Raphaèle Seror

Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud), Lutetia Parisorum, Île-de-France, France

Are you Raphaèle Seror?

Claim your profile

Publications (108)565.31 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To define parameters predictive of lymphoma development in patients with primary Sjögren's syndrome (pSS). Methods: A multicenter case-controls survey was performed to identify predictors of lymphoma. Cases were patients who developed lymphoma after pSS diagnosis. They were mainly recruited through the "Club Rhumatismes et Inflammation" network. For each case, 2 controls (matched on disease duration and age) were randomly selected among patients without lymphoma. Cases and controls were compared with univariate then multivariate analysis to identify independent predictors of lymphoma. Results: One hundred and one pSS patients with lymphoma were included; 87 were women (86.1%) with a mean age ± SD of 57.4 ±12.6 years. Histologic type was B cell non Hodgkin lymphoma (B-NHL) in 99/101 with 76 (76.8%) marginal zone including 58 (58.6%) developed from the Mucosa associated lymphoid tissue (MALT). The most frequent localization was salivary glands (43 cases). A specific treatment was initiated at diagnosis in 87/99 patients with B-NHL and remission was obtained in 61 patients (61.6%). In the multivariate analysis salivary gland enlargement, rheumatoid factor, low C4, cryoglobulinemia, lymphopenia and disease activity (excluding the lymphoma domain) were found predictors of lymphoma. We did not find any role of previous treatments of pSS for preventing or favoring lymphoma occurrence. Conclusion: In addition to previous known predictive factors of lymphoma occurrence, this case-control study of pSS-associated lymphoma demonstrated the independent role of rheumatoid factor and of disease activity. It highlights the role of chronic antigenic stimulation and disease activity in the development of this severe complication. This article is protected by copyright. All rights reserved.
    Arthritis and Rheumatology 11/2015; DOI:10.1002/art.39518

