Jacques-Eric Gottenberg

University of Strasbourg, Strasburg, Alsace, France

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Publications (110)551.38 Total impact

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    ABSTRACT: To reach a European consensus on the definition and characterization of the main organ-specific extraglandular manifestations in primary SS. 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. 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. 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. © 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) 07/2015; DOI:10.1093/rheumatology/kev200 · 4.44 Impact Factor
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    ABSTRACT: Systemic Sclerosis (SSc) is a chronic multisystemic connective tissue disease characterized by progressive fibrosis affecting skin and internal organs. Despite serious efforts to unveil the pathogenic mechanisms of SSc, they are still unclear. High levels of Reactive Oxygen Species (ROS) in affected patients have been shown, and ROS are suggested to play a role in fibrosis pathogenesis. In this study we evaluate ROS levels in non-fibrotic and fibrotic skin of patients with SSc and we compare them with those obtained from healthy controls.
    Free Radical Biology and Medicine 07/2015; DOI:10.1016/j.freeradbiomed.2015.07.002 · 5.71 Impact Factor
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    ABSTRACT: To determine which outcome measures detected rituximab efficacy in the Tolerance and Efficacy of Rituximab in Sjögren's Disease (TEARS) trial and to create a composite endpoint for future trials in primary SS (pSS). Post hoc analysis of the multicentre randomized placebo-controlled double-blind TEARS trial. The results were validated using data from two other randomized controlled trials in pSS, assessing rituximab (single-centre trial in the Netherlands) and infliximab, respectively. Five outcome measures were improved by rituximab in the TEARS trial: patient-assessed visual analogue scale scores for fatigue, oral dryness and ocular dryness, unstimulated whole salivary flow and ESR. We combined these measures into a composite endpoint, the SS Responder Index (SSRI), and we defined an SSRI-30 response as a ≥30% improvement in at least two of five outcome measures. In TEARS, the proportions of patients with an SSRI-30 response in the rituximab and placebo groups at 6, 16 and 24 weeks were 47% vs 21%, 50% vs 7% and 55% vs 20%, respectively (P < 0.01 for all comparisons). SSRI-30 response rates after 12 and 24 weeks in the single-centre rituximab trial were 68% (13/19) vs 40% (4/10) and 74% (14/19) vs 40% (4/10), respectively. No significant differences in SSRI-30 response rates were found between infliximab and placebo at any of the time points in the infliximab trial. A core set of outcome measures used in combination suggests that rituximab could be effective and infliximab ineffective in pSS. The SSRI might prove useful as the primary outcome measure for future therapeutic trials in pSS. © 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) 05/2015; DOI:10.1093/rheumatology/kev114 · 4.44 Impact Factor
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    ABSTRACT: The clinical presentation and outcome of hepatitis E virus (HEV) infection in inflammatory rheumatic diseases are unknown. We aimed to investigate the severity of acute HEV infection and the risk of chronic viral replication in patients with inflammatory arthritides treated with immunosuppressive drugs.All rheumatology and internal medicine practitioners belonging to the Club Rhumatismes et Inflammation in France were sent newsletters asking for reports of HEV infection and inflammatory arthritides. Baseline characteristics of patients and the course of HEV infection were retrospectively assessed by use of a standardized questionnaire.From January 2010 to August 2013, we obtained reports of 23 cases of HEV infection in patients with rheumatoid arthritis (n = 11), axial spondyloarthritis (n = 5), psoriatic arthritis (n = 4), other types of arthritides (n = 3). Patients received methotrexate (n = 16), antitumor necrosis factor α agents (n = 10), rituximab (n = 4), abatacept (n = 2), tocilizumab (n = 2), and corticosteroids (n = 10, median dose 6 mg/d, range 2-20). All had acute hepatitis: median aspartate and alanine aminotransferase levels were 679 and 1300 U/L, respectively. Eleven patients were asymptomatic, 4 had jaundice. The HEV infection diagnosis relied on positive PCR results for HEV RNA (n = 14 patients) or anti-HEV IgM positivity (n = 9). Median follow-up was 29 months (range 3-55). Treatment included discontinuation of immunosuppressants for 20 patients and ribavirin treatment for 5. Liver enzyme levels normalized and immunosuppressant therapy could be reinitiated in all patients. No chronic infection was observed.Acute HEV infection should be considered in patients with inflammatory rheumatism and elevated liver enzyme values. The outcome of HEV infection seems favorable, with no evolution to chronic hepatitis or fulminant liver failure.
