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Objectives To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. Methods A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. Results Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. Conclusions In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.

BackgroundLiver is considered one of the most commonly involved extra-glandular organs in patients with Sjögren’s syndrome (SS). Primary biliary cholangitis, hepatitis C virus infection, non-alcoholic fatty liver disease (NAFLD) and drug hepatotoxicity are the major contributors of liver disease among SS patients. Especially, NAFLD comprises a major health problem worldwide with a rapidly rising incidence and a prevalence of approximately 25% in the general population. In both NAFLD and SS, inflammatory and apoptotic pathways are implicated in pathogenesis, pathways that are also linked to fibrogenesis. No studies so far have investigated the net effect of SS in liver fibrosis.ObjectivesTo assess whether SS is associated with advanced liver fibrosis (LF) in the absence of viral, alcohol-related, autoimmune hepatitis or primary cholangitis.MethodsIn this prospective study, consecutive SS patients from the rheumatology outpatient clinic of the Department of Pathophysiology, “Laiko” General Hospital, Athens, Greece between June 1st and December 31st, 2021, underwent transient elastography (TE) with measurement of liver stiffness and controlled attenuation parameter, assessing LF and liver steatosis (LS), respectively. For LF the following cut-offs were used: F0-1: 2-7 kPa, F2: 7-10 kPa, F3: 10-14 kPa, and F4: >14 kPa. F0-F1 stages were considered as clinically insignificant and F2-F4 as advanced. For LS the following cut-offs were used: S0-S1: 100-260 dB/m, S2: 260-290 dB/m, and S3: >290 dB/m. LS stage S0-S1 was classified as low and S2-S3 as high. Individuals who were evaluated in the hepatology outpatient clinic for possible NAFLD/LS based on ultrasonographic criteria (higher echogenicity than renal cortex and/or splenic parenchyma) served as a comparator group. In all participants, those with viral or alcoholic hepatitis, autoimmune liver diseases, transaminasemia or liver disease attributed to drug hepatotoxicity were excluded. Clinical, demographic and laboratory data were collected from all participants at the time of TE.ResultsFifty-two patients with SS (49 females, 94.2%) with a median disease duration (range) of 8 (1-46) years and 198 comparators (104 females, 52.5%) were included in this study. The median age (range) of SS and comparators was 62.5 (30-81) and 55 (19-86) years, respectively. Comparators and SS patients had comparable prevalence regarding type 2 diabetes mellitus (T2DM), hyperlipidemia and body-mass index (BMI). Patients with SS had less frequently high LS (27% vs 62%, pTable 1.Multivariable logistic regression analysis for risk factors associated with advanced liver fibrosis among patients with Sjögren’s Syndrome and comparators.VariablesCoefficientOdds ratiop-valueCI lowCI upperAge0.0571.0590.0231.0191.1Body Mass Index0.0991.1050.1211.0121.207Presence of Sjögren’s syndrome-0.9410.4190.3460.0672.826High Liver Steatosis0.3441.4730.620.3556.167ConclusionSjögren’s syndrome per se is not associated with advanced liver fibrosis.References[1]Kaplan, M.J., et al. The liver is a common non-exocrine target in primary Sjögren’s syndrome: a retrospective review. BMC Gastroenterol2002, 2, 21, doi:10.1186/1471-230x-2-21.[2]Montaño-Loza, A.J., et al. Abnormal hepatic biochemistries and clinical liver disease in patients with primary Sjögren’s syndrome. Ann Hepatol2007, 6, 150-155.Disclosure of InterestsNone declared