  • Rheumatology (Oxford, England) 10/2015; DOI:10.1093/rheumatology/kev365 · 4.48 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective: The goal of this study was to determine how the choice of the primary endpoint influenced sample size estimates in randomised controlled trials (RCTs) of treatments for primary Sjögren's syndrome (pSS). Methods: We reviewed all studies evaluating biotechnological therapies in pSS to identify their inclusion criteria and primary endpoints. Then, in a large cohort (ASSESS), we determined the proportion of patients who would be included in RCTs using various inclusion criteria sets. Finally, we used the population of a large randomised therapeutic trial in pSS (TEARS) to assess the impact of various primary objectives and endpoints on estimated sample sizes. These analyses were performed only for the endpoints indicating greater efficacy of rituximab compared to the placebo. Results: We identified 18 studies. The most common inclusion criteria were short disease duration; systemic involvement; high mean visual analogue scale (VAS) scores for dryness, pain, and fatigue; and biological evidence of activity. In the ASSESS cohort, 35 percent of patients had recent-onset disease (lower than 4 years), 68 percent systemic manifestations, 68 percent high scores on two of three VASs, and 52 percent biological evidence of activity. The primary endpoints associated with the smallest sample sizes (nlower than 200) were a VAS dryness score improvement higher to 20 mm by week 24 or variable improvements (10, 20, or 30 mm) in fatigue VAS by week 6 or 16. For patients with systemic manifestations, the ESSDAI change may be the most logical endpoint, as it reflects all domains of disease activity. However, the ESSDAI did not improve significantly with rituximab therapy in the TEARS study. Ultrasound score improvement produced the smallest sample size estimate in the TEARS study. Conclusion: This study provides valuable information for designing future RCTs on the basis of previously published studies. Previous RCTs used inclusion criteria that selected a small part of the entire pSS population. The endpoint was usually based on VASs assessing patient complaints. In contrast to VAS dryness cut-offs, VAS fatigue cut-offs did not affect estimated sample sizes. SGUS improvement produced the smallest estimated sample size. Further studies are required to validate standardised SGUS modalities and assessment criteria. Thus, researchers should strive to develop a composite primary endpoint and to determine its best cut-off and assessment time point.
    PLoS ONE 09/2015; 10(9):e0133907. DOI:10.1371/journal.pone.0133907 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background: Control treatments in randomized controlled trials (RCTs) should not deliberately disadvantage patients. Objectives: To compare (a) willingness to include versus (b) willingness to prescribe control treatment among physicians randomized to assess, respectively, either (a) enrollment in a trial or (b) appropriateness of control treatment in a care context for the same fictional patient. Participants: Physicians were authors of articles about rheumatoid arthritis (RA), involved in RA patient care and used to enrolling patients in trials. Outcomes: Willingness to give control treatment: trial enrollment or control-treatment appropriateness in care context. Methods: We derived 3 case vignettes of fictional standard eligible patients for each of 30 RCTs assessing biologics in RA. Physicians were randomly allocated to the "trial" or "care" arm. For each of the 90 fictional patients, physicians assigned to the trial arm were asked if they would enroll the patient in the RCT the patient was derived from. For the same 90 fictional patients, physicians assigned to the care arm were asked if the control treatment of the RCT was appropriate in a context of usual care. Results: Of the 1,779 physicians invited to participate, 151 were randomized. Half of the fictional patients (41/90; 45% [95%CI 37-53%]) would be enrolled in the RCT even though the control-arm treatment of the RCT was not considered appropriate for them in the context of care. This rate differed by type of comparator (55% for non-head-to-head RCTs vs 6% for head-to-head RCTs; adjusted OR (aOR) 23.9 [95%CI 5.5-92.7]) and duration of trial control treatment (56% for ≤ 24 weeks and 15% for > 24 weeks; aOR 10.7 [95%CI 2.8-63.9]) but not patient RA activity (aOR 2.5 [95%CI 1.0-6.6]). Limitations: Fictional patients, RA only. Conclusions: Control treatments in RCTs of biologics in RA are often deemed not acceptable in the context of usual care, especially those for non-head-to-head RCTs. These findings raise ethical concerns and challenge the choice of the comparator in RCTs.
    Journal of clinical epidemiology 09/2015; DOI:10.1016/j.jclinepi.2015.08.016 · 3.42 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A germline and coding polymorphism (rs2230926) of TNFAIP3 (A20), a central gatekeeper of nuclear factor-kappa B (NF-kB) activation, was recently found associated with primary Sjögren's syndrome (pSS)-associated lymphoma in a French cohort. We aimed to replicate this association. The rs2230926 polymorphism was genotyped in cases and controls of European ancestry from two independent cohorts from UK and France. Case control association tests were performed (Fisher's test) in the two cohorts, followed by a meta-analysis of the two cohorts. The UK cohort included 308 controls and 590 patients with pSS including 31 with a history of lymphoma. The French cohort consisted of 448 controls and 589 patients with pSS including 47 with lymphoma. In both cohorts, the rs2230926 missense polymorphism was not associated with pSS. However, in the UK cohort, the rs2230926G variant was significantly associated with pSS-associated lymphoma (OR=2.74, 95% CI (1.07 to 7.03), p=0.0423, compared with patients with pSS without lymphoma, and OR=3.12, 95% CI (1.16 to 8.41), p=0.0314, compared with healthy controls) as observed in the French cohort. The meta-analysis of the two cohorts confirmed these results (OR=2.48, 95% CI (1.87 to 3.28) p=0.0037 and OR=2.60, 95% CI (1.91 to 3.53) p=0.0031, respectively). This study confirms the role of A20 impairment in pSS-associated lymphoma. Subtle germline abnormalities of genes leading to impaired control of NF-kB activation in B cells continuously stimulated by autoimmunity enhance the risk of lymphoma. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Annals of the rheumatic diseases 09/2015; DOI:10.1136/annrheumdis-2015-207731 · 10.38 Impact Factor
  • Raphaele Seror · Xavier Mariette ·