    Medicine 04/2015; 94(14):e675. DOI:10.1097/MD.0000000000000675 · 4.87 Impact Factor
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    ABSTRACT: Objectives To investigate the possible link between Porphyromonas gingivalis (P. gingivalis) infection and RA, according to antibody profile, genetic and environmental factors, and RA severity. Patients and Methods For assessing P. gingivalis infection, serum levels of antibodies directed against P. gingivalis LPS were measured in 694 early-RA patients not exposed to steroid or DMARD. Anti-P. gingivalis antibodies titers were compared between early-RA patients and various control groups, and according to various patients characteristics. Results The titre of anti-P. gingivalis antibodies did not significantly differ between RA and controls. Anti-P. gingivalis antibody titres did not significantly differ with ACPA, RF, or HLA-shared epitope status. Anti-P. gingivalis antibody titres were significantly higher among never smoker patients compared to ever-smoker (p= 0.0049). Among non-smokers, high anti-P. gingivalis antibody levels were associated with an higher prevalence of erosive change (mSHS erosion subscale ≥1: 47.5 vs. 33.3%, p=0.0135). Conclusion In this large early-RA cohort, we did not detect any association of anti-P. gingivalis antibodies with RA or with ACPA status. These results suggest that the association of periodontitis and RA could be linked to other bacterial species than P. gingivalis or to another mechanism than citrullination. Nevertheless we found higher anti-P. gingivalis antibody titres in non-smokers. In addition, in this population of non-smokers, high anti-P. gingivalis antibody titres were associated with a more severe disease. We hypothesize that the role of tobacco in RA pathogenesis is so high that the effect of P. gingivalis could be revealed only in a population not exposed to tobacco. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    Arthritis and Rheumatology 03/2015; DOI:10.1002/art.39118
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    ABSTRACT: To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögren's syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI). For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI. Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%. This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable. 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 12/2014; DOI:10.1136/annrheumdis-2014-206008 · 10.38 Impact Factor
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    ABSTRACT: We evaluated micro (mi) RNA-mediated regulation of BAFF expression in fibroblasts using two concomitant models: (i) synovial fibroblasts (FLS) isolated from healthy controls (N) or Rheumatoid Arthritis (RA) patients; (ii) human dermal fibroblasts (HDF) isolated from healthy controls (N) or Systemic Sclerosis (SSc) patients. Using RT-qPCR and ELISA, we first showed that SScHDF synthesized and released BAFF in response to Poly(I:C) or IFN-γ treatment, as previously observed in RAFLS, whereas NHDF released BAFF preferentially in response to IFN-γ. Next, we demonstrated that miR-30a-3p expression was down regulated in RAFLS and SScHDF stimulated with Poly(I:C) or IFN-γ. Moreover, we demonstrated that transfecting miR-30a-3p mimic in Poly(I:C)- and IFN-γ-activated RAFLS and SScHDF showed a strong decrease on BAFF synthesis and release and thus B cells survival in our model. Interestingly, FLS and HDF isolated from healthy subjects express higher levels of miR-30a-3p and lower levels of BAFF than RAFLS and SScHDF. Transfection of miR-30a-3p antisense in Poly(I:C)- and IFN-γ-activated NFLS and NHDF upregulated BAFF secretion, confirming that this microRNA is a basal repressors of BAFF expression in cells from healthy donors. Our data suggest a critical role of miR-30a-3p in the regulation of BAFF expression, which could have a major impact in the regulation of the autoimmune responses occurring in RA and SSc.
