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Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus

Author

Listed:
  • Sarfaraz A. Hasni

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH))

  • Sarthak Gupta

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH)
    Systemic Autoimmunity Branch, NIAMS, NIH)

  • Michael Davis

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH))

  • Elaine Poncio

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH))

  • Yenealem Temesgen-Oyelakin

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH))

  • Philip M. Carlucci

    (Systemic Autoimmunity Branch, NIAMS, NIH)

  • Xinghao Wang

    (Systemic Autoimmunity Branch, NIAMS, NIH)

  • Mohammad Naqi

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH))

  • Martin P. Playford

    (Section of Inflammation and Cardiometabolic Diseases, National Heart Lung and Blood Institute (NHLBI), NIH)

  • Rishi R. Goel

    (Systemic Autoimmunity Branch, NIAMS, NIH)

  • Xiaobai Li

    (NIH Clinical Center Biostatistics and Clinical Epidemiology Service)

  • Ann J. Biehl

    (Office of the Clinical Director, NIAMS, NIH)

  • Isabel Ochoa-Navas

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH))

  • Zerai Manna

    (Lupus Clinical Trials Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH))

  • Yinghui Shi

    (Translational Immunology Section, NIAMS, NIH)

  • Donald Thomas

    (Arthritis and Pain Associates of PG County)

  • Jinguo Chen

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Angélique Biancotto

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Richard Apps

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Foo Cheung

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Yuri Kotliarov

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Ashley L. Babyak

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Huizhi Zhou

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Rongye Shi

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Katie Stagliano

    (Trans-NIH Center for Human Immunology, Autoimmunity and Inflammation, NIH)

  • Wanxia Li Tsai

    (Translational Immunology Section, NIAMS, NIH)

  • Laura Vian

    (Translational Immunology Section, NIAMS, NIH)

  • Nathalia Gazaniga

    (Translational Immunology Section, NIAMS, NIH)

  • Valentina Giudice

    (Hematology Branch, NHLBI, NIH)

  • Shajia Lu

    (Translational Immunology Section, NIAMS, NIH)

  • Stephen R. Brooks

    (Biodata Mining and Discovery Section, NIAMS, NIH)

  • Meggan MacKay

    (Feinstein Institute for Medical Research)

  • Peter Gregersen

    (Feinstein Institute for Medical Research)

  • Nehal N. Mehta

    (Section of Inflammation and Cardiometabolic Diseases, National Heart Lung and Blood Institute (NHLBI), NIH)

  • Alan T. Remaley

    (Translational Vascular Medicine Branch, NHLBI, NIH)

  • Betty Diamond

    (Feinstein Institute for Medical Research)

  • John J. O’Shea

    (Molecular Immunology and Inflammation Branch, NIAMS, NIH)

  • Massimo Gadina

    (Translational Immunology Section, NIAMS, NIH)

  • Mariana J. Kaplan

    (Systemic Autoimmunity Branch, NIAMS, NIH)

Abstract

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.

Suggested Citation

  • Sarfaraz A. Hasni & Sarthak Gupta & Michael Davis & Elaine Poncio & Yenealem Temesgen-Oyelakin & Philip M. Carlucci & Xinghao Wang & Mohammad Naqi & Martin P. Playford & Rishi R. Goel & Xiaobai Li & A, 2021. "Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-23361-z
    DOI: 10.1038/s41467-021-23361-z
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