ESSPRI: EULAR Sjögren syndrome patient reported index; IgG: Immunoglobulin G;AcknowledgementsNECESSITY WP5 STAR development participants: Suzanne Arends (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Francesca Barone (Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK), Albin Björk (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden), Coralie Bouillot (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Guillermo Carvajal Alegria (University of Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France; Service de Rhumatologie, Centre de Référence Maladies Autoimmunes Rares CERAINO, CHU Cavale Blanche, Brest, France), Wen-Hung Chen (GlaxoSmithKline, Research Triangle Park, North Carolina, USA), Kenneth Clark (GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom), Konstantina Delli (Department of Oral and Maxillofacial Surgery, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands), Salvatore de Vita (Rheumatology Clinic, University Hospital of Udine, Italy), Liseth de Wolff (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Jennifer Evans (Novartis Pharmaceuticals corporation USA), Stéphanie Galtier (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Saviana Gandolfo (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Mickael Guedj (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Dewi Guellec (CHU de Brest, Service de Rhumatologie, Inserm, CIC 1412, Brest, France), Safae Hamkour (Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht 3584 GA, Netherlands), Dominik Hartl (Novartis Institutes for BioMedical Research, Basel, Switzerland), Malin Jonsson (Section for Oral and Maxillofacial Radiology, Department of Clinical Dentistry, Faculty of Medicine and Dentistry, University of Bergen, Norway), Roland Jonsson (Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway), Frans Kroese (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Aike Albert Kruize (University Medical Center Utrecht, Department Rheumatology and Clinical Immunology, Utrecht, Netherlands), Laurence Laigle (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Véronique Le Guern (AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, Paris, France), Wen-Lin Luo (Department of Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, New Jersey), Esther Mossel (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Wan-Fai Ng (Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK), Gaëtane Nocturne (Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France), Marleen Nys (Global Biometric Sciences, Bristol Myers Squibb, Braine L’Alleud, Belgium), Roald Omdal (Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, PO Box 8100, 4068, Stavanger, Norway), Jacques-Olivier Pers (LBAI, UMR1227, University of Brest, Inserm, Brest, France and CHU de Brest, Brest, France), Maggy Pincemin (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Manel Ramos-Casals (Department of Autoimmune Diseases, Hospital Clinic de Barcelona Institut Clinic de Medicinai Dermatologia, Barcelona, Catalunya, Spain), Philippe Ravaud (Centre d’Epidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France), Neelanjana Ray (Global Drug Development - Immunology, Bristol Myers Squibb Company, Princeton, New Jersey, USA), Alain Saraux (HU de Brest, Service de Rhumatologie, Univ Brest, Inserm, UMR1227, Lymphocytes B et Autoimmunité, Univ Brest, Inserm, LabEx IGO, Brest, France), Athanasios Tzioufas (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Gwenny Verstappen (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Arjan Vissink, Marie Wahren-Herlenius (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden). We thank the following experts: Esen Karamursel Akpek, Alan Baer, Chiara Baldini, Elena Bartoloni, Marí-Alfonso Begona, Johan Brun, Vatinee Bunya, Laurent Chiche, Troy Daniels, Paul Emery, Robert Fox, Roberto Giacomelli, John Gonzales, John Greenspan, Robert Moots, Susumu Nishiyama, Elizabeth Price, Christophe Richez, Caroline Shiboski, Roser Solans Laque, Muthiah Srinivasan, Peter Olsson, Tsutomu Takeuchi, Frederick Vivino, Paraskevi Voulgari, Daniel Wallace, Ava Wu, Wen Zhang. We thank the anonymous patients from the NECESSITY Patient Advisory Group and the Sjögren Foundation for their valuable contribution to the Delphi process. We thank EW StClair and AN Baer who generated the baminercept data and made them publicly available.Disclosure of InterestsRaphaèle Seror Consultant of: GlaxoSmithKline, Boehringer, Janssen and Novartis, Grant/research support from: GlaxoSmithKline and Amgen, Gabriel Baron: None declared, Marine Camus: None declared, Divi Cornec Consultant of: GlaxoSmithKline, Bristol Myers Squibb, Janssen, Amgen, Pfizer and Roche, Elodie Perrodeau: None declared, Simon J. Bowman Consultant of: Abbvie, Astra Zeneca, Galapagos and Novartis Pharmaceuticals, Michele Bombardieri Consultant of: UCB, Amgen/Medimmune, Janssen, and GlaxoSmithKline, Grant/research support from: Amgen/Medimmune, Janssen, and GlaxoSmithKline, Hendrika Bootsma: None declared, Jacques-Eric Gottenberg Consultant of: AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, Sanofi, Novartis, MSD, CSL-Behring and Genzyme, Grant/research support from: Bristol Myers Squibb, Benjamin Fisher Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Novartis, Bristol Myers Squibb, Janssen and Servier, Grant/research support from: Servier, Galapagos and Janssen, Wolfgang Hueber Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Joel van Roon: None declared, Valerie Devauchelle-Pensec: None declared, Peter Gergely Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Xavier Mariette Consultant of: Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer and UCB, Grant/research support from: Ose Pharmaceuticals, Raphaël Porcher: None declared

Introduction La physiopathologie de la pseudo-polyarthrite rhizomelique (PPR) reste mal comprise et il n’y a pas de mecanisme auto-immun clairement identifie a l’heure actuelle. D’un autre cote, l’augmentation de cytokines pro-inflammatoires a ete bien decrite. Malgre cela, la classification de la PPR en tant que maladie auto-immune ou maladie inflammatoire n’est toujours pas claire. Notre objectif etait d’etudier les marqueurs inflammatoires et auto-immuns dans une population bien caracterisee de PPR debutantes. Patients et methodes Dix-huit patients avec une PPR precoce, non traites et 18 temoins sains (TS) apparies pour le sexe et l’âge ont ete inclus. Les patients faisaient partie du protocole TENOR evaluant l’efficacite du tocilizumab en ouvert. Ils ont recu 3 perfusion de tocilizumab entre l’inclusion et la semaine 12 puis des corticoides de la semaine 12 a la semaine 24. Les leucocytes, neutrophiles, plaquettes, hemoglobine, γ-globulines, IgG, IgA et IgM ont ete compares entre les patients PPR et les TS avant et apres le traitement par tocilizumab dans le groupe PPR. Un large panel d’auto-anticorps depistables en routine a ete realise chez les patients PPR et chez les TS. Resultats L’âge moyen etait de 68 ± 7 et 66 ± 11 ans, et le taux serique moyen de proteine C-reactive etait de 82 ± 16 et 5 ± 2 mg/l pour les patients PPR et les TS, respectivement. A l’inclusion, les leucocytes (p Discussion Les donnees de notre etude soulignent les consequences de l’inflammation marquee dans la PPR. Le seul element orientant vers une possible auto-immunite est l’augmentation des gammaglobulines. Toutefois, cette augmentation peut egalement se voir dans les syndromes inflammatoires marques. De plus, il n’y a pas d’autoimmunite plus marquee chez les patients PPR, en comparaison aux HC, sur un large panel d’auto-anticorps. Il est toutefois possible qu’un mecanisme auto-immun impliquant des antigenes non identifies soit a l’oeuvre dans la PPR. Le lien fort existant entre la PPR et l’arterite a cellules geantes peut faire suspecter un mecanisme auto-immune, mais il est aussi possible que la PPR soit un etat tres inflammatoire qui puisse evoluer vers une vascularite si une composante auto-immune vient s’ajouter chez certains patients. Conclusion Cette etude suggere que la PPR est plus une maladie inflammatoire qu’une maladie auto-immune. Le tocilizumab ameliore tous les marqueurs de l’inflammation. Les patients PPR presentant des γ-globulines elevees repondent plus rapidement au tocilizumab.

