Modulation of cardiometabolic disease markers by type I interferon inhibition in systemic lupus erythematosus.

OBJECTIVES Neutrophil dysregulation and the type I interferon (IFN) axis have been proposed to contribute to premature cardiovascular disease, a leading cause of mortality in patients with systemic lupus erythematosus (SLE). We evaluated the ability of anifrolumab, a type I IFN receptor-blocking antibody, to reduce neutrophil extracellular trap (NET) formation and modulate cardiometabolic disease markers relative to placebo. METHODS Blood samples were collected pre- and post-dose from patients with moderate to severe SLE enrolled in the phase 2b MUSE trial (NCT01438489). Baseline (n=305) SLE samples were compared with healthy controls and post-treatment samples in anifrolumab 300-mg (n=99) and placebo groups (n=102). Baseline IFN gene signature test status was determined and IFN 21-gene signature was monitored over time. Serum proteins were measured by multiplex immunoassay or ultrasensitive Simoa™ technology. NET complexes, cholesterol efflux capacity (CEC), and full NMR LipoProfile® were assessed in plasma. RESULTS NET complexes, tumor necrosis factor alpha (TNF-α), and interleukin (IL)-10 correlated with type I IFN pathway activity; NET complexes and IL-10 were upregulated in patients with SLE versus healthy donors (p<0.008). Cardiometabolic disease markers CEC and GlycA were also dysregulated (p<0.001). Type I IFN receptor inhibition with anifrolumab significantly reduced NET complexes and GlycA and improved CEC from baseline (p<0.05), whereas no improvements were seen with placebo. TNF-α and IL-10 were reduced versus placebo (p<0.05). CONCLUSION These data support a key role for type I IFNs in modulating factors contributing to SLE vasculopathy and suggest that inhibiting this pathway could decrease cardiovascular risk in these patients.