BackgroundSjogren’s syndrome (SS) is a systemic autoimmune rheumatic disease characterized by symptoms of dryness. In fact, subjective manifestations of dry eyes or dry mouth are part of the inclusion criteria of the 2016 ACR-EULAR Classification Criteria for primary SS (pSS). However, some patients with SS diagnosis may present without subjective dryness, meeting the inclusion criteria based on the EULAR SS disease activity index (ESSDAI) questionnaire (1). Studies on non-dryness SS patients are missing.ObjectivesTo describe the clinical phenotype of pSS patients who lack subjective dryness symptoms.MethodsFrom 1738 consecutive pSS patients who fulfill the 2016 ACR-EULAR Classification Criteria for primary SS and were followed up in 4 centers from Greece and Italy (Universities of Athens, Pisa, Harokopio and Ioannina) (PAHI group), those without sicca symptoms were identified (non-Dryness Group) (1). Cumulative, clinical, laboratory, immunologic and histologic data were collected and compared with age, gender and disease duration-matched SS patients with both oral and eye dryness in 1:2 ratio (Dryness Group) (Table 1). Statistical analysis for categorical data was performed by Fisher exact test or χ2 square test accordingly and numerical data with Mann-Whitney test or t test.Table 1.Comparison of clinical and laboratory features of pSS patients with (Dryness Group) and without sicca manifestations (Non-dryness Group)Clinical and Laboratory featuresNon-Dryness Group, %, n=38Dryness Group, %, n=76p-valueANA positivity %10095.90.55RF positivity %58.364.30.7Anti-Ro positivity %10090.80.09Anti-La positivity %54.150.70.89Salivary gland biopsy positivity %93.989.80.71Focus score2.122.190.97Ocular tests positivity %55.693.9Salivary gland enlargement %26.330.30.83Arthralgias %52.656.60.84Arthritis %25.717.60.48Raynaud’s phenomenon %23.727.60.82Palpable purpura %7.918.40.17Lymphadenopathy %22.620.30.99Leukopenia %20.726.10.76Lymphopenia %017.30.049Neutropenia %20.85.80.1Thrombocytopenia %13.83.10.07Low C4 %23.330.30.65Cryoglobulinemia %10.53.90.3Lymphoma %10.86.70.47ResultsThirty-eight SS patients were found without sicca manifestations (2.19%). The most common presenting clinical manifestation of non-dryness pSS patients were arthralgias (47.4%), followed by parotid gland enlargement (23.6%), Raynaud’s phenomenon (10.5%), generalized lymphadenopathy (10.5%), fatigue (10.5%), palpable purpura (5.3%) and pulmonary symptomatology of dry cough or exertional dyspnea (5.3%). Despite the lack of ocular dryness, non-dryness group had positive ocular tests but statistically lower compared to those with sicca symptoms (55.6% vs 93.9%, pConclusionSS patients without subjective dryness are characterized by similar underlying immunopathologic processes as typical SS sicca patients.References[1]Shiboski CH, Shiboski SC, Seror R, Criswell LA, Labetoulle M, Lietman TM, et al. 2016 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Primary Sjogren’s Syndrome: A Consensus and Data-Driven Methodology Involving Three International Patient Cohorts. Arthritis Rheumatol. 2017;69(1):35-45.Disclosure of InterestsNone declared

Introduction: Sjogren's syndrome is a unique systemic autoimmune disease, placed in the center of systemic autoimmunity and at the crossroads of autoimmunity and lymphoproliferation. The diverse clinical picture of the disease, the inefficacy of current biologic treatments, and the co-existence with lymphoma conferring to the patients' morbidity and mortality force the scientific community to review disease pathogenesis and reveal the major implicated cellular and molecular elements.Areas covered: Biomarkers for early diagnosis, prediction, stratification, monitoring, and targeted treatments can serve as a tool to interlink and switch from the clinical phenotyping of the disease into a more sophisticated classification based on the underlying critical molecular pathways and endotypes. Such a transition may define the establishment of the so-called precision medicine era in which patients' management will be based on grouping according to pathogenetically related biomarkers. In the current work, literature on Sjogren's syndrome covering several research fields including clinical, translational, and basic research has been reviewed.Expert opinion: The perspectives of clinical and translational research are anticipated to define phenotypic clustering of high-risk pSS patients and link the clinical picture of the disease with fundamental molecular mechanisms and molecules implicated in pathogenesis.