Introduction Les atteintes cutanees sont habituelles au cours du syndrome de Gougerot-Sjogren primitif (SSp), mais leur prevalence et leurs caracteristiques sont difficiles a etablir precisement en raison du nombre limite de patients etudies dans la plupart des cohortes, de la variabilite des signes fonctionnels et cliniques evalues dans chaque cohorte, de la rarete de certains de ces signes et de l’heterogeneite des evaluations des etudes precedentes. L’objectif principal de cette etude etait de determiner, a partir de 3 groupes francais de patients souffrant de SSp (TEARS, ASSESS, DiapSS) dans lesquels differents criteres d’evaluation ont ete utilises, la prevalence des atteintes dermatologiques, les parametres cliniques et paracliniques qui leur sont associes. Materiel et methodes Nous avons utilise les donnees de deux cohortes francaises (ASSESS, qui a evalue la prevalence des atteintes cutanes chez 395 patients atteints de SSp, et DiapSS, qui comprend 139 patients atteints du syndrome de Gougerot-Sjogren diagnostique selon les criteres ACR-EULAR de 2016 parmi 325 patients suspectes d’etre atteints du SSp) et les donnees de base de l’essai randomise TEARS (110 patients atteints de SSp recent ou actif traites par rituximab ou placebo, evalues pour la secheresse cutanee a l’aide d’une echelle visuelle analogique sur 100). Resultats Les manifestations cutanees incluses dans l’indice EULAR d’activite du syndrome de Gougerot-Sjogren (ESSDAI) etaient rares dans la cohorte ASSESS (n = 16/395, 4,1 %), mais elles etaient associees a une activite dans les autres domaines de l’ESSDAI. L’etude TEARS a montre une forte prevalence de la secheresse cutanee (EVA > 50 ; 48,2 %) et a constate que les patients ayant la peau seche presentaient des scores EVA de douleur et de secheresse globale plus eleves (p = 0,003 et p Discussion Les signes dermatologiques inclus dans l’ESSDAI sont rares. Ces atteintes cutanees actives sont associees a l’activite de l’ESSDAI dans divers domaines. Un examen systematique par un dermatologue permettrait de mieux estimer les manifestations cutanees specifiques et non specifiques du syndrome de Gougerot-Sjogren. L’atteinte cutanee la plus courante est la secheresse cutanee mais elle n’est pas incluse dans les criteres d’evaluation de la maladie. Elle devrait donc etre evaluee par une EVA specifique.

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Background:Rheumatoid arthritis (RA) is associated with an increased risk of non-Hodgkin B-cell lymphoma (B-cell NHL).Objectives:1)To study the characteristics of B-cell NHL complicating RA2)To identify the factors associated with their occurrence.Methods:A multi-centre case-control study was performed in France. Cases were patients with RA fulfilling the ACR-EULAR 2010 criteria, who developed a B-cell NHL after the diagnosis of RA. Cases were reported following a call for observations by the “Club Rhumatismes et Inflammation” network, registries from the French society of Rheumatology (AIR, ORA and REGATE) and the ESPOIR cohort. For each case, 2 control patients were drawn at random from patients in the ESPOIR cohort with RA fulfilling the ACR-EULAR 2010 criteria; cases and controls were matched on age (age at lymphoma diagnosis for cases and age at the 10-year ESPOIR visit for controls). Patients with associated Sjögren’s syndrome were excluded. Cases and controls characteristics were compared for parameters associated with the occurrence of lymphoma.Results:A total of 54 cases were included and matched to 108 controls. Lymphomas were mostly diffuse large B-cell lymphomas (n=26, 48.2%)(Figure 1). EBV positivity was found in 4 cases among 27 tested (14.8%). Cases had a mean age of 63.5 years (SD=10.9), and had a mean RA duration of 12.4 years (SD=10.5) at the time of diagnosis of lymphoma; there was no significant difference with controls (p=0.47 and p=0.40 respectively). The mean duration of follow-up after the diagnosis of lymphoma was 5.2 years (SD=5.8). In univariate analysis, factors associated with occurrence of B-cell NHL were: male gender (OR=3.3, 95%CI: 1.7-6.7), positive ACPA (OR=5.1, 95%CI: 2.0-15.7), positive Rheumatoid Factor (RF) (OR=3.9, 95%CI=1.6-12.2), erosions on X-rays (OR=15.4, 95%CI: 6.9-37.7) and DAS28 (OR=2.0, 95%CI: 1.5-2.7). Methotrexate, TNF-blockers and the number of previous biologics were not associated with the occurrence of B-cell NHL. Hydroxychloroquine and sulfasalazine were more frequent in cases versus control, which could be linked to a date bias. Erosions and DAS28 remained significant in multivariate analysis(Table 1).Conclusion:This study revealed an association between markers of activity (DAS28), severity (erosions) and autoimmune B-cell activation (RF and ACPA) and the risk of B-cell NHL in patients with RA, supporting the continuum between autoimmunity and lymphomagenesis in RA.Figure 1.lymphomas histologyTable 1.association between RA characteristics and B-cell NHL in univariate and multivariate analysisVariablesCases (N=54)Controls (N=108)Univariate analysisMultivariate analysisOR (95%CI)p-valueOR (95%CI)p-valueMale gender, N (%)27 (50.0)25 (23.2)3.3(1.7-6.7)0.00062.2(0.8-6.1)0.13Positive ACPA, N (%)49 (90.7)71 (65.7)5.1(2.0-15.7)0.0006--Positive RF, N (%)49 (90.7)77 (71.3)3.9(1.6-12.2)0.005--Positive RF or ACPA, N (%)49 (90.7)80 (74.1)3.4(1.3-10.6)0.012.9(0.7-15.0)0.16Erosions on X-rays, N (%)44 (81.5)26 (24.1)15.4(6.9-37.7)< 0.00019.8(3.8-28.2)< 0.0001DAS28 at B-cell NHL diagnosis/at the 10th year visit*, mean(SD)4.1 (1.6)2.6 (1.4)2.0(1.5-2.7)< 0.00011.9(1.3-2.8)0.0007*B-cell NHL diagnosis for cases, 10thyear visit for controlsDisclosure of Interests:Joanna KEDRA: None declared, Raphaèle Seror Consultant of: BMS UCB Pfizer Roche, Philippe Dieudé: None declared, Arnaud Constantin: None declared, ERIC TOUSSIROT: None declared, Elias Kfoury: None declared, Charles Masson: None declared, Divi Cornec: None declared, Jean-Jacques Dubost: None declared, Laurent Marguerie: None declared, Sebastien Ottaviani: None declared, Franck Grados: None declared, Rakiba Belkhir: None declared, olivier fain: None declared, Philippe Goupille Grant/research support from: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Consultant of: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Speakers bureau: AbbVie, Amgen, Biogen, BMS, Celgene, Chugai, Lilly, Janssen, Medac, MSD France, Nordic Pharma, Novartis, Pfizer, Sanofi and UCB, Christelle Sordet: None declared, Bruno Fautrel Grant/research support from: AbbVie, Lilly, MSD, Pfizer, Consultant of: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Lilly, Janssen, Medac MSD France, Nordic Pharma, Novartis, Pfizer, Roche, Sanofi Aventis, SOBI and UCB, Peggy Philippe: None declared, Muriel PIPERNO: None declared, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Olivier Lambotte Consultant of: BMS France, MSD, Astra Zeneca, Incyte, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Jérémie SELLAM: None declared, Thomas Sene: None declared, Guillaume Denis: None declared, Thierry Lequerre: None declared, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB, Gaetane Nocturne: None declared

