Expression profiling by high throughput sequencing
Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE) and significantly contributes to morbidity and mortality. To date, no pharmacologic intervention has shown to reduce CV risk in SLE. Dysregulation of innate immune responses, including aberrant type I-Interferon (IFN)-neutrophil interactions, has been proposed to significantly contribute to enhanced CV risk in SLE. In lupus animal models, the Janus kinase/signal transducers and activators of transcription (JAK/STAT) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We hypothesized that JAK/STAT inhibition in SLE subjects would result in amelioration of cardiometabolic and immunologic parameters previously associated with enhanced CVD risk.
We conducted a phase 1b/2a randomized, double-blind, placebo-controlled clinical trial of oral tofacitinib, 5 mg twice daily, in 30 SLE subjects (2:1 drug to placebo ratio) with mild to moderate disease activity Patients were stratified by the presence or absence of the STAT4 risk allele, previously shown to be associated with more severe SLE Study duration was 84 days, with 56 days of active treatment followed by 28 days off drug We performed, non-invasive assessment of vascular function, measurements of cardiometabolic parameters, quantification of peripheral blood immune cell subsets by flow cytometry and gene expression by whole blood RNA sequencing, quantification of circulating neutrophil extracellular trap (NET) complexes and STAT phosphorylation (pSTAT) in immune cells Adverse events (AEs) were recorded as were assessments of lupus clinical disease activity