The aim of this study is to explore the role of labial minor salivary gland (LMSG) focus score (FS) in stratifying Sjögren's Syndrome (SS) patients, lymphoma development prediction and to facilitate early lymphoma diagnosis. Ιn an integrated cohort of 1997 patients, 618 patients with FS ≥ 1 and at least one-year elapsing time interval from SS diagnosis to lymphoma diagnosis or last follow up were identified. Clinical, laboratory and serological features were recorded. A data driven logistic regression model was applied to identify independent lymphoma associated risk factors. Furthermore, a FS threshold maximizing the difference of time interval from SS until lymphoma diagnosis between high and low FS lymphoma subgroups was investigated, to develop a follow up strategy for early lymphoma diagnosis. Of the 618 patients, 560 were non-lymphoma SS patients while the other 58 had SS and lymphoma. FS, cryoglobulinemia and salivary gland enlargement (SGE) were proven to be independent lymphoma associated risk factors. Lymphoma patients with FS ≥ 4 had a statistically significant shorter time interval from SS to lymphoma diagnosis, compared to those with FS 4 (4 vs 9 years, respectively, p = 0,008). SS patients with FS ≥ 4 had more frequently B cell originated manifestations and lymphoma, while in patients with FS 4, autoimmune thyroiditis was more prevalent. In the latter group SGE was the only lymphoma independent risk factor. A second LMSG biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS 4 and a history of SGE, at 9-years, may contribute to an early lymphoma diagnosis. Based on our results we conclude that LMSG FS, evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas.

Background:Sjögren’s Syndrome (SS) is a chronic systemic autoimmune disease of unknown etiology, carrying the highest lymphoma risk among autoimmune diseases, with significant impact on mortality and morbidity of patients.Objectives:To describe: i) the clinical phenotype of SS, ii) the histologic type, stage, treatment options regarding lymphomas and iii) the prognosis of patients with SS related lymphoproliferative disorders.Methods:Eight hundred and fifteen consecutive SS patients’ records from a single center fulfilling the 2016 ACR/EULAR were reviewed retrospectively for the purpose of this study. One hundred twenty-one patients with a diagnosis of non-Hodgkin Lymphoma (NHL) were identified and enrolled in the study population. Cumulative clinical, laboratory and histologic data were recorded and overall survival as well as event free survival curves were constructed using the Kaplan-Meier method. An event was defined as a disease progression, lymphoma relapse, treatment failure, histologic transformation, development of a 2nd lymphoma or death from any cause.Results:From 121 pSS patients with lymphoma the most common histologic type encountered was MALT lymphoma (92/121, 76,0%) followed by DLBCL (11/121, 9.0%) and NMZL (8/119, 6.6%). The remaining 10 patients had various lymphomas of B (follicular, lymphoplasmacytic, chronic lymphocytic leukemia} and T cell origin (peripheral T cell lymphoma not otherwise specified, primary cutaneous T cell lymphoma, angioimmunoblastic t-cell lymphoma). Permanent salivary gland enlargement (66.1%, 80/121), palpable purpura (34,7% 42/121), peripheral nervous involvement (9,9%, 12/121), interstitial lung disease (8,2%, 10/121) presence of serum cryoglobulins (38,7%, 43/111) and C4 hypocomplementemia (69,8% 81/116) present at least 1 year before the development of lymphoma were the main pSS related features. The median age at lymphoma diagnosis was 58 years old (range 29-82) while MALT lymphomas developed earlier compared to DLBCL from pSS diagnosis (8 vs 3 OR= 3.84, 95%CI: 0.29 to 10.46; p=0.0266). The commonest biopsy proven extranodal sites included the labial minor salivary (43,8% patients) and parotid glands (30,5%) while 11% of patients had more than 1 extranodal sites affected. Bone marrow involvement was evident in 24,3% of patients (29/119) while nodal involvement in 35,5% (42/118). The majority of patients (65%) had limited disease (stage I or II). A watch and wait therapeutic policy was chosen in 40 patients while the rest received rituximab with or without chemotherapy. The 10-year survival and event free rates were 79% and 45,5% for MALT lymphomas, 40,9% and 24,2% for DLBCL and 46% and 31% for NMZL respectively (Figure 1). The Mantel-Cox log-rank comparison of the overall survival curves revealed a statistically significant difference (p=0.0016) among lymphoma subtypes.Figure 1.Overall and event free survival of SS-associated lymphoma patients. A. Kaplan-Meier overall survival analysis. B. A Kaplan-Meier event free survival analysis.Conclusion:This is the largest single center series of SS- associated lymphoma patients, providing a detailed description of SS and lymphoma related features, combined with a 10-year survival and event free curves for the first time in the literature.Disclosure of Interests:None declared.

