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.
Highlights
Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE)
We found that there was a significant reduction in the percentage of low-density granulocytes (LDGs) in SLE subjects on tofacitinib compared to placebo at day 56 (P = 0.048) and the decrease was sustained at day 84 (P = 0.014; Fig. 2a), whereas total neutrophils did not significantly decrease during active treatment (Fig. 2b and Table 4)
Our exploratory analyses showed that tofacitinib led to significant positive modulation of cardiometabolic and immunologic parameters previously linked to increased coronary atherosclerotic plaque, vascular inflammation, and abnormalities in blood vessel function in lupus and in the general population[24,25]
Summary
Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). The Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. The role of the innate immune system, type I interferons, low-density neutrophils, and neutrophil extracellular traps (NETs), is recognized as a potential fundamental player in SLE pathogenesis and its associated vascular damage[2]. We hypothesized that mitigating the aberrant activation of innate immune pathways with a JAK inhibitor could lead to the improvement in cardiometabolic parameters and immune dysregulation associated with premature vascular damage in SLE. To this end, we conducted a phase Ib/IIa, double-blind, placebocontrolled clinical trial of tofacitinib in SLE subjects with mild-tomoderate disease. As the presence of the STAT4 risk allele (rs7574865) has been associated with more severe clinical phenotype and significantly increased risk of vascular disease in SLE, and since type I IFNs activate STAT4, we stratified subjects based on the presence (+) or absence (−) of STAT4 risk allele which has been suggested to increase the production of and sensitivity to type I IFNs in peripheral blood mononuclear cells of SLE patients, to investigate the effect(s) of these haplotypes on the clinical and immunologic response to tofacitinib[15,16,17]
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