Jacques-Eric Gottenberg

Unité Inserm U1077, Caen, Lower Normandy, France

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Publications (102)467.04 Total impact

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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;
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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;
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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; · 0.37 Impact Factor
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    ABSTRACT: . The aims of this study were to determine the incidence and prevalence of inflammatory myopathies (IMs), their epidemiological tendencies over time and their possible key determinants.
    Rheumatology (Oxford, England) 07/2014; · 4.24 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. · 29.98 Impact Factor
  • Revue du Rhumatisme 07/2014;
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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; · 0.87 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; · 4.24 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. · 2.89 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. · 8.11 Impact Factor
  • Joint, bone, spine: revue du rhumatisme 02/2014; · 2.25 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). · 13.98 Impact Factor
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    ABSTRACT: Follicular helper T cells (Tfh), which play a pivotal role in B cell activation and differentiation in lymphoid structures, secrete IL-21 whose augmented secretion is a hallmark of several autoimmune diseases. To decipher the cellular and molecular interactions occurring in salivary glands of patients suffering from primary Sjögren's syndrome (pSS), we investigated whether salivary gland epithelial cells (SGECs) were capable to induce Tfh differentiation. Co-cultures of naïve CD4(+) T cells and SGECs from both patients with pSS and controls were performed. Here, we report that IL-6 and ICOSL expression by SGECs contributes to naïve CD4(+) T differentiation into Tfh cells, as evidenced by their acquisition of a specific phenotype, characterized by Bcl-6, ICOS and CXCR5 expression and IL-21 secretion, but also but by their main functional feature: the capacity to enhance B lymphocytes survival. We demonstrated an increase of serum IL-21 with systemic activity. Finally, we analyzed the potential occurrence of a genetic association between IL-21 or IL-21R gene polymorphisms and pSS or elevated IL-21 secretion. This study, which demonstrates a direct induction of Tfh differentiation by SGECs, emphasizes a yet unknown pathogenic role of SGECs and suggests that Tfh and IL-21 might be relevant biomarkers and/or therapeutic targets in primary Sjögren's syndrome.
    Journal of Autoimmunity 01/2014; · 8.15 Impact Factor
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    ABSTRACT: Lymphocytic infiltration of different exocrine and non-exocrine epithelia is the pathological hallmark of primary Sjögren's syndrome, whereas involvement of salivary and lachrymal glands with the clinical counterpart of dry eye and dry mouth are the predominant features of the disease, together with fatigue and musculoskeletal pain. In addition, systemic manifestations, like arthritis, skin vasculitis, peripheral neuropathy, glomerulonephritis, may also be present in a consistent number of patients. As result, clinical features in SS can be divided into two facets: the benign subjective but disabling manifestations such as dryness, pain and fatigue, and the systemic manifestations. In the past decades, great efforts have been made to develop valid tools for the assessment of these both facets. Disease specific questionnaires such as Profile of Fatigue and Discomfort (PROFAD) and Sicca Symptom Inventory (SSI) have been proposed for evaluation of patients' symptoms, whereas different composite indexes have been suggested for the assessment of systemic disease activity. After that, an international project supported by EULAR, emerged to develop consensus disease activity indexes: the EULAR Sjögren's Syndrome Patients Reported Index (ESSPRI), and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), a systemic activity index to assess systemic manifestations. Both EULAR indexes have been developed in an international collaboration to be consensual. Both indices have now been validated in a large independent international cohort. They both have been shown to be feasible, valid and reliable instruments. Also, we have found that these two scores did not correlate, suggesting that these