Background:We1 and others2 have previously shown that ICU admitted patients with COVID-19 developed high titers of anti-SARS-CoV-2 antibodies, but also autoantibodies, some of which are pathogenic. We re-evaluated 8 patients of those survived after admission to the ICU of Evangelismos Hospital of Athens -1st Department of Internal Medicine, Medical School, NKUA3 6 months later. We did not know whether these autoantibodies still exist, are associated with COVID-19 or with ARDS as described after septic shock4.Objectives:To investigate the presence and titers of anti-SARS-CoV-2 antibodies and autoantibodies in patients survived after COVID-19 ICU stay, in the ICU and 6 months later.Methods:Case series to evaluate titers of anti-SARS-CoV-2 antibodies, specificities of autoantibodies as well as clinical features in ICU admitted COVID-19 patients, initially and 6 months after their discharge. Evaluation of current clinical status included evaluation of lung, heart, kidney, central and peripheral nervous system and mental status using standardized methods. Methods for detection of anti-SARS-CoV-2 antibodies and autoantibodies were described in our previous report1.Results:We had initially evaluated1 29 ICU admitted COVID-19 patients’ files and sera, of which 4 had been already died during serum evaluation. Six more patients died thereafter. Out of 19 having been discharged, 8 were willing to be re-evaluated. On second evaluation 6 months later, serum anti-SARS-CoV-2 antibodies were highly positive, although at lower titers compared to the titers at disease onset (median [range]) 8.705 (range: 7.95-9.56) vs 6.640 (range: 6.29-6.76), p=0.0002, Mann-Whitney test. Initially 3 out of 8 patients expressed antinuclear antibodies (ANA) at titers 1/160, 1/320 and 1/320 with a fine speckled pattern with the second patient also expressing at a titer of 1/160, antimitochondrial (AMA) antibodies. Six months later the same patients and not anyone else expressed ANA of the same pattern at titers 1/640, 1/160 and 1/160 respectively. Two patients with 1/20 p-ANCA and 1/640 c-ANCA initially, lost their respective autoantibodies after 6 months. One patient initially negative for IgM anti-β2GPI became positive at low titer and an initially positive became negative. One patient initially positive for anti-Ro60 antibody continued to be positive 6 months later. One patient initially negative developed anti-Tg antibodies and 3 patients initially positive for anti-TPO antibodies remained positive 6 months later.Conclusion:Patients with COVID-19 survived after ICU admission still retain high titers of anti-SARS-CoV-2 antibodies but significantly lower that at disease onset, but they tend to lose autoantibodies with pathogenic potential.References:[1]Vlachoyiannopoulos P et al, Ann Rheum Dis 2020,[2]2. Wang EY et al, medRxiv preprint doi: https://doi.org/10.1101/2020.12.10.20247205[3]National and Kapodistrian University of Athens, Athens, Greece[4]Burbelo et al. Journal of Translational Medicine 2010Disclosure of Interests:None declared

Background:Primary Sjögren Syndrome (SS) is a slowly progressive systemic autoimmune disease complicated by lymphoma, with mucosa associated lymphoid tissue (MALT) type being the most common lymphoma form. Several predictors related to pSS associated lymphomas have been described, but there are no studies focusing on specific risk factors for the MALT histologic subtype.Objectives:To identify predictors at SS diagnosis for MALT lymphoma development in pSS patients using simple clinical features.Methods:From 815 SS patients of a single center fulfilling the 2016 ACR/EULAR criteria, those with subsequent development of MALT lymphoma according to the 2016 WHO classification were identified and matched in 1:2 ratio, with non-lymphoma SS control patients according to age, disease duration from SS diagnosis and gender. Lymphoma patients diagnosed within a year from SS diagnosis were excluded from the current study. Clinical, laboratory, histologic