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

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, Ann J. Biehl, Isabel Ochoa-Navas, Zerai Manna, Yinghui Shi, Donald Thomas, Jinguo Chen, Angélique Biancotto, Richard Apps, Foo Cheung, Yuri Kotliarov, Ashley L. Babyak, Huizhi Zhou, Rongye Shi, Katie Stagliano, Wanxia Li Tsai, Laura Vian, Nathalia Gazaniga, Valentina Giudice, Shajia Lu, Stephen R. Brooks, Meggan MacKay, Peter Gregersen, Nehal N. Mehta, Alan T. Remaley, Betty Diamond, John J. O’Shea, Massimo Gadina and Mariana J. Kaplan
Additional contact information
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)
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

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-23361-z

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