    Arthritis and Rheumatology 08/2015; DOI:10.1002/art.39400
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: To investigate DKK-1 and SOST serum levels among patients with recent inflammatory back pain (IBP) fulfilling ASAS criteria for SpA and associated factors. Methods: The DESIR cohort is a prospective, multicenter French cohort of 708 patients with early IBP (duration >3 months and <3 years) suggestive of AxSpA. DKK-1 and SOST serum levels were assessed at baseline and were compared between the subgroup of patients fulfilling ASAS criteria for SpA (n = 486; 68.6%) and 80 healthy controls. Results: Mean SOST serum levels were lower in ASAS+ patients than healthy controls (49.21 ± 25.9 vs. 87.8 ± 26 pmol/L; p<0.0001). In multivariate analysis, age (p = 5.4 10-9), CRP level (p<0.0001) and serum DKK-1 level (p = 0.001) were associated with SOST level. Mean DKK-1 serum levels were higher in axial SpA patients than controls (30.03 ± 15.5 vs. 11.6 ± 4.2 pmol/L; p<0.0001). In multivariate analysis, DKK-1 serum levels were associated with male gender (p = 0.03), CRP level (p = 0.006), SOST serum level (p = 0.002) and presence of sacroiliitis on radiography (p = 0.05). Genetic association testing of 10 SNPs encompassing the DKK-1 locus failed to demonstrate a significant contribution of genetics to control of DKK-1 serum levels. Conclusions: DKK-1 serum levels were increased and SOST levels were decreased among a large cohort of patients with early axial SpA compared to healthy controls. DKK-1 serum levels were mostly associated with biological inflammation and SOST serum levels.
    PLoS ONE 08/2015; 10(8):e0134974. DOI:10.1371/journal.pone.0134974 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To report the efficacy and safety of long-term treatment of SS with belimumab, targeting the B-cell-activating factor. Patients with primary SS were included in the BELISS open-label phase II study, a 1-year open-label trial, if they were positive for anti-SSA or anti-SSB antibodies and had systemic complications or persistent salivary gland enlargement or early disease or biomarkers of B-cell activation. They received belimumab, 10 mg/kg i.v., at weeks 0, 2 and 4 and then every 4 weeks; if response was observed at week 28, or if the clinician and the patient agreed to continue the study in the absence of side effects, treatment was continued for 1 year. Efficacy and safety were analysed during the 1-year period of treatment. Among the 30 patients recruited, 28 were evaluated at week 28 as already reported. Nineteen terminated the 52-week study, 15 of them being responders and 4 non-responders at week 28. Thirteen of the 15 responders at week 28 also responded at week 52 (86.7%). The improvement in the EULAR Sjögren's Syndrome Disease Activity Index and EULAR Sjögren's Syndrome Patient Reported Index scores observed at week 28 showed a trend to further improvement at week 52, and the amelioration of peculiar EULAR Sjögren's Syndrome Disease Activity Index domains (glandular, lymphadenopathy, articular) appeared of particular relevance. The decrease in biomarkers of B-cell activation observed at week 28 persisted unchanged until week 52, with RF decreasing further. Salivary flow, Schirmer's test and the focus score of salivary biopsy did not change. Safety of treatment was good. Long-term treatment with belimumab may be beneficial in SS. Randomized, double-blind, controlled studies in larger populations are encouraged. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    Rheumatology (Oxford, England) 08/2015; 74(Suppl 2). DOI:10.1093/rheumatology/kev257 · 4.48 Impact Factor