data as well as the ESSDAI scores at the time of SS diagnosis were recorded and compared between lymphoma and non-lymphoma patients. Independent lymphoma predictors were identified by a data driven Fast Correlation Based Feature selection (FCBF)/Logistic Regression (LR) algorithm.Results:A unified dataset of 57 MALT lymphoma patients and 114 non lymphoma controls along with 39 features/variables was generated. The median age of SS diagnosis and the disease duration from SS diagnosis to lymphoma diagnosis (lymphoma group) or last follow up (control group) was 50,5 years old (range 25-77) and 7 years (range 0- 30) for the control group and 50 years old (range 24-70) and 8 years (range 1 -30) for the lymphoma group, respectively. MALT lymphoma patients presented more frequently with palpable purpura (23,2% vs 5,3% p=0,001), cryoglobulinemia (30,2% vs 1,6% pConclusion:MALT is the predominant pSS related lymphoproliferative histologic type, associated with systemic disease activity and vasculitic manifestations at SS diagnosis. Cryoglobulinemia and ESSDAI score were proven independent risk factors for MALT lymphoma development.Table 1.An FCBF-based multivariable logistic regression analysis results for investigating risk factors for MALT lymphoma developmentProminent featureRegression coefficientOdds ratiop-valueCI lowCI upperCryoglobulinemia1.675.3420.033*1.1824.327Total ESSDAI at diagnosis0.281.3181.2081.439Kidney involvement0.071.0690.50.1010.351•< 0.05 (95% confidence interval). The rest of the features that participated in the analysis include the following: Palpable purpura, Low C4, Salivary gland enlargement, Lacrimal gland enlargement, ANA Titers, RF, Focus score at Sjögren diagnosis, PNS involvement, Anti-La, Disease duration from SS onset to SS diagnosis, Neutrophils•AUC=0.78Disclosure of Interests:None declared

Background:The typical histologic picture of focal sialadenitis in the labial minor salivary gland (LMSG) tissues has been incorporated as a parameter in the majority of Sjögren’s syndrome (SS) classification criteria, with focus score (FS) being the most widely used (1). In previous studies, higher FS has been associated with the presence of autoantibodies and extra-glandular manifestations including lymphoma, implying that FS can predict severe disease (2,3). However, there are no studies exploring the association of FS with lymphoma development along with the time interval from SS diagnosis to lymphoma diagnosis.Objectives:To investigate an association of focus score grading with lymphoma development and time to lymphoma occurrence.Methods:From a total population 1998 consecutive patients fulfilling the 2016 ACR-EULAR criteria for SS who were followed-up in 5 Rheumatology centers from Greece and Italy (Universities of Athens, Pisa, Udine, Harokopio and Ioannina) (UPAHI group), those with positive (LMSG) (FS ≥1) were identified. (1). Patients who had not been subjected to an LMSG biopsy or had a negative biopsy (FSResults:A unified dataset of 618 SS patients with FS≥1 and at least one year of disease duration from SS diagnosis to lymphoma diagnosis or last follow up, with 30 clinical, laboratory and histologic features, was constructed. The median age at SS diagnosis was 53 (range: 15 – 80) years old, the female to male ratio was 20:1 and the median disease duration was 6 years (range: 1-35). Half (49%) of the study population had focus score between one and two (1≤FSConclusion:This is the largest study of SS patients’ histologic analysis exploring the association of LMSG FS grading with lymphoma development and the time interval until its diagnosis. Higher FS values correlate with increased lymphoma risk and early lymphoma occurrence.Figure 1.Pearson correlation between FS and time interval until lymphoma diagnosisReferences:[1]Shiboski et al. Arhtritis Rheumatol. 2017[2]Carrubi et al. Lupus 2015[3]Risselada AP et al. Ann Rheum Dis 2014Disclosure of Interests:None declared