two indexes assess two different disease components that poorly overlap, but were complementary. The sensitivity to change of both scores has been assessed, they are both able to detect change, however, ESSDAI score, like other systemic score, is more sensitive to change than ESSPRI and other patient scores. Current work is ongoing to define disease activity levels and clinically important changes for defining significant clinical improvement with the systemic score ESSDAI, and ESSPRI. We hope that this increased knowledge on the way to assess patients with primary SS, along with the emergence of new targeted therapy, will put a great input in the improvement of conduction of clinical trials in pSS.
    Journal of Autoimmunity 01/2014; · 8.15 Impact Factor
  • Ghada Alsaleh, Jacques-Eric Gottenberg
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    ABSTRACT: MicroRNAs (miRNAs) have emerged as key players in the degradation of target mRNAs. They have been associated with diverse biological processes, and recent studies have demonstrated that miRNAs play a role in inflammatory responses. The identification of miRNA and their corresponding messenger RNA (mRNA) targets can therefore be very helpful. In this chapter, we first overview the field of miRNAs and then show the fundamental techniques for the identification of miRNAs and confirmation of their role on target mRNAs.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1142:55-63. · 1.29 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 01/2014; 9(10):e111266. · 3.53 Impact Factor
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    ABSTRACT: Objective Patients with primary Sjögren's syndrome (SS) are at greater risk of developing lymphoma. This study was undertaken to evaluate whether the Fms-like tyrosine kinase 3 ligand (Flt-3L) might be associated with lymphoma in primary SS. Methods Serum levels of Flt-3L were measured in 369 patients with primary SS from the French Assessment of Systemic Signs and Evolution of Sjögren's Syndrome study cohort and in 10 patients with primary SS at the time of lymphoma diagnosis in an Italian cohort. Associations between increased levels of Flt-3L and a history of lymphoma, history of previously diagnosed criteria related to a high risk of lymphoma, and greater extent of disease activity were evaluated. ResultsAmong patients with primary SS, higher levels of Flt-3L were significantly associated with a history of lymphoma (P = 0.0001). Previous markers for risk of lymphoma development, such as presence of purpura, low levels of C4, presence of lymphocytopenia, low levels of IgM, high levels of β2-microglobulin, and a higher primary SS disease activity score, were all associated with higher levels of Flt-3L. The levels of Flt-3L were also increased in serum obtained from patients with primary SS at the time of lymphoma diagnosis. Furthermore, the Flt-3L levels were elevated in the serum of 6 patients up to 94 months (mean 46 months) prior to the diagnosis of lymphoma. Receiver operating characteristic curve analysis showed that an Flt-3L level of 175 pg/ml was the ideal cutoff value for demonstrating an association with lymphoma (specificity 97.5%, sensitivity 44%, negative predictive value 97%). Conclusion Flt-3L is associated with lymphoma in primary SS, and constitutes a good biologic marker. Higher levels of this cytokine are present several years before the diagnosis of lymphoma, and may be useful as a predictive marker of lymphoproliferative disorders in primary SS.
    Arthritis & Rheumatology 12/2013; 65(12). · 7.48 Impact Factor
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    ABSTRACT: Whipple disease is a rare infection caused by Tropheryma whipplei. Although patients commonly complain of osteoarticular involvement, musculoskeletal manifestations have been poorly described. We report cases of Whipple disease with rheumatic symptoms and describe their clinical presentation, modes of diagnosis, and outcomes. This retrospective multicenter study included patients with Whipple disease diagnosed and referenced between 1977 and 2011 in 10 rheumatology centers in France and Italy. Twenty-nine patients were included. The median age was 55 years. The median time to diagnosis from first symptoms was 5 years. Polyarthritis was the most frequent presentation (20/29), and was most often chronic, intermittent (19/29), seronegative (22/23), and nonerosive (22/29). In all cases, the symptoms had led to incorrect diagnosis of inflammatory rheumatic disease and immunosuppressants, including biotherapy, were prescribed in most cases (24/29) without success. The diagnosis of