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.

Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, inteferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3’-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

BackgroundA pharmacologic intervention that modulates JAK/STAT signaling pathways represents a novel approach for the treatment of Systemic Lupus Erythematosus (SLE). In animal models of SLE, tofacitinib improved clinical features, immune dysregulation and vascular dysfunction. The STAT4 risk allele is associated with higher risk of severe manifestations in SLE. We hypothesized that immune modulation in response to JAK/STAT inhibition would be more robust in SLE subjects that carry the STAT4 risk allele.MethodsWe 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, stratified by the presence or absence of STAT4 risk allele. Study duration was 84 days (56 days of active treatment ; 28 days of off drug). In addition to recording adverse events (AEs), lipoprotein profile, non-invasive vascular function studies, immuno-phenotyping, and gene expression studies were performed.ResultsTofacitinib was well tolerated with no worsening of SLE disease activity, and no severe AEs, opportunistic infections or liver function abnormalities. A total of 43 AEs (mostly mild respiratory infections) occurred in the treated group compared to 28 AEs in placebo. There was a significant increase in HDL-C and HDL particle size in tofacitinib-treated patients at day 56 (p=0.006) accompanied by significant improvements in plasma protein lecithin: cholesterol acyltransferase (LCAT) concentration. There were also trends for improvements in vascular stiffness in the tofacitinib-treated group. The Interferon response genes (type I IFN), the levels of low- density granulocytes (LDGs) and neutrophil extracellular trap (NET remnants) significantly decreased in the tofacitinib treated group who were STAT 4 risk allele positive but not in the placebo group at day 56, accompanied by significant changes in pSTAT phosphorylation of different immune cells. Levels of activation and checkpoint markers CD103, CXCR3, ICOS, and PD-1 were significantly decreased on multiple T cell subsets, in tofacitinib treated individuals that lack the STAT4 risk allele.Abstract 183 Figure 1Adverse Events by Organ System. Adverse Events in Subjects on Tofacitinib vs PlaceboConclusionsIn a short-term trial, tofacitinib was well tolerated in SLE subjects with mild-moderate disease activity. Use of tofacitinib resulted in improvements in lipoprotein profile and HDL function and decreases in the type I IFN and aberrant neutrophil responses characteristic of SLE. Long-term studies are needed to determine the efficacy of tofacitinib in the various manifestations of SLE.Funding Source(s):Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health and in part by Pfizer Inc.Adverse Events in Subjects on Tofacitinib vs Placebo