BackgroundIn schizophrenia, sleep spindles are reduced, supporting the hypothesis that the thalamus and glutamate receptors play a crucial etio-pathophysiological role, whose underlying mechanisms remain unknown. We hypothesized that a reduced function of NMDA receptors is involved in the psychosis-related spindle deficit.MethodsAn electrophysiological multisite cell-to-network exploration was used to investigate, in sleeping rats, the effects of a ketamine-induced psychosis-relevant transition state in the sensorimotor and associative/cognitive thalamocortical (TC) systems.ResultsUnder the control condition, spontaneously-occurring spindles (intra-frequency: 10-16 waves/s) and delta-frequency (1-4Hz) oscillations were recorded in the EEG of the frontoparietal cortex, in thalamic extracellular recordings (n=16), in dual juxtacellularly recorded GABAergic thalamic reticular nucleus (TRN) and glutamatergic TC neurons (n=8), and in intracellularly recorded TC neurons (n=8). The TRN cells rhythmically exhibited robust high-frequency bursts of action potentials (7 to 15 APs at 200-700 Hz). A single administration of low-dose ketamine fleetingly reduced TC spindles and delta oscillations, amplified ongoing gamma-(30-80Hz) and higher-frequency oscillations, and switched the firing pattern of both TC and TRN neurons from a burst mode to a single AP mode. Furthermore, ketamine strengthened the gamma-frequency band TRN-TC connectivity (n=11). The antipsychotic clozapine consistently prevented the ketamine effects on spindles, delta- and gamma-/higher-frequency TC oscillations (n=7).ConclusionThe present findings support the hypothesis that NMDA receptor hypofunction is involved in the psychosis-related reduction in sleep spindles and delta oscillations. The ketamine-induced swift conversion (from burst to single APs) of ongoing TC-TRN activities may have involved both the ascending reticular activating system and the corticothalamic pathway.LAY ABSTRACTSchizophrenia is a chronic debilitating disease. Sleep disturbances associated with a reduction in spindles are observed as warning signs prior to the first psychotic episode. Every spindle is a short-lasting (~0.5 s) set of bioelectric sinusoidal waves at the frequency of 10-16 Hz generated within the thalamus. Sleep spindles, easily identifiable in a scalp electroencephalogram, occur hundreds of times during sleep and are implicated in cognition like memory processes. For this reason, spindles are seen as an electro-biomarker of the quality of sleep and cognitive performance. In patients at high risk of psychotic transition, the density (number/time unit) of spindles is reduced. The underlying mechanisms of this change are unknown. Glutamate-mediated neurotransmission in the thalamus plays a key role in the generation of spindles and the etiology of schizophrenia. Therefore, we tested the hypothesis that a reduced function of glutamate receptors at the thalamic level is involved in the psychosis-related reduction in spindles. Using cell-to-network neurophysiological methods in sleeping rats, we demonstrate that systemic administration of the NMDA glutamate receptor antagonist, ketamine, significantly decreases spindle density. This effect is consistently prevented by the widely used antipsychotic drug, clozapine. These original findings support the hypothesis of the involvement of a reduced function of NMDA glutamate receptors in the sleep spindle deficit observed in psychosis-related disorders. The present findings lay the foundation for the development of innovative therapies aimed at preventing psychotic, bipolar, and depressive disorders.HIGHLIGHTSLow-dose ketamine has a fast onset arousal promoting effect.Ketamine fleetingly reduces, in the first-/higher-order thalamocortical systems, sleep spindles and slow-waves, and amplifies gamma- and higher-frequency oscillations.Ketamine switches the firing pattern from a burst mode to a single action potential mode in both the glutamatergic thalamocortical neurons and the GABAergic thalamic reticular nucleus neurons.Ketamine strengthens the gamma-frequency band connectivity between thalamocortical and thalamic reticular nucleus neurons.The reference antipsychotic clozapine consistently prevents the ketamine effects.

Background:The analysis of annotated transcripts from genome-wide expression studies data is of paramount importance to understand the molecular phenomena underlying the occurrence of complex diseases, such as systemic sclerosis (SSc).Objectives:To perform whole-blood transcriptome and pathway analysis on whole-blood (WB) RNA collected in two cohorts of European SSc patients. Via a discovery and validation strategy we aimed at characterizing the molecular pathways that differentiate SSc from controls and that are reproducible in geographically diverse populations.Methods:WB samples from 252 controls and 162 SSc patients were collected in RNA stabilizers. Patients were divided into a discovery (n=79; Southern Europe) and validation cohort (n=83; Central-Western Europe). RNA sequencing was performed by an Illumina assay. Functional annotations of Reactome pathways were performed with the FAIME algorithm. In parallel, a immunophenotyping analysis on 28 circulating cell populations was assessed. We then tested: the presence of differentially expressed genes or pathways and the correlation between absolute cell counts and RNA transcripts/FAIME scores in regression models. Results significant in both populations were considered as replicated.Results:A total of 15224 genes and 1277 related functional pathways were available for analysis. Among these, 99 genes and 225 pathways were significant in both sets. The heatmap in figure shows the relative expression of replicated pathways and the distribution of cases and controls (red and green bars). Among the significant pathways we found a deregulation in: type-I IFN, TLR-cascade and signalling, function of the tumor suppressor p53 protein, platelet degranulation and activation. Correlation analysis showed that the count of several cell subtypes is jointly associated with RNA transcripts or FAIME scores with strong differences in relation to the geographical origin of samples; neutrophils emerged as the major determinant of gene expression in SSc-whole-blood samples.Conclusion:We discovered a set of differentially expressed genes and pathways that could be validated in two independent sets of SSc patients highlighting a number of deregulated molecular processes that have relevance for the pathogenesis of autoimmunity and SSc.Acknowledgments:This work was supported by EU/EFPIA/Innovative Medicines Initiative Joint Undertaking PRECISESADS grant No. 115565.Disclosure of Interests:Lorenzo Beretta Grant/research support from: Pfizer, Guillermo Barturen: None declared, Barbara Vigone: None declared, Chiara Bellocchi: None declared, Nicolas Hunzelmann: None declared, Ellen Delanghe: None declared, László Kovács: None declared, Ricard Cervera: None declared, Maria Gerosa: None declared, Rafaela Ortega Castro: None declared, Isabel Almeida: None declared, Divi Cornec: None declared, Carlo Chizzolini Consultant of: Boehringer Ingelheim, Roche, Jacques-Olivier Pers: None declared, Zuzanna Makowska Employee of: Bayer AG, Anne buttgereit Employee of: Bayer AG, Ralf Lesche Employee of: Bayer, Martin Kerick: None declared, Marta Alarcon-Riquelme: None declared, Javier Martin Ibanez: None declared

