Phase 1 double-blind randomized safety trial of the Janus kinase inhibitor tofacitinib in systemic lupus erythematosus

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.

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies

“…JAK inhibitors also improve HDL function by increasing the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts free cholesterol to cholesterol esters and supports cholesterol efflux to lipoproteins), thereby increasing HDL efflux capacity (refs. 103 , 106 , and Figure 1C ). Other effects such as alterations in lipoprotein size and content have been described ( 103 , 108 ); therefore, these therapies may contribute to drug-induced dyslipidemia and exacerbate the lipid imbalances already associated with AIRDs.…”

“…JAK inhibitors block cell signaling via the JAK/STAT pathway ( Table 3 ) but also have cell metabolic effects (including decreased mitochondrial membrane potential, mitochondrial mass, and ROS and inhibition of metabolic genes in synovial tissue) ( 100 ) and modify systemic lipid metabolism. Tofacitinib and baricitinib significantly increased HDL-C and LDL-C compared with baseline and other DMARD treatments alone in randomized controlled trials in RA and SLE ( 101 – 106 ), an effect reversed by statins ( 107 ). JAK inhibitors also improve HDL function by increasing the activity of lecithin-cholesterol acyltransferase (LCAT; an enzyme that converts free cholesterol to cholesterol esters and supports cholesterol efflux to lipoproteins), thereby increasing HDL efflux capacity (refs.…”

Unmet Medical Needs in Chronic, Non-communicable Inflammatory Skin Diseases

“…VIB7734, another monoclonal antibody that targets PDCs, showed efficacy in CLE in a phase 1 trial ( 330 ) and is of interest for future trials in CLE, although an ongoing phase 2 trial is in SLE. Janus Kinase (JAK) inhibitors have demonstrated improvement in a range of dermatological conditions and are actively being investigated for SLE ( 331 , 332 ). Further studies that include patients with moderate to severe skin disease are necessary to elucidate their potential benefit in CLE.…”

Pathogenesis and Treatment of T-Large Granular Lymphocytic Leukemia (T-LGLL) in the Setting of Rheumatic Disease

“…The role of the JAK-STAT pathway in SLE has extensively been studied with ongoing randomized controlled trials evaluating use of JAK inhibition in the treatment of SLE ( 39 – 41 ). (NCT03616912), (NCT03616964), (NCT03252587).…”