  • The Journal of Rheumatology 08/2015; 42(8):1536-1537. DOI:10.3899/jrheum.141318 · 3.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: Non-Hodgkin lymphoma (NHL) is a severe complication of primary Sjogren's syndrome (pSS). Salivary glands ectopic germinal centers (GC) are predictors of NHL occurrence. Given the association between CCL11 and CXCL13 and ectopic GC, we assessed the link between these chemokines and NHL in pSS patients and the association between these chemokines and disease activity. Methods: CCL11 and CXCL13 serum levels were evaluated in 385 patients included in ASSESS cohort by multiplex assay. The association between chemokine levels, B-cell biomarkers and subsets of patients was assessed using Spearman's test for continuous data and nonparametric Mann-Whitney test for categorical data. Multivariate analyses were performed to identify parameters associated with lymphoma and disease activity. Results: 17 patients had a history of lymphoma and 5 had developed the NHL during follow-up. The median [IQR] serum levels of CCL11 and CXCL13 in the total cohort were 106.48 [69.33-149.85] pg/ml and 108.31 [58.88-200.13] pg/ml, respectively. Patients with lymphoma presented higher levels of CXCL13 compared to patients without (p=0.006) and a trend for a higher level of CCL11 (p=0.056). Low C4 and high BAFF levels were associated with NHL in multivariate analysis (p=0.01 and p=0.0002 respectively). CCL11 and CXCL13 levels positively correlated with rheumatoid factor, κ/λ free light chain ratio and β2-microglubulin levels. CXCL13 was the only parameter associated with disease activity in multivariate analysis. Conclusion: This study demonstrates a link between CXCL13 and CCL11 and disease activity and lymphoma. This highlights the continuum between chronic B-cell activation, disease activity and lymphomagenesis in pSS patients. This article is protected by copyright. All rights reserved.
    Arthritis and Rheumatology 08/2015; DOI:10.1002/art.39315
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: To reach a European consensus on the definition and characterization of the main organ-specific extraglandular manifestations in primary SS. Methods: The EULAR-SS Task Force Group steering committee agreed to approach SS-related systemic involvement according to the EULAR SS Disease Activity Index (ESSDAI) classification and proposed the preparation of four separate manuscripts: articular, cutaneous, pulmonary and renal ESSDAI involvement; muscular, peripheral nervous system, CNS and haematological ESSDAI involvement; organs not included in the ESSDAI classification; and lymphoproliferative disease. Currently available evidence was obtained by a systematic literature review focused on SS-related systemic features. Results: The following information was summarized for articular, cutaneous, pulmonary and renal involvement: a clear, consensual definition of the clinical feature, a brief epidemiological description including an estimate of the prevalence reported in the main clinical series and a brief list of the key clinical and diagnostic features that could help physicians clearly identify these features. Unfortunately we found that the body of evidence relied predominantly on information retrieved from individual cases, and the scientific information provided was heterogeneous. The analysis of types of involvement was biased due to the unbalanced reporting of severe cases over non-severe cases, although the main sources of bias were the heterogeneous definitions of organ involvement (or even the lack of definition in some studies) and the heterogeneous diagnostic approach used in studies to investigate involvment of each organ. Conclusion: The proposals included in this article are a first step to developing an optimal diagnostic approach to systemic involvement in primary SS and may pave the way for further development of evidence-based diagnostic and therapeutic guidelines.
    Rheumatology (Oxford, England) 07/2015; DOI:10.1093/rheumatology/kev200 · 4.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Refractory and corticodependent Systemic Lupus Erythematous (SLE) often represents a therapeutic challenge. Only one biologic, belimumab, has been approved to date, but others are used off-label. However, the strategy of use remains a “grey area” in the available recommendations (1-3), because of the lack of evidence-based data and the wide range of situations encountered in real-life practice. We decided to set-up recommendations, following the French High Authority for Health (HAS) guidelines. Objectives To establish Recommendations of Good Practice (RGP) for the use of biologics in SLE, in 5 domains: Which patient might benefit from biologics?; Which biologic might be used?; Which information and co-medication(s) should be given to patients?; How should the effectiveness of a biologic be evaluated?; When does the biologic have to be discontinued? Methods We used the “Experts Formalized Consensus” methodology, as recommended by HAS. In brief, the degree of agreement on each recommendation is formalized, and a recommendation is validated only after a consensus has been reached. In case of controversy, proposed recommendations are modified and submitted again to the panel of experts until a consensus is reached. This process highlights extremes and not only median opinion. Transparency