Modulation Of Cardiometabolic Disease Markers By Type I Interferon Inhibition In Systemic Lupus Erythematosus
ARTHRITIS & RHEUMATOLOGY
Casey KA, Smith MA, Sinibaldi D, Seto NL, Playford MP, Wang X, Carlucci PM, Wang L, Illei G, Yu B, Wang S, Remaley AT, Mehta NN, Kaplan MJ and White WI.
Arthritis Rheumatol. 2020 Sep 10.
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.