    PLoS ONE 10/2014; 9(10):e111266. DOI:10.1371/journal.pone.0111266 · 3.23 Impact Factor
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive devastating, yet untreatable fibrotic disease of unknown origin. We investigated the contribution of the B-cell activating factor (BAFF), a TNF family member recently implicated in the regulation of pathogenic IL-17-producing cells in autoimmune diseases. The contribution of BAFF was assessed in a murine model of lung fibrosis induced by airway administered bleomycin. We show that murine BAFF levels were strongly increased in the bronchoalveolar space and lungs after bleomycin exposure. We identified Gr1+ neutrophils as an important source of BAFF upon BLM-induced lung inflammation and fibrosis. Genetic ablation of BAFF or BAFF neutralization by a soluble receptor significantly attenuated pulmonary fibrosis and IL-1β levels. We further demonstrate that bleomycin-induced BAFF expression and lung fibrosis were IL-1β and IL-17A dependent. BAFF was required for rIL-17A-induced lung fibrosis and augmented IL-17A production by CD3+ T cells from murine fibrotic lungs ex vivo. Finally we report elevated levels of BAFF in bronchoalveolar lavages from IPF patients. Our data therefore support a role for BAFF in the establishment of pulmonary fibrosis and a crosstalk between IL-1β, BAFF and IL-17A.
    Journal of Autoimmunity 10/2014; 56. DOI:10.1016/j.jaut.2014.08.003 · 7.02 Impact Factor
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    ABSTRACT: Despite very different aetiologies and clinical expressions, advancing knowledge in the physiopathology and treatment of immune and inflammatory diseases (IID) prompts us to consider them as a whole. These are chronic, often incapacitating and painful illnesses that progress and destroy organs. Management by discipline too often leads to erroneous diagnoses and sometimes inappropriate treatment. More integrated translational research would further understanding of the complex relationships between cytokines and organ damage, which vary with the conditions and patients, making it possible to develop new biomarkers and personalize treatment. The research in France has very many strengths but its organization is fragmented. Better coordinated research into IID, which could be based on creating a strategic valorization field (domaine de valorisation stratégique, DVS) and thematic multi-organization institute (Institut thématique multi-organismes ITMO), would advance patient management.
    Thérapie 08/2014; DOI:10.2515/therapie/2014050 · 0.40 Impact Factor
  • Alain Meyer · Nicolas Meyer · Mickael Schaeffer · Jacques-Eric Gottenberg · Bernard Geny · Jean Sibilia
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    ABSTRACT: Methods. All original articles in English or French regarding the prevalence and/or incidence of IMs were searched. The methods of case ascertainment, epidemiological analysis and diagnostic criteria were systematically analysed. Results. Forty-six articles published between 1966 and 2013 were found in which the incidence of IMs as a whole ranged from 1.16 to 19/million/year and their prevalence ranged from 2.4 to 33.8 per 100 000 inhabitants. Methodological heterogeneities limited comparisons, although certain epidemiological tendencies were highlighted. The relative incidence of DM may follow a latitudinal gradient in the northern hemisphere that may be explained by the immunomodulatory action of ultraviolet radiation. The prevalence of sporadic inclusion body myositis (sIBM) was correlated with the frequency of HLA-DR3. Juvenile myositis onset was non-random over seasons and/or time, consistent with a role of infectious diseases, although other environmental factors may be involved. Disparities according to sex, age and geographical origin were also found. The frequency of IM increased over time, which may reflect progress in diagnostic performance, although there is still a need to increase the level of awareness with regard to these diseases, especially sIBM, as attested by its considerably delayed diagnosis. Conclusion. This first systematic literature review confirms the rarity of IM and may highlight certain genetic and environmental determinants of IM. There is a need for uniformity in diagnostic and classification criteria as well as more exhaustive case ascertainment to refine IM epidemiology.
    Rheumatology (Oxford, England) 07/2014; 54(1). DOI:10.1093/rheumatology/keu289 · 4.44 Impact Factor
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    ABSTRACT: Primary Sjögren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited.
