Background/Purpose: Cardiovascular disease is a leading cause of death for patients with systemic lupus erythematosus (SLE), and the disease is widely known to feature premature atherosclerosis promoted by immune dysregulation. Neutrophil extracellular traps (NETs) can induce endothelial dysfunction and promote inflammatory events. Furthermore, sources of reactive oxygen species released during NET formation promote oxidized high-density lipoprotein, leading to deficient cholesterol efflux capacity (CEC). Type I interferons (IFNs) stimulate NET formation and inhibit vascular repair. Anifrolumab is a fully human, IgG1 κ monoclonal antibody that binds to IFNAR1 and blocks signaling of all type I IFNs. Thus, anifrolumab may decrease mechanisms of vascular damage in SLE. We evaluated the ability of anifrolumab to reduce in-vivo NET formation and improve CEC relative to standard of care (SOC) in MUSE.¹

Methods: Baseline IFN gene signature (IFNGS) test status (high/low) of MUSE patients was determined as described.¹ All patients satisfied the ACR classification criteria for lupus.¹ Plasma samples from fasting patients (n=190) were obtained at days 1 and 365 of the MUSE study. Plasma MPO-, HNE- and CitH3-DNA NET complexes were quantified by ELISAs in the MUSE and healthy donor (HD) samples (n=20) as described.² Wilcoxon rank-sum test assessed differences between groups. Post-treatment samples from the 300 mg anifrolumab (n=73) and placebo (n=52) groups were compared with baseline samples. Significance of change from baseline was determined using Wilcoxon signed-rank test. CEC was tested as described.³ Reproducibility of the CEC assay was assessed using percent coefficient of variation (CV) from the analysis of variance (ANOVA). SLE patients with defective baseline CEC were identified as those with CEC < (the HD mean value – 2 standard deviations) in the same testing run.

Results: All 3 neutrophil NET complexes (NNCs) were elevated in SLE patients (p<0.01) and were significantly enriched in IFN test–high patients (p<0.05). Anifrolumab significantly decreased all 3 NNCs at Day 365 vs. Day 1 (p≤0.05), whereas in the placebo group, complexes did not change or increased. The repeatability of the CEC assay was 7.5% across 2 days of testing for a subset of 26 baseline samples, and longitudinal changes in steroid dosage for the placebo group did not affect CEC. Greater baseline NET complex levels significantly correlated with poor baseline CEC (p<0.05). Anifrolumab significantly increased CEC in IFNGS test–high patients with defective CEC at baseline (p<0.001), whereas no significant changes occurred in the placebo group.

Conclusion: Circulating NNCs were significantly elevated in patients with moderate to severe SLE compared with HDs. Anifrolumab decreased circulating NNCs. Although changes in steroid dosages during MUSE did not affect CEC, anifrolumab significantly improved CEC. This work supports continued assessment of anifrolumab effects on vascular diseases and endothelial damage in SLE.

¹Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.

²Demoruelle MK, et al. Arthritis Rheumatol. 2017;69:1165–75.

³Salahuddin T, et al. Eur Heart J. 2015;36:2662–5.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/alteration-of-vascular-inflammatory-markers-in-sle-by-anifrolumab-in-the-phase-iib-muse-study/