Background:Cutaneous involvement is common during primary Sjogren’s Syndrome (pSS) but prevalence and characteristics are difficult to establish precisely because of the limited number of patients studied in most cohorts, the variability of the disorders evaluated in each cohort, the rarity of some of them, and the heterogeneity of evaluations from previous studies (1).Objectives:To determine the prevalence and significance of dermatological disorders in primary Sjogren Syndrome.Methods:We use 2 French cohorts (ASSESS, in which prevalence of skin disorders in 395 pSS patients was evaluated, and diapSS in which 91 consecutive 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 out of 100).Results:Skin manifestations included in the ESSDAI were rare in the ASSESS cohort (n=16/395, 4.1%, mainly purpuras; only 3 had high activity) but associated with activity in the other ESSDAI domains (peripheral neurological (p50; 48.2%) and that these dry skin patients had higher pain VAS (61.5+/-28.2 vs 46.8+/-27.0; p=0.003) and drought (79.4+/-15.2 vs 62.5+/-21.7; pCutaneous involvementNo Cutaneous involvementTotalp values*Muscular3/16 (18.8)10/373 (2.7)13/389 (3.3)0.001Peripheral nervous system PNS4/16 (25)34/373 (9.1)38/389 (9.8)0.00001Biological8/16 (50)138/371 (37.2)146/387 (37.7)0.017Hematologic7/16 (43.8)55/373 (14.7)62/389 (15.9)0.017History of arthritis12/16 (75)154/374 (41.2)166/390 (42.6)0.008History of splenomegaly2/16 (12.5)10/3762.7)12/392 (3.1)0.024History of lymphoma0/16 (0)18/379 (4.7)18/395 (4.6)0.372Mean (SD) ESSDAI score14.5 (6.8)4.4 (5.1)0.00001Mean (SD) ESSDAI score after excluding the points awarded by skin manifestations8.1 (6.2)4.4 (5.1)0.014Gammaglobulin levels (mean +/- SD)23.1 +/-7.318.5 +/-8.1-0.006Conclusion:The most common skin disorder is dryness, which is associated with a higher level of pain and overall subjective dryness. ESSDAI skin activity is rare, associated with hypergammaglobulinemia and ESSDAI activity. Systematic dermatological examination is informative for non-specific pSS lesionsReferences:[1]Orgeolet L, Foulquier N, Misery L, Redou P, Pers J-O, Devauchelle-Pensec V, et al. Can artificial intelligence replace manual search for systematic literature? Review on cutaneous manifestations in primary Sjögren’s syndrome. Rheumatol Oxf Engl. 2019 Aug 31;Disclosure of Interests:Camille Villon: None declared, Laure Orgeolet: None declared, Anne-Marie Roguedas-Contios: None declared, Laurent Misery: None declared, Jacques-Eric Gottenberg Grant/research support from: BMS, Pfizer, Consultant of: BMS, Sanofi-Genzyme, UCB, Speakers bureau: Abbvie, Eli Lilly and Co., Roche, Sanofi-Genzyme, UCB, Divi Cornec: None declared, Sandrine Jousse-Joulin: None declared, Raphaèle Seror Consultant of: BMS UCB Pfizer Roche, Jean-Marie Berthelot: None declared, Philippe Dieudé: None declared, Jean-Jacques Dubost: None declared, anne-laure Fauchais: None declared, Vincent Goeb: None declared, Eric Hachlla: None declared, Pierre-Yves Hatron: None declared, Claire Larroche: None declared, Gilles Hayem: None declared, Véronique LE GUERN Grant/research support from: UCB for GR2 study (to our institution), Aleth Perdriger: None declared, Jacques Morel: None declared, Olivier VITTECOQ: None declared, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB, Valerie Devauchelle-Pensec: None declared, alain saraux: None declared

Background Myositis prevalence in primary Sjogren’s syndrome (pSS) and whether it is associated with peculiar extra-muscular involvement and/or a biological profile is unknown. Objectives To refine prevalence and characteristics of patients with pSS and myositis. Methods In the national multicenter prospective cohort ASSESS (395 patients with pSS with a 5 year-prospective follow-up), patients with suspected myositis were identified. Their charts were reviewed and the patients were compared with the rest of the cohort. Results Myositis was suspected in 38 patients (2 men, 36 women, 5829–78 yr old) because of myalgia and/or exercise intolerance (n=38) along with high blood CK level (n=28). As compared with the rest of the cohort, they had higher patient-reported signs including pain VAS, dryness VAS and patient reported index ESSPRI (6.3 vs 5.3, p=0.007). In contrast, proportion of systemic involvements (76.3% vs 70.9%, p=0.57) and systemic disease activity measured by the ESSDAI, without taking the muscular domain into account (2 vs 3, p=0.93), were not different from patients without suspected myositis. Demographic characteristics and disease duration were also similar. Electromyographic recording and/or muscle histology performed in these 38 patients objective muscular involvement in only 4 patients (1% of the cohort). - Three patients were diagnosed with inclusion body myositis (sIBM). Accordingly, age at first sign was 49 years,49–60 muscle disease had progressive onset as suggested by the 11 years1–28 delay between first muscle sign and diagnosis. CK level was - One pSS patient with myositis was a 39 years old woman with polymyositis. She developed proximal muscle weakness, CK was 750UI/L and muscle biopsy found endomysial infiltrate. Muscle force and CK level normalised with immunomodulatory drugs. Compared to the rest of the cohort, patient with myositis had longer disease duration at inclusion (15 vs 5 year, p=0.01) and tended to be younger at pSS diagnosis (41.5 vs 53 year, p=0.07). They had more frequent history of systemic manifestations (100% vs 65.0%, p=0.011) but ESSDAI at baseline (2 vs 3, p=0.56) and the biological characteristics were not different from patients without myositis. In contrast with the patients with suspected but not confirmed myositis, patient-reported signs (i.e. fatigue, pain, dryness and ESSPRI score) were similar to patients without myositis. Conclusions Myositis is frequently suspected in patients with pSS, especially when patients-reported signs are particularly disabling. Myositis occurs very infrequently (1% of the cohort), in patients with longer disease duration. sIBM was the most predominant subset of myositis in the present study. Disclosure of Interest None declared