    JAMA The Journal of the American Medical Association 07/2014; 312(3):249-58. DOI:10.1001/jama.2014.7682 · 30.39 Impact Factor
  • Revue du Rhumatisme 07/2014; DOI:10.1016/j.rhum.2013.12.008
  • Thérapie 07/2014; 69(4):291-296. DOI:10.2515/therapie/2014049 · 0.40 Impact Factor
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    ABSTRACT: Recently, the use and evaluation of biologics increased in systemic lupus erythematosus (SLE). However, no international recommendation is available concerning the use of biologics with regards to the subset of patients who should be treated, the optimal time to treat, the objective of treatment and the manner to discontinue it. To address these complex questions, we focused on biologics already evaluated in at least two published randomized controlled trials. We summarized the results of these trials and available observational data in registries. Taking into account the clinical evidence, we proposed some guidance on the way biologics could be used in SLE. Many areas of uncertainty persist and require intensifying efforts from the academic world to set up new trials, and develop international recommendations.
    La Presse Médicale 06/2014; DOI:10.1016/j.lpm.2014.04.006 · 1.17 Impact Factor
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    ABSTRACT: Objective. The response rate to many therapies for RA is lower in women. The aim of this study was to analyse the influence of gender on the response to rituximab (RTX) in patients with RA.Methods. A total of 1709 RA patients were included in the French Autoimmunity and Rituximab (AIR) registry. Disease activity assessed by the 28-joint DAS (DAS28) was recorded at baseline and at follow-up (6, 12, 18 and 24 months). Response criteria [European League Against Rheumatism (EULAR) remission defined as a DAS28 < 2.6 and EULAR response] were compared in both sexes.Results. Seventy-seven per cent of the patients were female (age 61.4 years, disease duration 16 years). Approximately 78.6% of the patients were positive for RF and 75.8% for anti-CCP. Women had a longer disease duration (P < 0.001), less frequently had anti-CCP (P = 0.03) and had lower CRP levels at baseline (P < 0.001). Six months after RTX, 11% were in remission and 62% had a good to moderate EULAR response, irrespective of gender (P = 0.81 and P = 0.38, respectively). No differences were observed in terms of remission or EULAR response during the follow-up except at 12 months, when men achieved remission more frequently (18% vs 12%, P = 0.045). In the cases of anti-TNF failure, remission rates were higher in men than in women at 6, 12 and 18 months. Re-treatment delay between the first and second courses was similar in both genders (P = 0.26).Conclusion. In this large cohort of RA patients we found no significant differences in EULAR response to RTX between men and women during the 2-years of follow-up, but there was a previous anti-TNF exposure-dependent effect of gender on remission rate.
    Rheumatology (Oxford, England) 05/2014; 53(10). DOI:10.1093/rheumatology/keu176 · 4.44 Impact Factor
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    ABSTRACT: Primary Sjögren's syndrome is a systemic autoimmune disease, characterized by a lymphocytic exocrinopathy. Oral and ocular dryness, asthenia and pain represent hallmarks of the disease. Systemic manifestations concern a third of patients, including lymphoma in 5% of the patients. The American European Consensus Group classification criteria have been used in current practice and clinical trials since 2002. New classification criteria were recently proposed by the American Congress of Rheumatology. A group of international experts are currently working to reach a new consensus between the American European Consensus Group classification criteria and the American Congress of Rheumatology proposal for disease classification. In addition, international consensus disease activity scores were recently established. Regarding treatment modalities, symptomatic treatments remain the cornerstone of therapy in pSS, but new biologic treatments are currently evaluated.
