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

作者：Sarfaraz Hasni, Sarthak Gupta, Michael A. Davis, Elaine Poncio, Yenealem Temesgen‐Oyelakin, Philip M. Carlucci, Xinghao Wang, Mohammad Naqi, Martin P. Playford, Rishi R. Goel, Xiaobai Li, Ann Biehl, Isabel Ochoa-Navas, Zerai Manna, Yinghui Shi, Donald E. 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 K. Gregersen, Nehal N. Mehta, Alan T. Remaley, Betty Diamond, John J. O’Shea, Massimo Gadina, Mariana J. Kaplan · 发表于：Nature Communications · 年份：2021 · DOI：10.1038/s41467-021-23361-z · 被引用次数：202 · 研究领域：Systemic Lupus Erythematosus Research、Atherosclerosis and Cardiovascular Diseases、Cytokine Signaling Pathways and Interactions

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 allel...