requires publishing all comments that are not retained. If the degree of agreement is not strong enough, proposals may be rejected. Results Three strictly independent SLE experts groups were established: a steering group SG (n=9), an evaluation group EG (n=28) and a reading group RG (n=40). Cf Fig. 1. A systematic literature review was conducted by SG in Pubmed-MeSH. The search terms were “SLE” AND [biological] – [mode of action] – [study design]. Until June 2014, 444 references matched. According to the state of art, 20 initial recommendations were drafted by the SG and then submitted to the EG. Each individual expert of the EG scored his degree of agreement from 1 to 9 (1: lowest agreement; 9: strongest agreement). The 1st evaluation round showed 4 recommendations with strong agreement (median ≥7; values ≥7), 5 with relative agreement (median ≥7; some values <7); and 11 recommendations without sufficient consensus. These latter recommendations are currently being reformulated before a 2nd round scoring. The SG will then formulate a last version. Then the RG will score and comment each recommendation. At last, the recommendations will be finalized and published by the SG. Conclusions After the 1st evaluation round, the large number of uncertainties is due to some extreme values in score distribution, which illustrates the wide range of practice among experts. The methodology provides several rounds to try to reach a consensus, by taking into account punctual disagreement. We report our experience of using the Experts Formalized Consensus methodology in the establishment of international recommendations for the use of biologics in SLE. 2nd round results and/or final recommandations will be prepared and presented at EULAR. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):343.1-343. DOI:10.1136/annrheumdis-2015-eular.3693 · 10.38 Impact Factor
  • E. Gamon · G. Mouterde · C. Lukas · M. Orsini · R. Seror · B. Combe ·
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Environmental factors may play a crucial role in auto-immune diseases. Besides tobacco, other factors like vitamin D are suspected to impact the onset and the subsequent activity of inflammatory arthritis including rheumatoid arthritis (RA), but its association with severity of the disease has not been evaluated yet. Objectives To examine the association of baseline vitamin D serum level with RA severity, disability, disease activity, response to treatment over the first year in early arthritis patients. Methods Patients presenting with synovitis of at least 2 joints for 6 weeks to 6 months were included in the multicenter French ESPOIR cohort. 25OH vitamin D2 and D3 was measured at baseline and then separated into 3 groups: deficiency (<10 ng/ml), insufficiency (10-30 ngl/mL), normal level (≥30ng/mL). Correlation between vitamin D levels and DAS28, HAQ and van der Heijde modified total Sharp score (mTSS) were assessed at baseline by a Spearman correlation analysis. Bivariate analyses of the association between baseline vitamin D level and other outcomes were conducted: radiographic progression defined by an increase of at least 1 point of the mTSS at 12 months; disability (defined by an HAQ≥1); disease activity (DAS28) and RA diagnosis (2010 ACR/EULAR criteria) at baseline, 6 and 12 months; response to treatment (EULAR response) at 6 and 12 months. Forward stepwise multiple logistic regression was used to evaluate independent association between baseline variables and formerly described outcomes. Results Among 813 patients included in the cohort, 810 were analyzed and 138 (16.97%), 522 (64.21%), 150 (18.45%) had vit D<10, 10-30 and ≥30ng/mL respectively. Vitamin D levels were found to be correlated with DAS28, mTSS and HAQ at baseline (Rho=-0.11, p=0.0016; Rho=-0.07, p=0.0335 and Rho=-0.11, p=0.0016 respectively). In bivariate analyses, patients with vitamin D deficiency had more radiographic progression at 12 months compared to vitamin D normal group (OR=1.82 95% CI 1.05-3.15, p=0.0323). Patients with a HAQ ≥1 were more frequent in deficiency group compared to normal group at baseline and 6 months (OR=1.89 95% CI 1.18-3.03, p=0.008 and OR=2 95% CI 1.15-3.49 p=0.0146 respectively). Patients with DAS28>5.1 were more frequent in deficiency group compared to normal group at baseline (OR=1.84 95%CI 1.15-2.87 p=0.011). There was no link between vitamin D level and RA diagnosis at baseline, 6 and 12 months nor with response to treatment at 6 and 12 months. In multivariate analysis, radiographic progression at 12 months was associated with vitamin D deficiency (OR=1.95 95% CI 1.05-3.62, p=0.038), age, ACPA, CRP, alcohol consumption and season of onset. Likewise, disability at baseline was associated with vitamin D deficiency (OR=1.73 95% CI 1.05-2.85, p=0.03), age, CRP, corticosteroid use and disease duration; disability at 6 months was associated with vitamin D deficiency (OR=2.01 95% CI 1.15-3.52, p=0.025), age and sex. Conclusions Vitamin D deficiency may be predictive of radiographic progression at 1 year and is associated with increased disability at baseline and 6 months in early arthritis patients. These data reinforce the role of environmental factors in the development and outcome of RA. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):432.2-432. DOI:10.1136/annrheumdis-2015-eular.3951 · 10.38 Impact Factor