Background:CXCL13 has been implicated in the formation of ectopic germinal centers (GC) in minor salivary gland (MSG) inflammatory lesions of SS patients. Recent studies suggest that serum CXCL13 levels associate with disease severity and risk for non-Hodgkin’s lymphoma (NHL) development.Objectives:To validate the clinical utility of CXCL13 by investigating potential associations of saliva and serum CXCL13 levels with various histopathologic (including severity of MSG autoimmune infiltrates and GC formation), serologic and clinical features of the disease, as well as NHL.Methods:CXCL13 levels were measured by a commercially available ELISA (sensitivity: 1 pg/ml; Abcam, Cambridge, UK) in paired serum and saliva specimens from 25 SS patients (9 with NHL; SSL), 9 sicca controls (SC; sicca-complaining individuals with no infiltrates in diagnostic MSG biopsy and negative autoantibody profile) and 6 healthy controls (HC). From the 16 SS patients without evidence of NHL, 5 had mild, 6 intermediate and 5 severe lesions at MSGs, as arbitrarily defined by focus (FS) and Tarpley (TS) biopsy scores (mild: FS:1-1.7, TS:1, intermediate: FS:1.8-2.95, TS:2 and severe: FS: 3.0-11, TS: 3-4). Furthermore, the organization of the MSG infiltrates to GCs has been evaluated in 23 patients revealing 10 with GCs.Results:Kruskal-Wallis analysis revealed that serum CXCL13 levels were significantly increased in SS patients without or with NHL (median: 94.83 pg/ml and 96.70 pg/ml, respectively), compared to SC and HC (35.44 and 40.92 pg/ml respectively; pvs 69.64 pg/ml, p:0.0015), rheumatoid factor (105.0 vs 53.72 pg/ml, p: 0.015) and marginally with anti-Ro/La antibodies (121.8 vs 65.05 pg/ml, p: 0.06) compared to those without. Furthermore, CXCL13 levels were significantly increased in SS patients at high risk to develop NHL compared to low risk (149.3 vs 71.54 pg/ml, respectively, p: 0.0275). Saliva levels were not found to associate with the studied features.Conclusion:Serum and to a lesser extend saliva CXCL13 levels are increased in SS and SSL patients and associate with the degree of MSG infiltration, as assessed by focus score. Serum, but not saliva, CXCL13 associates with various disease features, including GC formation, and may have a clinical utility in identifying SS patients at high risk to develop lymphoma.Disclosure of Interests:None declared

Background:Sjögren’s syndrome (SS) is characterized by B cell hyperactivity reflected by hypergammaglobulinemia as well as a plethora of autoantibodies including antinuclear antibodies (ANA), anti-Ro/SSA, anti-La/SSB and rheumatoid factors (RF). Previous studies have focused on the phenotype of single positive (ANA or anti-Ro/SSA or anti-La/SSB) or double positive (anti-Ro/SSA and anti-La/SSB positive) SS patients, showing differences regarding the age of diagnosis, sicca manifestations and specific extraglandular manifestations. To our knowledge, no study has ever explored the clinical spectrum of triple seronegative (anti-Ro/SSA + anti-La/SSB + RF negative) and quadruple seronegative (ANA +anti-Ro/SSA + anti-La/SSB + RF negative) SS patients.Objectives:To study the differences in the clinical phenotype of triple and quadruple seronegative (SS) patients in a large cohort of well characterized patients, after comparison with anti-Ro/SSA positive patients.Methods:From a total cohort of 1723 consecutive SS patients who fulfill the 2016 EULAR/ACR criteria and are followed up in 4 clinical centers ([Universities of Pisa and Athens, Harokopio and Ioannina, (PAHI)], those who have been found triple or quadruple seronegative were identified and compared with matched anti-Ro/SSA positive SS patients according to age of SS onset, disease duration and gender, in 1:1 and 1:2 ratio respectively. Glandular (dry mouth, dry eyes, parotid gland enlargement) and extra-glandular manifestations (Raynaud’s phenomenon, chronic fatigue arthralgias/myalgias, arthritis, palpable purpura, liver involvement, kidney involvement, lung involvement, neurologic involvement, long