Whipple disease was made by histological analysis, molecular biology tests, or both in 21%, 36%, and 43% of the cases, respectively. Duodenal biopsies were performed in most cases (86%). Synovial biopsies were performed in 18% of cases, but all contributed to diagnosis. The clinical outcomes after antibiotic therapy were good for all patients. Polyarthritis is the main feature observed in cases of Whipple disease; it is seronegative and associated with general and gastrointestinal symptoms. The molecular analysis of duodenal tissue and/or other tissues remains the method of choice to confirm the diagnosis. Reducing the time to diagnosis is important because severe late systemic and fatal forms of the disease may occur.
    The Journal of Rheumatology 11/2013; · 3.26 Impact Factor
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    ABSTRACT: Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease characterized by a lymphocytic exocrinopathy. However, patients often have evidence of systemic autoimmunity, and they are at markedly increased risk for the development of non- Hodgkin's lymphoma. Similar to other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, although the precise etiology remains uncertain. NCR3/NKp30 is a natural killer (NK)-specific activating receptor regulating the cross talk between NK and dendritic cells and type II IFN secretion. We performed a case-control study of genetic polymorphisms of the NCR3/NKp30 gene and found that rs11575837 (G>A) residing in the promoter was associated with reduced gene transcription and function as well as protection to pSS. We also demonstrated that circulating levels of NCR3/NKp30 were significantly increased among pSS patients compared with controls and correlated with higher NCR3/NKp30 but not CD16-dependent IFN-γ secretion by NK cells. Excess accumulation of NK cells in minor salivary glands correlated with the severity of the exocrinopathy. B7H6, the ligand of NKp30, was expressed by salivary epithelial cells. These findings suggest that NK cells may promote an NKp30-dependent inflammatory state in salivary glands and that blockade of the B7H6/NKp30 axis could be clinically relevant in pSS.
    Science translational medicine 07/2013; 5(195):195ra96. · 10.76 Impact Factor
  • Coralie Varoquier, Jean-Hugues Salmon, Jean Sibilia, Jacques-Éric Gottenberg
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    ABSTRACT: Sjögren's syndrome is a frequent autoimmune disease but its diagnostis is sometimes diffcult and delayed, because of miscellaneous symptoms. The most frequent clinical features include oral and ocular dryness, asthenia and pain. However, extraglandular manifestations concern one third of patients and severe complications, such as lymphoma, can reveal the disease. American European Consensus Group Criteria are used in current practice. They take into account subjective and objective clinical parameters and immunological and histological criteria. New criteria, recently proposed by the ACR, take into account objective ocular dryness, salivary lymphocytic infiltrates and the presence of immunological abnormalities (antinuclear and rheumatoid factors or anti-SSA/SSB). Primary Sjögren's syndrome must continue to benefit from a consensual diagnostic approach to ensure the quality of basic and clinical research and the applicability of their results to all patients. A group of international experts are currently working to reach a new consensus for the diagnosis of the disease.
    Revue du Rhumatisme Monographies 02/2013; 80(1):20–25.

Publication Stats

2k Citations
467.04 Total Impact Points

Institutions

  • 2012–2014
    • Unité Inserm U1077
      Caen, Lower Normandy, France
    • CHRU de Strasbourg
      Strasburg, Alsace, France
  • 2007–2014
    • University of Strasbourg
      • Institut de Biologie Moléculaire et Cellulaire (IBMC)
      Strasburg, Alsace, France
    • Université René Descartes - Paris 5
      • Faculté de Médecine
      Paris, Ile-de-France, France
  • 2013
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
    • Institut de Cancérologie Gustave Roussy
      Île-de-France, France
  • 2006–2012
    • Université Paris-Sud 11
      Orsay, Île-de-France, France
  • 2011
    • University Hospital Estaing of Clermont-Ferrand
      Clermont, Auvergne, France
  • 2009–2010
    • Assistance Publique Hôpitaux de Marseille
      • Service de rhumatologie 2
      Marseille, Provence-Alpes-Cote d'Azur, France
  • 2004–2008
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2003
    • Hôpital Bicêtre (Hôpitaux Universitaires Paris-Sud)
      Lutetia Parisorum, Île-de-France, France