  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):99.1-99. DOI:10.1136/annrheumdis-2015-eular.5149 · 10.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Little is known about the pathogenesis of fatigue, a hallmark of primary Sjögren's syndrome. The respective contribution of depression, disease activity, or auto-immunity itself has never been studied ever since international disease activity scores were established. We therefore investigated the association between fatigue and other characteristics of the disease in a large multi-center prospective cohort. Methods ASSESS is a multi-center prospective cohort which included 395 patients. At baseline and every year of the follow-up, systemic disease activity and patient-related outcome are evaluated by the ESSDAI and ESSPRI (the average of patient's visual analogic scales (VAS) for fatigue, pain and dryness), respectively, and patients fill questionnaires including the Hospital Anxiety and Depression (HAD) scale. Serum markers of B-cell activation, BAFF, interferon (IFN)-inducible chemokines, and IL-21 were assessed. Results Median (25th-75th) fatigue VAS was 6 (4-8). Fatigue VAS was correlated with dryness VAS (r=0.46, p<0.0001) and pain VAS (r=0.54, p<0.0001). Fatigue VAS was not correlated with age or disease duration, the ESSDAI, unstimulated salivary flow or Schirmer's test. Fatigue VAS was significantly higher in patients with depression (defined by a HAD subscale for depression (HAD-D) ≥8 (median fatigue VAS of 7 (6-9) in patients with depression and of 6 (4-8) in patients without depression, p<0.0001). In patients without depression, fatigue VAS remained not associated with anti-SSA, the ESSDAI, unstimulated salivary flow and Schirmer's test. Among patients without depression, a high fatigue VAS (≥5, the median of fatigue VAS in these patients) was not associated with a higher level of serum IFN-inducible chemokines (CCL2, CXCL10, CCL19), B-cell activating cytokines such as BAFF or IL-21, markers of B-cell activation (total Ig levels, free light chains of immunoglobulins, rheumatoid factor levels). Conclusions These results confirm the diversity of factors associated with fatigue in primary Sjögren's syndrome, including depression and the two other main symptoms, dryness and pain. Even when focusing on patients without depression, no association was observed between fatigue and systemic disease activity, autoantibody profile, serum surrogate markers of the IFN signature and of B-cell activation. Further work is necessary to determine the existence of potential other immunological drivers. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):796.2-796. DOI:10.1136/annrheumdis-2015-eular.3949 · 10.38 Impact Factor

