Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus
| Autor: | Meggan Mackay, Xinghao Wang, Richard Apps, Rishi R. Goel, Ashley Babyak, Valentina Giudice, Nathalia R Gazaniga, Betty Diamond, Ann Biehl, Martin P. Playford, Stephen R. Brooks, Katie Stagliano, Laura Vian, Peter K. Gregersen, Zerai Manna, Michael Davis, Shajia Lu, Elaine Poncio, Yinghui Shi, Nehal N. Mehta, Xiaobai Li, Yuri Kotliarov, Mohammad Naqi, Angelique Biancotto, Sarfaraz Hasni, Rongye Shi, Yenealem Temesgen-Oyelakin, Jinguo Chen, Donald E Thomas, Isabel Ochoa-Navas, Alan T. Remaley, Sarthak Gupta, Foo Cheung, Massimo Gadina, Huizhi Zhou, Wanxia Li Tsai, Philip M. Carlucci, John J. O'Shea, Mariana J. Kaplan |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine General Physics and Astronomy Autoimmunity Gastroenterology law.invention 0302 clinical medicine Piperidines Randomized controlled trial law immune system diseases Clinical endpoint Lupus Erythematosus Systemic skin and connective tissue diseases Janus kinase inhibitor Multidisciplinary Systemic lupus erythematosus Middle Aged STAT4 Transcription Factor Vasodilation Treatment Outcome Tolerability Female Adult medicine.medical_specialty Science Article General Biochemistry Genetics and Molecular Biology Young Adult 03 medical and health sciences Vascular Stiffness Double-Blind Method Internal medicine medicine Animals Humans Janus Kinase Inhibitors Genetic Predisposition to Disease Aged 030203 arthritis & rheumatology Lupus erythematosus Tofacitinib business.industry Cholesterol HDL General Chemistry Atherosclerosis medicine.disease Pyrimidines 030104 developmental biology Heart Disease Risk Factors Janus kinase business |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-11 (2021) Nature Communications |
| Popis: | 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. Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|