Institut de recherche biomédicale
     

    Systemic sclerosis

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    Principal investigator: Yannick Allanore

    Contact : yannick.allanore[at]inserm.fr – Phone : +33 1 58 41 25 63

     

    Objective

    Systemic sclerosis (SSc) is an orphan disease characterized by vascular, immune and connective tissue anomalies. Among the many different immune-mediated rheumatic diseases, SSc stands out as a severely incapacitating and life-threatening disease, the pathogenesis of which is largely unknown and for which therapeutic options are few and insufficient. SSc is not inherited in a Mendelian fashion and it is believed that both genetic and environmental factors contribute to disease susceptibility and disease progression.

    Our group is from a long time committed to decipher the genetics of SSc through several large multinational candidate gene studies and the recent achievement of  genome-wide association studies (including a trans-ethnic meta-gwas). Major progresses have been recently achieved and several risk loci have been identified, most of them are involved in autoimmunity. This is a major breakthrough in SSc, switching to a new paradigm of the disease which was until recently considered only as a fibroblast dysfunction condition. However, this also raises new questions such as the precise role of these immune genes on SSc phenotype in comparison to other autoimmune diseases to which they are also often associated. Therefore, there is a clear need to proceed now to their functional validation through a translational approaches. To this end, we aim to delineate the role of SSc-associated genes and to unravel the molecular pathways by which they are implicated in tissue fibrosis with the use of relevant and complementary SSc animal models

    Therefore, we are using genetic and also genomic unbiased approaches to identify some actors that could contribute to the vascular, immune and fibrotic disturbances that characterize SSc. We have the skills to investigate in depth relevant cellular models and animal models to determine whether the candidate deserves or not a follow-up in this context. We will use genome editing technology to provide empirical evidence as to target genes and the functionnal importance of identified elements containing SSc-associated variants. If the target appears as relevant and robust, we have internal resources and collaborations to determine the value and performance of the candidate as a biomarker or therapeutic target.

    Concomitantly, we are performing several clinical and epidemiological research projects in particular in the cardiovascular aspects of the disease and also to try to improve riskstratification of SSc patients with the aim to improve SSc clinical trials.

    Our group has been labelled as a French Center of Reference for « rare systemic autoimmune diseases » and also a European center of excellence within the ERNs called and the network RECONNET.

     

    People

    Jérome Avouac, MD, PhD, Assistant professor

    Julien Wipff, MD, PhD,

    Muriel Elhai, MD, PhD, assistant professor

    Anne Cauvet Burgein , ingeneer

    Sonia Pezet, technician

    Virginie Gonzalez, Research Technician
     

    Camelia Frantz, PhD student

    Boleto Gonçalo, Master 2 student

     

    Funding

    • INSERM : ATIP/AVENIR Programme
    • Société Française de Rhumatologie
    • Courtin Arthritis Foundation
    • Association des Sclérodermies de France
    • SATT Ile de France
    • Pharmaceutical compagnies : Sanofi, Roche, Inventiva, BMS

     

    Main publications

    BASIC and TRANSLATIONAL:

    Terao C, Kawaguchi T, Dieude P, Varga J, Kuwana M, Hudson M, Kawaguchi Y, Matucci-Cerinic M, Ohmura K, Riemekasten G, Kawasaki A, Airo P, Horita T, Oka A, Hachulla E, Yoshifuji H, Caramaschi P, Hunzelmann N, Baron M, Atsumi T, Hassoun P, Torii T, Takahashi M, Tabara Y, Shimizu M, Tochimoto A, Ayuzawa N, Yanagida H, Furukawa H, Tohma S, Hasegawa M, Fujimoto M, Ishikawa O, Yamamoto T, Goto D, Asano Y, Jinnin M, Endo H, Takahashi H, Takehara K, Sato S, Ihn H, Raychaudhuri S, Liao K, Gregersen P, Tsuchiya N, Riccieri V, Melchers I, Valentini G, Cauvet A, Martinez M, Mimori T, Matsuda F, Allanore Y. Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.Ann Rheum Dis. 2017 Jun;76(6):1150-1158. 

    Avouac J, Konstantinova I, Guignabert C, Pezet S, Sadoine J, Guilbert T, Cauvet A, Tu L, Luccarini JM, Junien JL, Broqua P, Allanore Y. Pan-PPAR agonist IVA337 is effective in experimental lung fibrosis and pulmonary hypertension. Ann Rheum Dis. 2017 76(11):1931-1940

    Ruzehaji N, Frantz C, Ponsoye M, Avouac J, Pezet S, Guilbert T, Luccarini JM, Broqua P, Junien JL, Allanore Y. Pan PPAR agonist IVA337 is effective in prevention and treatment of experimental skin fibrosis. Ann Rheum Dis. 2016 Dec;75(12):2175-2183.

