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Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.
Hasni, Sarfaraz A; Gupta, Sarthak; Davis, Michael; Poncio, Elaine; Temesgen-Oyelakin, Yenealem; Carlucci, Philip M; Wang, Xinghao; Naqi, Mohammad; Playford, Martin P; Goel, Rishi R; Li, Xiaobai; Biehl, Ann J; Ochoa-Navas, Isabel; Manna, Zerai; Shi, Yinghui; Thomas, Donald; Chen, Jinguo; Biancotto, Angélique; Apps, Richard; Cheung, Foo; Kotliarov, Yuri; Babyak, Ashley L; Zhou, Huizhi; Shi, Rongye; Stagliano, Katie; Tsai, Wanxia Li; Vian, Laura; Gazaniga, Nathalia; Giudice, Valentina; Lu, Shajia; Brooks, Stephen R; MacKay, Meggan; Gregersen, Peter; Mehta, Nehal N; Remaley, Alan T; Diamond, Betty; O'Shea, John J; Gadina, Massimo; Kaplan, Mariana J.
Afiliación
  • Hasni SA; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA. hasnisa@mail.nih.gov.
  • Gupta S; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • Davis M; Systemic Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA.
  • Poncio E; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • Temesgen-Oyelakin Y; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • Carlucci PM; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • Wang X; Systemic Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA.
  • Naqi M; Systemic Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA.
  • Playford MP; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • Goel RR; Section of Inflammation and Cardiometabolic Diseases, National Heart Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA.
  • Li X; Systemic Autoimmunity Branch, NIAMS, NIH, Bethesda, MD, USA.
  • Biehl AJ; NIH Clinical Center Biostatistics and Clinical Epidemiology Service, Bethesda, MD, USA.
  • Ochoa-Navas I; Office of the Clinical Director, NIAMS, NIH, Bethesda, MD, USA.
  • Manna Z; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • Shi Y; Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, MD, USA.
  • Thomas D; Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.
  • Chen J; Arthritis and Pain Associates of PG County, Greenbelt, MD, USA.
  • Biancotto A; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Apps R; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Cheung F; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Kotliarov Y; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Babyak AL; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Zhou H; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Shi R; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Stagliano K; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Tsai WL; Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH, Bethesda, MD, USA.
  • Vian L; Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.
  • Gazaniga N; Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.
  • Giudice V; Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.
  • Lu S; Hematology Branch, NHLBI, NIH, Bethesda, MD, USA.
  • Brooks SR; Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.
  • MacKay M; Biodata Mining and Discovery Section, NIAMS, NIH, Bethesda, MD, USA.
  • Gregersen P; Feinstein Institute for Medical Research, Manhasset, NY, USA.
  • Mehta NN; Feinstein Institute for Medical Research, Manhasset, NY, USA.
  • Remaley AT; Section of Inflammation and Cardiometabolic Diseases, National Heart Lung and Blood Institute (NHLBI), NIH, Bethesda, MD, USA.
  • Diamond B; Translational Vascular Medicine Branch, NHLBI, NIH, Bethesda, MD, USA.
  • O'Shea JJ; Feinstein Institute for Medical Research, Manhasset, NY, USA.
  • Gadina M; Molecular Immunology and Inflammation Branch, NIAMS, NIH, Bethesda, MD, USA.
  • Kaplan MJ; Translational Immunology Section, NIAMS, NIH, Bethesda, MD, USA.
Nat Commun ; 12(1): 3391, 2021 06 07.
Article en En | MEDLINE | ID: mdl-34099646
Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study's primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels (p = 0.0006, CI 95%: 4.12, 13.32) and particle number (p = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration (p = 0.024, CI 95%: 1.1, -26.5), cholesterol efflux capacity (p = 0.08, CI 95%: -0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Pirimidinas / Aterosclerosis / Inhibidores de las Cinasas Janus / Lupus Eritematoso Sistémico Tipo de estudio: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Pirimidinas / Aterosclerosis / Inhibidores de las Cinasas Janus / Lupus Eritematoso Sistémico Tipo de estudio: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Adult / Aged / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido