Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus.
Adult
Aged
Animals
Atherosclerosis
/ blood
Cholesterol, HDL
/ blood
Double-Blind Method
Female
Genetic Predisposition to Disease
Heart Disease Risk Factors
Humans
Janus Kinase Inhibitors
/ administration & dosage
Lupus Erythematosus, Systemic
/ blood
Male
Middle Aged
Piperidines
/ administration & dosage
Pyrimidines
/ administration & dosage
STAT4 Transcription Factor
/ genetics
Treatment Outcome
Vascular Stiffness
/ drug effects
Vasodilation
/ drug effects
Young Adult
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
07 06 2021
07 06 2021
Historique:
received:
03
04
2020
accepted:
22
04
2021
entrez:
8
6
2021
pubmed:
9
6
2021
medline:
16
6
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34099646
doi: 10.1038/s41467-021-23361-z
pii: 10.1038/s41467-021-23361-z
pmc: PMC8185103
doi:
Substances chimiques
Cholesterol, HDL
0
Janus Kinase Inhibitors
0
Piperidines
0
Pyrimidines
0
STAT4 Transcription Factor
0
STAT4 protein, human
0
tofacitinib
87LA6FU830
Banques de données
ClinicalTrials.gov
['NCT02535689']
Types de publication
Clinical Trial, Phase I
Journal Article
Randomized Controlled Trial
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
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