  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):803.2-804. DOI:10.1136/annrheumdis-2015-eular.6116 · 10.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background High throughput study of metabolic pathways might help identify new biomarkers and therapeutic targets in autoimmune diseases. Primary Sjögren's syndrome (pSS) currently lacks prognostic biomarkers and efficacious and specific treatments. We therefore assessed serum levels of 35 metabolites in pSS using high-resolution magic-angle spinning (HRMAS) proton magnetic resonance spectroscopy. Methods The blood samples of 194 patients with pSS enrolled in the prospective multicenter ASSESS cohort and 41 blood donors were analysed in this study. After cryopreservation at -80°C, the samples were studied with HRMAS proton magnetic resonance spectroscopy (1H-MRS). Spectra were recorded on a Bruker Avance III 500 spectrometer operating at a proton frequency of 500 MHz. All the 1D NMR spectra were acquired during 76 min. Supervised clustering was performed on the spectral region between 0.5 and 4.7 ppm using partial least square discriminant analysis (PLS-DA). Results Supervised clustering of the 194 samples allowed to discriminate all patients with pSS from healthy controls (R2Y=0.88 and Q2=0.86 (figure 1)). Interestingly, 4 serum metabolites were significantly increased in pSS compared to healthy controls: threonine, lactate, glutamine and acetate. 6 metabolites were significantly decreased in pSS compared to healthy controls: myo-inositol, creatine, lysine, aspartate, glutamate and alanine Conclusions This first high-throughput analysis of metabolic pathways disclosed a specific metabolomic signature of pSS allowing discriminating all patients with pSS from controls. This new and very potent means of metabolic analysis may help to increase our knowledge on the pathogenesis of pSS, identify biomarkers, and new therapeutic targets. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):948.2-948. DOI:10.1136/annrheumdis-2015-eular.3978 · 10.38 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objectives To characterize and quantify systemic involvement at diagnosisinalarge international cohort of patients diagnosed with primary Sjogren syndrome (SS). Methods The Big Data Sjögren Project is an international, multicenter registry formed in 2014 with the aim of taking a “high-definition” picture of the main features of primary SS at diagnosis by merging international SS databases. By January 2015, the database included 5027 consecutive patients fulfilling the 2002 classification criteria for primary SS from 13 countries (9 European, 4 American). Systemic involvement was defined according to the ESSDAI and retrospectively calculated. Results Baseline ESSDAI data was collected in3314 patients (94% female, mean age at diagnosis 54.25 years). The main features of systemic involvement at diagnosis included biological activity in 43%of patients, articular involvement in 35%, hematological activity in 25%and glandular involvementin 19%. The mean ESSDAI score at diagnosis of the entire cohort was 5.63 (range, 0-62). Low DAS was reported in 1267 (38%) patients, moderate DASin 943 (28%) and high DAS in 378 (11%) patients; in the remaining 726 patients (22%), the ESSDAI score at diagnosis was 0. The mean baseline ESSDAI was higher in males (7.33 vs 5.52, p<0.001), patients diagnosed ≤35 years (6.71 vs 5.63, p=0.001), those with positive ocular tests (5.75 vs 4.98, p=0.023) and those with positive immunological markers including ANA (6.71 vs 4.63, p<0.001), RF (7.46 vs 5.49, p<0.001), anti-Ro/SSA (6.77 vs 5.48, p<0.001) and anti-La/SSB (6.91 vs 6.0, p<0.001). According to the number of criteria fulfilled at diagnosis, a higher mean baseline ESSDAI was found in patients fulfilling the six criteria (7.67 vs 5.65 in those fulfilling 5 criteria and 5.23 in those fulfilling 3-4 criteria, p<0.001). Conclusions Epidemiological features (male sex, younger age at diagnosis) and positive autoantibodies at diagnosis were closely-related to greater systemic activity. Using the ESSDAI in real-life situations may help identify epidemiological and immunological subsets with high systemic activity at diagnosis and, therefore, at high risk of suffering a complicated clinical course. Disclosure of Interest None declared
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):578.2-578. DOI:10.1136/annrheumdis-2015-eular.4752 · 10.38 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In this study, we sought to address changes in blood lymphocyte subpopulations and labial salivary gland (LSG) inflammation after belimumab treatment in patients with primary Sjögren's syndrome (pSS) and to identify predictors of response to treatment. Sequential blood lymphocyte subsets and LSG biopsies were analysed between week 0 (W0) and W28 in 15 patients with pSS treated with belimumab. Systemic response to treatment was defined as a decrease in the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index score of ≥3 points at W28. After belimumab, we observed a decrease in blood B lymphocytes primarily involving CD27-negative/immunoglobulin D-positive naïve B cells (p=0.008). Lymphocytic sialadenitis (focus score >1) that was present in 12 patients (80.0 %) before belimumab treatment became negative in 5 of them after treatment (p=0.03). The median (interquartile range) LSG B-cell/T-cell ratio decreased from 0.58 (0.5-0.67) to 0.50 (0.5-0.5) (p=0.06). B-cell activating factor (BAFF) staining was detected in 11 (78.6 %) of 14 patients before belimumab treatment compared with 7 (50.0 %) of 14 after belimumab therapy (p=0.10). The median percentage of BAFF-positive cells in foci significantly decreased from 27.5 % (10-40) to 5 % (0-20) (p=0.03). A systemic response was achieved in six patients (40 %). The only predictor of response was the presence of a low number of natural killer (NK) cells, both in blood (8.5 % [7-10] vs 11 % [9-21]; p=0.04) and in LSG (20.6/mm(3) [20.0-21.4] vs 30.0/mm(3) [25.0-100.0], p=0.003). Serum BAFF levels did not influence response to treatment. Low blood and salivary NK cell numbers are associated with a better response to belimumab. This suggests that two distinct subsets of pSS may exist: one with a predominant type I interferon (IFN)-BAFF-B-cell axis, representing good responders to belimumab; and one with a predominant type II IFN-NK cell axis, representing non-responders. ClinicalTrials.gov identifier: NCT01160666 . Registered 9 July 2010.
    Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):339.3-340. DOI:10.1136/annrheumdis-2015-eular.5261 · 10.38 Impact Factor

  • Annals of the Rheumatic Diseases 06/2015; 74(Suppl 2):579.1-579. DOI:10.1136/annrheumdis-2015-eular.5236 · 10.38 Impact Factor

Publication Stats

1k Citations
565.31 Total Impact Points


  • 2015
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      • Service de Rhumatologie
      Lutetia Parisorum, Île-de-France, France
  • 2011-2015
    • Assistance Publique – Hôpitaux de Paris
      • Département de Médecine Interne
      Lutetia Parisorum, Île-de-France, France
  • 2010-2015
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 2007-2014
    • Université René Descartes - Paris 5
      • • Faculté de Médecine
      • • Faculty of medicine
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2012
    • Hôtel-Dieu de Paris – Hôpitaux universitaires Paris Centre
      Lutetia Parisorum, Île-de-France, France
  • 2008-2011
    • Hôpital Bichat - Claude-Bernard (Hôpitaux Universitaires Paris Nord Val de Seine)
      Lutetia Parisorum, Île-de-France, France