standing lymphadenopathy and lymphoma) were compared between the 2 seronegative groups and the anti-Ro/SSA positive control group. Statistical analysis for categorical variables was performed by Fisher exact or chi-square tests and for continuous variables with t test or Mann-Whitney accordingly.Results:Two hundred and four SS patients (11,8%) were identified as triple negatives and 53 (3,0%) as quadruple, with a median disease duration of 6 years (range: 0-41) and 5 years (range: 0-32) respectively. The matched anti-Ro/SSA controls were 204 for the triple and 103 for the quadruple negatives. Triple negatives had lower frequency of monoclonal gammopathy (5,5% vs 12,1% p=0,04), low C4 serum levels (23% vs 36%, p=0,009) and lymphoma (3,4% vs 9,8%, OR= 3,06, 95% CI =1,27-7,85) while quadruple negatives exhibited higher prevalence of dry eyes (100% vs 90%) and lower prevalence of long standing lymphadenopathy (2,7% vs 19,5%, p=0,001) and lymphoma (0% vs 15%, p=0,001) compared to anti-Ro/SSA matched controls.Conclusion:Combined seronegativity account for more than 10% of SS population and is associated with lower prevalence of lymphoma compared to anti-Ro/SSA positive patients.Disclosure of Interests:Loukas Chatzis: None declared, Vasileios Pezoulas: None declared, Francesco Ferro: None declared, Valentina Donati: None declared, Aliki Venetsanopoulou: None declared, Evangelia Zampeli: None declared, Maria Mavromati: None declared, Paraskevi Voulgari: None declared, Clio Mavragani: None declared, Dimitris Fotiadis: None declared, Fotini Skopouli: None declared, Salvatore De Vita Consultant of: Roche, Human Genome Science, Glaxo Smith Kline and Novartis, Chiara Baldini: None declared, Haralampos M. Moutsopoulos: None declared, Athanasios Tzioufas: None declared, Andreas Goules: None declared

Background:Sjögren’s syndrome (SS) affects mainly individuals of the 4thor 5thdecade of life, although patients with early (≤35 years old) or late (≥65 years old) disease onset have been described in the literature. The clinical spectrum of the disease extends from mild dryness to severe systemic vasculitis and lymphoproliferative disorders. The phenotypic diversity of SS is defined by many factors, including age, since many parameters related to age may affect the clinical expression of the disease. Few studies have been conducted to study the effect of age on the clinical phenotype of SS, though with limited number of patients. Large and well-defined groups of SS are required to address such questions.Objectives:To study the clinical phenotype of SS patients with early and late disease onset and to explore the association of age with lymphoma development in a unified multicenter cohort.Methods:From a total cohort of 1997 consecutive SS patients who fulfill the 2016 EULAR/ACR criteria and are followed up in 5 clinical centers ([Universities ofUdine,Pisa andAthens,Harokopio andIoannina, (UPAHI)], those with either early (≤35 years) or late (≥65 years) disease onset were identified and matched according to gender and disease duration with middle aged controls whose disease onset was at the 4thor 5thdecade of life. Glandular manifestations, extra-glandular manifestations, serologic characteristics and histologic features were compared between the 2 age groups and the middle-aged control groups. Statistical analysis for categorical variables was performed by Fisher exact or chi-square tests and for continuous variables with t test or Mann-Whitney accordingly.Results:Three hundred seventy-nine (19%) SS patients with early and 293 (15%) with late disease onset were identified and compared with 353 and 285 middle aged SS controls respectively. The median disease duration of patients with early onset was 12 years (range:0-68) and for those with late disease onset was 5 years (range: 0-27). SS patients with early disease onset had statistically significant higher frequency of Raynaud’s phenomenon, lymphadenopathy, hypergammaglobulinemia, anti-Ro/SSA, anti-La/SSB, rheumatoid factor, salivary gland enlargement, low C4 complement levels, leukopenia and lymphoma (10,3% vs 5,7%, p= 0.03, OR= 1,91, 95% CI: 1,11-3,27) while SS patients with late disease onset had more frequently dry mouth, interstitial lung disease and lymphoma (6,8% vs 2,1%, p=0,01, OR= 3,4. 