Background In everyday practice, myofascial lesions are not usually evaluated on MRIs obtained for patients with PMR. Objectives To assess the prevalence of myofascial inflammatory lesions visible by magnetic resonance imaging (MRI) and their changes after tocilizumab therapy in active polymyalgia rheumatica (PMR). Methods We conducted a post hoc analysis of data from the TENOR study of tocilizumab monotherapy in PMR.1 The 18 patients each received tocilizumab injections at weeks 0, 4, and 8. The shoulder and pelvic girdles were assessed at baseline then at weeks 2 and 12 using T1- and T2-STIR-weighted MRI. Radiologists blinded to patient data assessed each muscle group for myositis and fasciitis on baseline, week-2, and week-12 MRIs. Reproducibility was estimated by having two radiologists assess the week-2 MRIs of 13 patients then computing the kappa coefficient. Results For myofascial lesion detection, intraobserver reproducibility was almost perfect (κ=0.890) and interobserver reproducibility was substantial (κ=0.758). At baseline, all patients had at least one inflammatory myofascial lesion (example on right shoulder fig 1); sites involved were the shoulder in 10 (71.4%) patients, hip in 13 (86.7%), ischial tuberosity in 9 (60.0%), and pubic symphysis in 12 (80.0%). Sites involved at week 12 were the shoulder in 8 (53.3%) patients, hip in 5 (33.3%), ischial tuberosity in 1, and pubic symphysis in 3 (20.0%). At week 12, of 103 muscle groups studied in all, 43 (41.7%) had no inflammatory lesions, compared to 33 at baseline (Mac Nemar; p Conclusions Myositis and fasciitis are common in recent-onset PMR and improve during tocilizumab therapy. They could be used for the diagnosis in routine practice and as criteria of outcome evaluation. References [1] Devauchelle-Pensec V, Berthelot JM, Cornec D, Renaudineau Y, Marhadour T, Jousse-Joulin S, et al. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann Rheum Dis2016;75:1506–1510. Disclosure of Interest J. P. Laporte: None declared, F. Garrigues: None declared, A. Huwart: None declared, S. Jousse-Joulin: None declared, T. Marhadour: None declared, D. Guellec: None declared, D. Cornec: None declared, V. Devauchelle-Pensec: None declared, A. Saraux Grant/research support from: Chugai, Speakers bureau: Chugai

Background Technological advances have improved phenotypical characterisation of blood cells, and flow cytometry is currently used in haematology, infectious disease, systemic auto-immune diseases. Abnormalities of blood B cell subset profile might provide a useful diagnostic tool in systemic auto-immune diseases, especially for primary Sjogren’s Syndrome1 in which the activated B cells to memory B cells ratio is increased. Nevertheless, we observed that some patients suffering from chronic infection had lymphocytes disturbances similar to those observed in primary Sjogren’s Syndrome. Objectives Whipple’disease (WD) is a rare, systemic, disease caused by intracellular gram positive bacterium, Tropheryma Whipplei (TW). No previous study evaluated the role of B cells in WD. The aim of this study was to analyse whether the circulating blood B cell subset disturbances is characteristic of WD. Methods We collected characteristics of all patients coming for inflammatory rheumatism in our rheumatology department between April 2010 and December 2016. All of them had systematically routine examination, immunological tests, lymphocyte subsets in peripheral blood by flow cytometric analysis. We selected among this population those patients who also had PCR for TW for suspicion of WD, and compared the distribution of lymphocyte subsets of those with and without WD. Then, we evaluated their diagnostic value for WD using a ROC curve. Results Among 3494 patients with inflammatory rheumatism, 121 patients (212 visits) had a suspicion of WD and the diagnosis of WD was retained by an expert rheumatologist for 9 (7.4%) (22 visits). T cells and NK cells were not different whereas percentage of circulating memory B cells (IgD-CD38low) was lower (18.0%±9.7% vs 26.0±14.2%, p=0.041) and the ratio of activated B cells to memory B cells higher (4.4±2.0 vs 2.9±2.2, p=0.023), in patients compared with controls. More precisely, the analysis of the frequency of peripheral blood B cells showed that IgD +CD27 – naive B cells were higher (66.2%±18.2% vs 54.6±18.4%, p=0.047) and IgD-CD27 +switched memory B cells lower (13.3%±5.7% vs 21.4±11.9%, p=0.023), in patients compared with the controls. The best diagnostic value was obtained for the IgD +CD27- naive B cells (cut off 70.5, sensitivity 73%, specificity 80%). Conclusions Our study provides data on blood B cells disturbances and a first step towards understandings of immunological abnormalities in WD. These disturbances provide guidance for diagnosis and allow physiopathological hypothesis. Reference [1] Binard A, Le Pottier L, Devauchelle-Pensec V, Saraux A, Youinou P, Pers J-O. Is the blood B-cell subset profile diagnostic for Sjogren syndrome?Ann Rheum Dis2009;68(9):1447–52. Disclosure of Interest None declared

Background Abatacept is a CD152 agonist known to inhibit T cell proliferation but recent data suggest that it could act directly on B cells.1–2 Objectives To demonstrate the effect of Abatacept (versus IgG control) on regulatory functions of B cells on T cell proliferation in an established in vitro co-culture model. To evaluate its role, in vivo, by measuring the regulatory functions of B cells from rheumatoid arthritis patients before and after the Abatacept treatment. Methods Peripheral and tonsilar T cell and B cell from healthy controls were purified. The biotinylation of Abatacept was used to study its binding on T and B cells by flow cytometry and confocal microscopy. A well-established co-culture model between CpG-stimulated B cells and anti-CD3/anti-CD28 stimulated T cells was set up in which Abatacept or an IgG control was added to evaluate any change in B cell regulatory functions. Activation markers (e.g. CD25, CD69, CD40, CD152) and regulation markers (e.g. FoxP3, TGF-β) were assessed by flow cytometry. Similar analysis were also performed on rheumatoid arthritis patients before and three months after Abatacept therapy. All patients gave their informed consent. Results Abatacept increases the inhibition of T cell proliferation by B cells compared to IgG control in the co-culture model (p=0.03). Interestingly, alone, Abatacept does not modify T cell proliferation. This can be explained by the increase in IL-10 and TGF-β producing B cells and the CD152 expression. Abatacept is able to bind B cells at day 0 of co-culture and B and T cells at day 4.5 of co-culture. Abatacept has a direct effect on B cells by increasing the CD25 (p=0.03) and CD152 expression (p=0.02) reflecting a higher activation level. Nevertheless, Abatacept had no direct effect on B cell proliferation. In RA patients, the treatment with Abatacept resulted in an increased regulation of T cell proliferation and this effect is related to a higher percentage of IL-10 secreting B cells 3 months after the therapy (p=0.03). Conclusions In our in vitro and in vivo models, Abatacept has a direct effect on B cells leading to an increase capability of regulation of T cell proliferation which directly linked to higher production of IL-10 and TGFβ. References [1] Gazeau, et al. Rheumatology (Oxford)2016Jun;55(6):1138–40. [2] Carvajal Alegria, et al. Ann Rheum Dis2016Nov;75(11):e73. Disclosure of Interest None declared