    Elhai M, Avouac J, Hoffmann-Vold AM, Ruzehaji N, Amiar O, Ruiz B, Brahiti H, Ponsoye M, Fréchet M, Burgevin A, Pezet S, Sadoine J, Guilbert T, Nicco C, Akiba H, Heissmeyer V, Subramaniam A, Resnick R, Molberg Ø, Kahan A, Chiocchia G, Allanore Y. OX40L blockade protects against inflammation-driven fibrosis. Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):E3901-10.

    Ponsoye M, Frantz C, Ruzehaji N, Nicco C, Elhai M, Ruiz B, Cauvet A, Pezet S, Brandely ML, Batteux F, Allanore Y, Avouac J. Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis. Ann Rheum Dis. 2016 Dec;75(12):2142-2149.

    Arismendi M, Giraud M, Ruzehaji N, Dieudé P, Koumakis E, Ruiz B, Airo P, Cusi D, Matucci-Cerinic M, Salvi E, Cuomo G, Hachulla E, Diot E, Caramaschi P, Riccieri V, Avouac J, Kayser C, Allanore Y. Identification of NF-κB and PLCL2 as new susceptibility genes and highlights on a potential role of IRF8 through interferon signature modulation in systemic sclerosis. Arthritis Res Ther. 2015 Mar 21;17:71.

    Ruzehaji N, Avouac J, Elhai M, Frechet M, Frantz C, Ruiz B, Distler JH, Allanore Y Combined effect of genetic background and gender in a mouse model of bleomycin-induced skin fibrosis. . Arthritis Res Ther. 2015 May 30;17:145.

    Avouac J, Palumbo-Zerr K, Ruzehaji N, Tomcik M, Zerr P, Dees C, Distler A, Beyer C, Schneider H, Distler O, Schett G, Allanore Y, Distler JH. The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor β and contributes to the development of experimental dermal fibrosis. Arthritis Rheumatol. 2014 Nov;66(11):3140-50.

     

    CLINICAL and EPIDEMIOLOGICAL:

    Terao C, Kawaguchi T, Dieude P, Varga J, Kuwana M, Hudson M, Kawaguchi Y, Matucci-Cerinic M, Ohmura K, Riemekasten G, Kawasaki A, Airo P, Horita T, Oka A, Hachulla E, Yoshifuji H, Caramaschi P, Hunzelmann N, Baron M, Atsumi T, Hassoun P, Torii T, Takahashi M, Tabara Y, Shimizu M, Tochimoto A, Ayuzawa N, Yanagida H, Furukawa H, Tohma S, Hasegawa M, Fujimoto M, Ishikawa O, Yamamoto T, Goto D, Asano Y, Jinnin M, Endo H, Takahashi H, Takehara K, Sato S, Ihn H, Raychaudhuri S, Liao K, Gregersen P, Tsuchiya N, Riccieri V, Melchers I, Valentini G, Cauvet A, Martinez M, Mimori T, Matsuda F, Allanore Y. Transethnic meta-analysis identifies GSDMA and PRDM1 as susceptibility genes to systemic sclerosis.Ann Rheum Dis. 2017 Jun;76(6):1150-1158. 

    Valentini G, Iudici M, Walker UA, Jaeger VK, Baron M, Carreira P, Czirják L, Denton CP, Distler O, Hachulla E, Herrick AL, Kowal-Bielecka O, Pope J, Müller-Ladner U, Riemekasten G, Avouac J, Frerix M, Jordan S, Minier T, Siegert E, Ong VH, Vettori S, Allanore Y. The European Scleroderma Trials and Research group (EUSTAR) task force for the development of revised activity criteria for systemic sclerosis: derivation and validation of a preliminarily revised EUSTAR activity index. Ann Rheum Dis. 2017 Jan;76(1):270-276.

    Elhai M, Avouac J, Walker UA, Matucci-Cerinic M, Riemekasten G, Airò P, Hachulla E, Valentini G, Carreira PE, Cozzi F, Balbir Gurman A, Braun-Moscovici Y, Damjanov N, Ananieva LP, Scorza R, Jimenez S, Busquets J, Li M, Müller-Ladner U, Kahan A, Distler O, Allanore Y; EUSTAR co-authors. A gender gap in primary and secondary heart dysfunctions in systemic sclerosis: a EUSTAR prospective study. Ann Rheum Dis. 2016 Jan;75(1):163-9.

    Avouac J, Walker UA, Hachulla E, Riemekasten G, Cuomo G, Carreira PE, Caramaschi P, Ananieva LP, Matucci-Cerinic M, Czirjak L, Denton C, Ladner UM, Allanore Y; EUSTAR collaborators*; EUSTAR collaborators. Joint and tendon involvement predict disease progression in systemic sclerosis: a EUSTAR prospective study. Ann Rheum Dis. 2016 Jan;75(1):103-9.

     

    PATENTS:

    Patent (prioritary) n° EP16020154.7, untiled «INHIBITORS FOR TREATING OR PREVENTING A PULMONARY ARTERIAL HYPERTENSION IN SYSTEMIC SCLEROSIS PATIENTS AND METHOD FOR DIAGNOSING SAID DISEASE», submitted on April 26th 2016.

     

     

     

     

     

     

     

     

     

     

     

     

     

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