    Expert Review of Clinical Immunology 04/2014; 10(4):543-51. DOI:10.1586/1744666X.2014.897230 · 3.34 Impact Factor
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    ABSTRACT: A large body of evidence supports the role of microRNAs (miRNAs) in inflammatory diseases. Concerning rheumatoid arthritis (RA), several miRNAs exhibiting deregulated expression pattern were identified in various fluids (serum or synovial) or different cell types (macrophages, synoviocytes). The potential interest of these molecules as biomarkers is increasingly considered, but their precise mode of action still remains largely hypothetical because the identification of their physiological mRNA targets is challenging. To evaluate the overall importance of miRNAS in the pathogenesis of RA, we investigated the expression of genes involved in miRNA biogenesis in FLS isolated from healthy donors and RA patients. We also used a mouse mutant line carrying a hypomorphic mutation in the Dicer gene to monitor the impact of reduced miRNA maturation on experimental arthritis triggered by K/BxN serum transfer. Human FLS were isolated from synovial tissues from RA and OA patients and healthy controls after informed consent. Mice FLS were isolated from Dicer d/d and littermates controls. IL-6 release was measured in culture supernatants and following RNA extraction using TRIzol and reverse transcription, real-time quantitative RT-qPCR was performed. Handling of mice and procedures were in accordance with the French Law for the Protection of Laboratory Animals and reviewed by the Regional Ethical Committee for Animal Experimentation (CREMEAS) of the Strasbourg University (authorisation number A-67-345). Serum collected from 9-week old arthritic K/BxN mice was used to trigger arthritis in adult Dicer (d/d) and + / + mice by two successive i.p. injection (150 μL). The articular arthritis index was visually determined on a 0-4 scale (0 = no swelling or erythema, 4 = excessive edema with joint rigidity). Dicer is the only gene involved in the miRNA biogenesis pathway showing significantly reduced expression in FLS isolated from RA patients compared to controls or OA. Similarly, mutant mice (Dicer (d/d)) with reduced Dicer expression exhibit more severe arthritis symptoms upon K/BxN serum transfer. miRNAs are important players to keep pro inflammatory molecules under tight control. Mutations globally affecting mature miRNAs production represent a previously unidentified risk factor for RA.
    Annals of the rheumatic diseases 03/2014; 73 Suppl 1:A31. DOI:10.1136/annrheumdis-2013-205124.70 · 10.38 Impact Factor
  • Joint, bone, spine: revue du rhumatisme 02/2014; 81(3). DOI:10.1016/j.jbspin.2014.01.005 · 3.22 Impact Factor
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    ABSTRACT: Primary Sjögren syndrome (pSS) is an autoimmune disorder characterized by ocular and oral dryness or systemic manifestations. To evaluate efficacy and harms of rituximab in adults with recent-onset or systemic pSS. Randomized, placebo-controlled, parallel-group trial conducted between March 2008 and January 2011. Study personnel (except pharmacists), investigators, and patients were blinded to treatment group. (ClinicalTrials.gov: NCT00740948) SETTING: 14 university hospitals in France. 120 patients with scores of 50 mm or greater on at least 2 of 4 visual analogue scales (VASs) (global disease, pain, fatigue, and dryness) and recent-onset (<10 years) biologically active or systemic pSS. Randomization (1:1 ratio) to rituximab (1 g at weeks 0 and 2) or placebo. Primary end point was improvement of at least 30 mm in 2 of 4 VASs by week 24. No significant difference between groups in the primary end point was found (difference, 1.0% [95% CI, -16.7% to 18.7%]). The proportion of patients with at least 30-mm decreases in at least two of the four VAS scores was higher in the rituximab group at week 6 (22.4% vs. 9.1%; P = 0.036). An improvement of at least 30 mm in VAS fatigue score was more common with rituximab at weeks 6 (P < 0.001) and 16 (P = 0.012), and improvement in fatigue from baseline to week 24 was greater with rituximab. Adverse events were similar between groups except for a higher rate of infusion reactions with rituximab. Low disease activity at baseline and a primary outcome that may have been insensitive to detect clinically important changes. Rituximab did not alleviate symptoms or disease activity in patients with pSS at week 24, although it alleviated some symptoms at earlier time points. Programme Hospitalier de Recherche Clinique 2010.
    Annals of internal medicine 02/2014; 160(4). DOI:10.7326/M13-1085 · 16.10 Impact Factor

Publication Stats

3k Citations
551.38 Total Impact Points

Institutions

  • 2007–2015
    • University of Strasbourg
      • Institut de Biologie Moléculaire et Cellulaire (IBMC)
      Strasburg, Alsace, France
    • French National Centre for Scientific Research
      Lutetia Parisorum, Île-de-France, France
  • 2014
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2013–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2006–2010
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2003–2006
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France