Background While extensive studies have been performed to characterize ANCA, little is known about the auto-reactive B cells that produce these autoantibodies. Indirect evidence previously suggested the presence of circulating PR3-specific B cells in patients with PR3-ANCA-associated vasculitis (AAV). Objectives To develop a method to detect circulating PR3-specific B cells in patients with PR3-AAV, to study their proportion among the different B-cell subsets and to assess their relationship with disease activity. Methods An enzymatically inactive, conformationally mature, recombinant PR3 (rPR3) was tagged using FITC or biotin. To study the ability of this rPR3 to bind specifically to cells expressing PR3-specific immunoglobulins on their surface, we used two hybridoma cell lines, MCPR3–2 (producing an anti-human PR3 monoclonal antibody) and MCPR3–13 (producing an anti-mouse PR3 monoclonal antibody, with no cross-reactivity with human PR3). We measured the proportion of PR3-FITC positive B cells among PBMCs in 13 patients with PR3-AAV and 14 healthy controls (HCs) by flow cytometry. We then developed a multi-color flow cytometry including CD19, IgD, CD27, CD38, CD24 and biotinylated rPR3 to measure the proportion of PR3-specific B cells among different B-cell subsets in an independent group of 13 patients with PR3-AAV and 11 HCs. Results rPR3 efficiently bound MCPR3–2 hybridoma cells but not MCPR3–13. Specificity of the staining was confirmed by competition experiments: pre-incubation of MCPR3–2 cells with untagged human rPR3 totally abrogated rPR3-FITC staining, whereas pre-incubation with mouse rPR3 had no effect. Dose-ranging experiments defined the optimal concentration of rPR3 to stain cells expressing anti-PR3 immunoglobulin. The mean (SEM) proportion of rPR3-FITC-stained B cells was higher in patients with PR3-AAV compared to HCs: 2.10% (2.33) vs 0.45% (0.19) respectively, p Conclusions This study describes an original method to detect and study circulating auto-reactive B cells in patients with PR3-AAV, and suggests that PR3-specific B cells are associated with disease activity and may represent a promising biomarker to predict relapse risk in patients in clinical remission. The progressive enrichment in PR3-specific B cells during the B-cell maturation steps in patients suggest that auto-reactive B cells are actively selected and escape peripheral tolerance checkpoints. Disclosure of Interest None declared

Background New consensual classification criteria for primary Sjogren9s syndrome (pSS) have been recently developed and endorsed by ACR and EULAR. They differ substantially from previously used AECG criteria in that they consider systemic involvement (defined as ESSDAI score ≥1) as well as sicca symptoms as entry criteria before applying a weighted score. Evaluation of the concordance and differences between the two sets of criteria in independent patient populations is mandatory to establish how future clinical studies using the new criteria will be comparable to previously published studies. Major salivary gland ultrasonography (SGUS) has demonstrated promising diagnostic performance in previous studies, but was not included in these new classification criteria. Methods This cross-sectional study was conducted in the monocentric Brittany cohort (DIApSS cohort) of patients with suspected pSS (sicca symptoms, parotidomegaly or extraglandular manifestations suggestive of pSS). All patients had standardized clinical examination, basic biology, immunological tests and minor labial salivary gland biopsy. SGUS in mode B was performed by the same experienced operator, who was blinded to the diagnosis. Agreement between the two sets of criteria was assessed using Cohen9s κ coefficient and the characteristics of discordant patients were detailed. Results 290 patients were prospectively included between 2006 and 2016. Mean age was 55.6±13.2 years, 92.1% were female and mean duration of the symptoms 6.0±6.6 years. More patients fulfilled ACR/EULAR criteria (n=125, 43.1%) than AECG criteria (n=114, 39.3%). 114 patients (39.3%) fulfilled both criteria, 11 (3.8%) fulfilled ACR/EULAR only, 0 AECG only and 165 (56.9%) none of the criteria. Concordance between both criteria was good (kappa=0.9). Compared to patients fulfilling both criteria, patients fulfilling ACR/EULAR but not AECG criteria (n=11) had similar age, similar symptom duration, but less frequent sicca symptoms (eye dryness 18.2% versus 96.5%; mouth dryness 54.5% versus 97.4%, p Conclusions Agreement between AECG criteria and new ACR/EULAR criteria is good suggesting that they select quite similar patients. ACR/EULAR criteria display a slightly higher sensitivity and are able to detect more patients with systemic involvement, but some of these patients did not have pSS according to the physician diagnosis. As previously demonstrated for AECG criteria, SGUS inclusion into ACR/EULAR criteria may further enhance their sensitivity. Disclosure of Interest None declared

Background The ultrasonography of salivary glands (USSG) has proved its utility in diagnosing and following primary Sjogren patient9s (pSS) (1,2). The evaluation of disease activity is still of interest and can be studied by assessing the inflammatory status of SG using US Doppler. Objectives To evaluate the vascularization of salivary glands, and particularly the parotid gland (PG) using Pulsed Doppler color ultrasonography (USSGPD) in patients complaining of xerostomia before and after treatment by pilocarpine. Methods We prospectively included patients with objective dry mouth syndrome (using salivary flow rate) at Brest University Hospital (DiapSS cohort). The vascularization was assessed by the resistive index (RI) at the left parotid. Only patients with pathological RI ( Results Among the 19 patients included, 11 received pilocarpine treatment for the whole 3 months period, 6 of the 8 remaining patients stopped the pilocarpine due to side effects. Among the 11 patients with a follow-up evaluation at 3 months, 5 had pSS according to AECG criteria. The differences of RI before and after lemon stimulation were on average of -0.04 at baseline and -0.04 at M3. The sum of ultrasound9s grades average of the four glands was 3.47 at M0 and 4.18 at M3. The non-simulated salivary flow was on average of 1.96 mL/mn at M0 and 5.23 mL/mn at M3, whereas the average of stimulated salivary flow was 2.84 mL/mn at M0 and 8.51 mL/mn at M3. None of these observed differences were statistically significant before and after 3 months of treatment by Pilocarpine: RI before and after lemon stimulation (p=0.953), the sum of the four glands9 grades (p=0.858), the non-stimulated (p=0.26) and stimulated salivary flow (p=0.139). Concerning the 3 patients with Sjogren9s syndrome, there was no differences using RI before and after treatment but the RI was lower in this subgroup compared to the xerostomia patients.The study was marked by a large number of pilocarpine9s discontinuation (31%) due to adverse effects. Conclusions Preliminary results showed no significant differences between the 4 gland9s grade, ultrasound9s RI and salivary non and stimulated flow before and after three months of pilocarpine9s treatment. The vascularisation of salivary glands could be an opportunity to follow our treated patients with Sjogren9s syndrome or with xerostomia but more studies are needed to prove the interest of this procedure. References Cornec D, et al. Contribution of salivary gland ultrasonography to the diagnosis of Sjogren9s syndrome: toward new diagnostic criteria? Arthritis Rheum. 2013 Jan;65(1):216–25. Jousse-Joulin S et al. Brief Report: Ultrasonographic Assessment of Salivary Gland Response to Rituximab in Primary Sjogren9s Syndrome. Arthritis Rheumatol. 2015 Jun;67(6):1623–8. Acknowledgements We thank the Professor luc Bressollette and Muriel Korpet for their contribution in the study. Disclosure of Interest None declared

International audience; Considering the implications of B, T, and natural killer (NK) cells in the pathophysiology of systemic autoimmune diseases, the assessment of their distribution in the blood could be helpful for physicians in the complex process of determining a precise diagnosis. In primary Sjögren's syndrome, transitional and active naive B cells are increased and memory B cells are decreased compared to healthy controls and other systemic diseases. However, their utility to improve the accuracy of classification criteria has not been proven. In early untreated rheumatoid arthritis, proportions of regulatory T cells are constantly reduced, but other patterns are difficult to determine given the heterogeneity of published studies. In systemic lupus erythematosus, the lack of studies using large cohorts of patients and the diversity of the possible pathological mechanisms involved are also important impediments. Nevertheless, transitional B cell and plasma cell proportions are increased in most of the studies, the CD4/CD8 ratio is decreased, and the number of NK cells is reduced. Despite the low number of studies, anomalies of lymphocyte subset distribution was also described in ANCA-associated vasculitis, systemic scleroderma, and myositis. For now, flow cytometric analysis of lymphocyte subsets has focused mainly on specific subpopulations and is more useful for basic and translational research than for diagnostics in clinical practice. However, new modern methods such as mass cytometry and bioinformatics analyses may offer the possibility to simultaneously account for the relative proportions of multiple lymphocyte subsets and define a global profile in homogeneous groups of patients. The years to come will certainly incorporate such global lymphocyte profiling in reclassification of systemic autoimmune diseases.