95%CI: 1,35-1,81).Conclusion:In a multicenter cohort of 1997 consecutive SS patients, those with early and late disease onset comprise more than one third of the total SS population. Patients with early disease onset, exhibit robust B cell responses with traditional risk factors for lymphoma as opposed to patients with late disease onset. Both age groups have increased lymphoma prevalence but presumably for different reasons, since late onset patients lack classical predictors of lymphoma. Therefore, these predictors deserve further study in different disease subsets.Disclosure of Interests:Andreas Goules: None declared, Ourania Argyropoulou: None declared, Vasileios Pezoulas: None declared, Francesco Ferro: None declared, Saviana Gandolfo: None declared, Valentina Donati: None declared, Marco Binutti: None declared, Sara Zandonella Callegher: None declared, Loukas Chatzis: None declared, Aliki Venetsanopoulou: None declared, Evangelia Zampeli: None declared, Maria Mavromati: None declared, Paraskevi Voulgari: None declared, Clio Mavragani: None declared, Chiara Baldini: None declared, Fotini Skopouli: None declared, Dimitris Fotiadis: None declared, Salvatore De Vita Consultant of: Roche, Human Genome Science, Glaxo Smith Kline and Novartis, Haralampos M. Moutsopoulos: None declared, Athanasios Tzioufas: None declared

Background:Sjögren’s syndrome (SS) is characterized by the presence of lymphocytic infiltration around the ductal epithelium of the salivary and lachrymal glands. The periepithelial inflammatory lesions and the enclosed B cell component are responsible for the glandular and extraglandular manifestations of the disease. Previous studies have shown that the severity of inflammation observed within the salivary glands is correlated with the occurrence of extraglandular manifestations. However, in these studies either the number of patients is small or the SS criteria are not well defined. To explore the association between the degree of inflammation within the salivary glands and the phenotype of the disease, large and well characterized cohorts of SS patients is required.Objectives:To compare the phenotypic features of SS patients with low and high degree of inflammation within the minor salivary glands as reflected by the focus score (FS).Methods:From a total cohort of 1723 consecutive SS patients who fulfill the 2016 EULAR/ACR criteria and are followed up in 4 clinical centers ([Universities ofPisa,Athens,Harokopio andIoannina, (PAHI)], those who had performed a lip biopsy and the focused score was available, were classified into low grade (FSResults:Eight hundred and eight minor salivary gland biopsies were available and evaluated based on focus score at the initial evaluation of SS patients, of whom 753 had low grade (FSConclusion:SS patients with FS ≥3 at the initial evaluation, display higher prevalence of lymphoma as well as higher B cell hyperactivity and certain clinical manifestations (SGE, PNS, lymphadenopathy) that constitute risk factors for lymphoma development.Disclosure of Interests:Loukas Chatzis: None declared, Vasileios Pezoulas: None declared, Francesco Ferro: None declared, Valentina Donati: None declared, Aliki Venetsanopoulou: None declared, Evangelia Zampeli: None declared, Maria Mavromati: None declared, Paraskevi Voulgari: None declared, Clio Mavragani: None declared, Dimitris Fotiadis: None declared, Fotini Skopouli: None declared, Salvatore De Vita Consultant of: Roche, Human Genome Science, Glaxo Smith Kline and Novartis, Gorgoulis Vassilis: None declared, Chiara Baldini: None declared, Haralampos M. Moutsopoulos: None declared, Andreas Goules: None declared, Athanasios Tzioufas: None declared