RT Journal Article
SR Electronic
T1 OP0174 Alteration of mediators of vascular inflammation by anifrolumab in the phase iib muse study in sle
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 136
OP 137
DO 10.1136/annrheumdis-2018-eular.3541
VO 77
IS Suppl 2
A1 White, W.I.
A1 Seto, N.L.
A1 Playford, M.P.
A1 Casey, K.A.
A1 Smith, M.A.
A1 Carlucci, P.
A1 Yu, B.
A1 Wang, L.
A1 Illei, G.
A1 Mehta, N.
A1 Kaplan, M.J.
YR 2018
UL http://ard.bmj.com/content/77/Suppl_2/136.3.abstract
AB Background Cardiovascular disease remains one of the leading causes 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 oxidised HDL, 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 signalling of all type I IFNs. Thus, anifrolumab may decrease mechanisms of vascular damage in SLE.Objectives We evaluated the ability of anifrolumab to reduce in-vivo NET formation and improve CEC relative to standard of care (SOC) in the MUSE study.1 Methods Baseline IFN gene signature (IFNGS) test status (high or low) of MUSE patients was determined as described.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 was used to assess differences between groups. Post-treatment samples from the placebo (n=52) and 300 mg anifrolumab (n=73) 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 <2 standard deviations from the HD mean value in the same testing run.Results All three 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 three NNCs at Day 365 vs Day 1 (p≤0.05), whereas in the placebo group, complexes did not change or increased. The CEC assay was reproducible (16.4% CV) 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.Conclusions Circulating NNCs were significantly elevated in patients with moderate to severe SLE as compared with HDs. Anifrolumab decreased circulating NNCs. Although changes in steroid dosages during MUSE did not affect CEC, anifrolumab significantly improved CEC over SOC. This work supports continued assessment of anifrolumab effects on vascular inflammation and endothelial damage in SLE.References [1] Furie R, et al. Arthritis Rheumatol2017;69:376–86.[2] Demoruelle MK, et al. Arthritis Rheumatol2017;69:1165–75.[3] Salahuddin T, et al. Eur Heart J2015;36:2662–5.Disclosure of Interest W. White Shareholder of: AstraZeneca, Employee of: MedImmune, N. Seto: None declared, M. Playford: None declared, K. Casey Shareholder of: AstraZeneca, Employee of: MedImmune, M. Smith Shareholder of: AstraZeneca, Employee of: MedImmune, P. Carlucci: None declared, B. Yu Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Consultant for: MedImmune, N. Mehta Grant/research support from: Abbvie, Novartis, Janssen, Celgene, Employee of: NHLBI, M. Kaplan Grant/research support from: MedImmune