International audience

To define parameters predictive of lymphoma development in patients with primary Sjögren's syndrome (SS).A multicenter case-control survey was performed to identify predictors of lymphoma. Cases were patients who developed lymphoma after diagnosis of primary SS and were mainly recruited through the Club Rhumatismes et Inflammation network. For each case, 2 controls (matched for disease duration and age) were randomly selected among patients with primary SS and without lymphoma. Cases and controls were compared using univariate analysis and then using multivariate analysis to identify independent predictors of lymphoma.One hundred one patients with primary SS and lymphoma were included. Eighty-seven patients were women (86.1%), and the mean ± SD age at lymphoma diagnosis was 57.4 ± 12.6 years. The most frequent histologic type was B cell non-Hodgkin's lymphoma (NHL) in 99 of 101 patients, with marginal-zone lymphoma in 76 of the 99 patients (76.8%) including 58 (58.6%) with lymphoma of the mucosa-associated lymphoid tissue type. Lymphomas were most frequently located in the salivary glands (43 patients). A specific treatment was initiated at diagnosis in 87 patients with B cell NHL, and 61 patients (61.6%) achieved complete sustained remission after the first line of treatment. In the multivariate analysis, salivary gland enlargement, the presence of rheumatoid factor (RF), low C4, cryoglobulinemia, lymphopenia, and disease activity according to the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (excluding the lymphoma domain) were found to be predictors of lymphoma. No previous treatment for primary SS was associated with any effect on lymphoma occurrence.In addition to previously known factors predictive of lymphoma occurrence, the independent roles of RF and disease activity were demonstrated in this case-control study of primary SS-associated lymphoma. Our findings highlight the roles of chronic antigenic stimulation and disease activity in the development of this severe complication.

International audience; BACKGROUND AND OBJECTIVES: The immunosuppressive function of regulatory B cells (Breg) is defective in B cells from systemic lupus erythematosus (SLE) patients. Since the Ca(2+) pathway is also altered in SLE B cells, the aim of the study was to explore the contribution of the Ca(2+) channel Orai1 and its regulator, the stromal interaction molecule 1 (STIM1), on regulatory B cell functions. MATERIALS AND METHODS: Thirty SLE patients and healthy controls (HC) were included in the study. Orai1 and STIM1 expressions were explored in CD40/CpG activated B cells, and in the stimulated (anti-CD3, anti-CD28 plus CpG-ODN 2006) T- and B- cell autologous co-culture Breg model. Transfection were used using either siRNAs to down-modulate STIM1 in SLE B cells, or either the cDNA STIM1 vector in HC B cells. RESULTS: After 3 days, in CD40/CpG activated HC B cells, and in HC B cells stimulated during co-cultures, acquisition of the Breg phenotype (IgD/CD38/CD24/CD5(high)) was associated with an over-expression of the Ca(2+) regulator STIM1 (x10.8 and x7.1 fold increase respectively). At day 4 and even more at day 5, STIM1 expression declined in co-cultures and this down-regulation was accompanied with IL-10 and TGF-beta up-regulation in B cells, FoxP3(+) regulatory T cell expansion, and a reduction of T cell proliferation. Expression of the Ca(2+) channel Orai1 was stable. In SLE B cells, STIM1 expression was overexpressed at basal level when compared to HC B cells (x4.3 fold) and remains elevated in B cells during all the time of the autologous co-culture (x8.8 fold). Then we hypothesised that maintaining high levels of STIM1 was critic in the regulatory capacity of SLE B cells. Accordingly, we demonstrated that STIM1 downregulation in SLE B cells, using a specific siRNA, was effective to restore IL-10, but not TGF-beta, expression, FoxP3(+) regulatory SLE T cell expansion, and SLE T cell inhibition. In HC B cells, forcing STIM1 expression, with a STIM1 vector, was effective to reproduce the abnormalities observed in SLE B cells. No association was observed between STIM1 expression at basal level and organ involvement, disease activity (SLEDAI), or serological parameters thus suggesting that STIM1 over-expression and Ca(2+) dysregulations are primary events in SLE. CONCLUSIONS: Altogether, this study reveals that acquisition of the Breg phenotype and Breg functions are tightly regulated by STIM1. Furthermore, this observation could provide innovative B-cell based treatment to convert B cells into immunosuppressive cells with applications in human autoimmunity and in SLE. KEY WORDS: lupus, regulatory B cells, calcium, STIM1, IL-10.

Background Although allopurinol reminds the first urate lowering therapy (ULT), its limited dosage in gouty patients with stage 4 or 5 chronic kidney disease (CKD 4/5) prevents to achieve serum uric acid (sUA) level target ( Methods In this retrospective 9 multicenter study, clinical records of all gouty patients with estimated glomerular filtration rate (eGRF) ≤30 ml/min/1.73 m 2 (MDRD formula) at febuxostat initiation and at least 3 month-long follow-up period were selected. Items to collect (demographic data, co-morbidity, renal disease, gout history and former treatments, increasing serum urate drugs, laboratory data and any adverse effects-AEs) were approved by all participant centers. Analysis variables were: sUA level at initiation and last available sUA level; variation of eGFR; the percentage of patients who achieved sUA level Results Seventy-three gouty patients (mean age 70.19 ± 11.84, 61 men) from 9 french different rheumatology and nephrology departments were included. 31 patients (41.47%) suffered from vascular CKD and 18 patients (24.66%) had had renal transplant. Mean duration of gout was 6 years. 32 patients (43.48%) had tophi, 28 (38.36%) gout arthropathies. Diuretics were used in 57 patients (78.08%). Cardiac dysfunction was present in 9 patients (16.4%). 72 patients had hypertension, 22 diabetes melitus, 48 dyslipidemia, 28 (38.36%) had past history of vascular events (stroke, heart infraction). Mean sUA level and eGFR at febuxostat initiation were 98.6 ± 28.5 mg/L and 21.5 ± 6.2 ml/min (6–30ml/min), respectively. Febuxostat initiation dosage was 80 mg daily for 47 patients (68.12%), 80mg every 2 days for 17 patients (24.64%) and 120 mg daily for 5 patients (7.25%). At the last visit (mean follow-up was 68.4 weeks (12–260)) mean sUA level was 50.5 mg/L ± 23.3. Forty-seven patients (64.38%) achieved sUA level target Conclusions Febuxostat appears efficient in gouty patents with stage 4/5 CKD or renal transplants. However, safety data is not clear regarding renal function. Further studies with larger sample are warrant to assess this point. Disclosure of Interest None declared

Background Abnormalities in B-cell population distribution were recently reported in polymyalgia rheumatica (PMR), which improved with glucocorticoids. Data about cytokine involvement in PMR pathophysiology are scarce and contradictory. Objectives Our objective was to analyze the subsets of lymphocytes and level of cytokines in patients with PMR and to follow their evolution after tocilizumab treatment. Methods The TENOR study [Clinicaltrials.gov (NCT01713842)] was an open labeled prospective trial including patients with recent PMR fulfilling the Chuang criteria. Patients had active disease and were glucocorticoids (GCs) free. Patients with suspected giant cell arteritis were excluded. Patients were treated with tocilizumab infusions (week 0, 4 and 8) without GCs (period 1) and then by low-dose GCs from week 12 to week 24 (period 2). Peripheral blood lymphocyte profiling was performed by multicolor flow cytometry in 18 patients at week (W) 0 (before first tocilizumab infusion), W2, W12 and W24. Cytokine levels were estimated using membrane cytokine array enabling detection of 34 different cytokines. Interleukine (IL) 6 and 10 levels were evaluated by ELISA at W0 and W12. They were compared to 16 sex and age-matched healthy controls (HC). Results At baseline, total lymphocyte (p=0.31), T cell (p=0.46), B cell (p=0.08) and NK cell (p=0.905) levels were similar between PMR patients and HC. Transitional B cells (CD24 high , CD38 high ) and mature-naive B cells (CD24 low , CD38 low ) were lower in patients with PMR than in HC, 3±6 vs 6±6 per mm 3 (p=0.01) and 46±41 vs 92±53 per mm 3 (p=0.01), respectively. After tocilizumab, total lymphocyte count slightly increased (1739±539/mm 3 at W0, 2030±591/mm 3 at W2, 2068±775/mm 3 at W12, and 2031±584/mm 3 at W24, p + T cells and NK cells were unaffected by the treatment. In contrast, both absolute number and proportion of B cells increased between W0 and W12, respectively from 176±105/mm 3 to 260±192/mm 3 (p=0.004) and from 10.1% to 13.0% (p Conclusions The drastic clinical improvement following tocilizumab monotherapy in PMR patients is paralleled by an increase in peripheral blood memory B cells. These observations suggest that B cells are involved in disease pathophysiology, and that IL-6 blockade could restore B-cell homeostasis. Disclosure of Interest None declared

Objectives To identify the main determinants of quality of life (QoL) alteration in patients with active primary Sjogren9s syndrome (pSS) participating in a large therapeutic trial. Methods At the inclusion visit in the TEARS trial, 120 patients with active pSS completed the Short Form survey 36 (SF36), a validated tool measuring the level of QoL. The association of demographic data, patient-reported outcomes (including the EULAR SS Patient Reported Index (ESSPRI) score), objective measurements of dryness and autoimmunity, and the physician evaluation of systemic activity (using the EULAR SS Disease Activity Index (ESSDAI) score) with SF36 physical and mental components were assessed by univariate then multivariate linear regression analyses. Results SF36 results showed a marked alteration of QoL in this population of patients with active pSS. The strongest predictors of a low QoL (for both physical and mental components, Table 1) were patient-reported symptoms, best assessed using the ESSPRI, with pain and ocular dryness intensity displaying independent association with QoL. Conversely, systemic activity level was not associated to QoL alteration, even in the subset of patients with moderate to high systemic activity as defined by the ESSDAI. Conclusions pSS cardinal symptoms (dryness, fatigue and pain) are the major predictors of QoL alteration and should be targeted in future therapeutic trials in addition to systemic involvement. Disclosure of Interest None declared

Background CD24high CD38high transitional B cells represent a key stage in the developmental pathway of B cell peripheral tolerance and functional maturation. These B cells have been widely ascribed regulatory functions. However, the phenotypic and functional overlap between these cells and regulatory B cells remains controversial. Objectives In this study, we use multi-color flow cytometry with bioinformatic analyses and functional studies to show that CD24high CD38high B cells can be differentiated into multiple subsets. Results The study also reveals for the first time that human transitional B cells encompass transitional type 1 (T1) and T2 B cells but also distinct anergic T3 B cells as well as IL-10-producing CD27+ transitional B cells. Interestingly, the latter two subsets differentially regulate CD4+ T cell proliferation and polarization towards Th1 effector cells. Additional analyses show that the percentage of T3 B cells is reduced while the frequency of CD27+ transitional B cells is increased in patients with autoimmune diseases compared with matched healthy individuals. Conclusions This study provides evidence for the existence of different transitional B cell subsets each displaying unique phenotypic and regulatory functional profiles.Furthermore, the study indicates that altered distribution of transitional B cells subsets highlights different regulatory defects in autoimmune diseases. Disclosure of Interest None declared

Background Primary Sjogren9s syndrome (pSS) is the autoimmune disease with the highest risk of lymphoma. Identification of predictors with this complication is mandatory to allow a more accurate follow-up and to highlight pathogenic pathways involved in lymphomagenesis. Objectives To define predictors of lymphoma development in pSS patients. Methods Eighty-two pSS patients who developed lymphoma were included in this retrospective study. Demographic data, clinical and biological features were reviewed. A case-controls study was performed to identify predictors of lymphoma based on the 64 patients who developed lymphoma after pSS diagnosis. These cases were compared to 128 pSS patients without lymphoma randomly selected from the ASSESS cohort. Cases and controls were matched on disease duration and age at lymphoma development or evaluation. The association between lymphoma and disease features was assessed by a Wilcoxon test (continuous data) and a Fisher exact test (categorical data). A multivariate analysis (backward elimination) was performed to identify independent predictors of lymphoma. Results Among the 82 patients, 71 were women (86.6%) with a mean age ± SD of 57.8±13.1 years. Histologic type was a B cell non Hodgkin lymphoma (B-NHL) in 80/82 (97.6%) with 60 (75%) marginal zone including 47 (58.8) developed from the MALT, 13 (16.2) DLBCL, 2 follicular lymphomas, 2 chronic lymphoid leukemia, 1 chronic EBV-related lymphoproliferation and 2 B-NHL without any details. The most frequent localization was salivary glands (27 cases). A specific treatment was initiated at diagnosis in 68 patients with B-NHL (85%) and remission was obtained in 56 patients. Relapses occurred in 15 patients. Mean disease duration was 8.1±6.6 and 8.7±6.7 years in controls and cases. Predictors of lymphoma are summarized in the table. Clinical parameters associated with lymphoma were history of parotid gland enlargement and purpura. History of arthritis was found to be protective. Biological parameters associated with lymphoma were closely linked to chronic antigenic stimulation: positivity of anti-SSA, rheumatoid factor and cryoglobulinemia, presence of monoclonal component and low C4. Lymphopenia and disease activity (ESSDAI ≥5 and ClinESSDAI≥5 at evaluation before lymphoma (thus not including the weight of lymphoma)) were also associated with lymphoma occurrence. ESSDAI was not included in multivariate analysis because it includes the majority of the features found associated with lymphoma. Multivariate analysis confirmed parotid gland enlargement, RF, cryoglobulinemia and lymphopenia as predictors of lymphoma. History of arthritis was found to be significantly protective. Conclusions This case-control study of 64 cases of pSS-associated lymphoma highlights the role of chronic antigenic stimulation and disease activity in the development of this severe complication. Disclosure of Interest None declared