FRI0256 Effects of anifrolumab on oxidative stress and macrophage activation: novel biomarkers and impact of type i interferon blockade in systemic lupus erythematosus
Authors: X. Guo, S. Wang, L. Wang, L.K. Roskos, W.I. White
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Type I interferons (IFNs) drive several aspects of systemic lupus erythematosus (SLE) etiology and pathophysiology. Anifrolumab, a fully human anti-IFN-α receptor monoclonal antibody, substantially reduced disease activity compared with placebo in a Phase IIb study of SLE patients.<sup>1</sup> Previous results indicated beneficial effects of anifrolumab on dysregulated lymphocyte, neutrophil, and complement systems in SLE.<sup>2</sup> However, the impact of type I IFN blockade remains to be fully elucidated. <h3>Objectives</h3> We characterised biomarkers for oxidative stress and macrophage activation in SLE and assessed downstream effects of anifrolumab on those two key disease pathways. <h3>Methods</h3> In the MUSE study,<sup>1</sup> 305 patients with moderate to severe SLE were randomised in a 1:1:1 ratio to receive placebo or anifrolumab (300 or 1,000 mg) every 4 weeks for 48 weeks. A four-gene expression assay was used to define type I IFN gene signature (IFNGS) test status. In our study, four protein biomarkers were measured in sera of healthy controls (HCs) and SLE patients with samples available at baseline, and 85, 169, and 365 days after administration, using a multiplex luminex immunoassay. Wilcoxon rank-sum test was used to evaluate baseline protein concentrations and posttreatment changes between different groups. <h3>Results</h3> Two oxidative stress biomarkers, peroxiredoxin 4 (PRDX4) and aldose reductase (AKR1B1), were found in greater serum concentrations in 195 SLE patients than in 20 HCs (p&lt;0.01). Their increased concentrations were associated with greater SLEDAI scores and abnormal anti-dsDNA concentrations (p&lt;0.05). PRDX4 concentrations were greater for IFNGS test–high (n=144) vs IFNGS test–low (n=51) patients (p&lt;0.01), whereas AKR1B1 was not associated with type I IFNGS-test status. Anifrolumab suppressed PRDX4 in IFNGS test–high patients compared with placebo (p&lt;0.05). In contrast, no significant changes were observed for AKR1R1 after anifrolumab treatment. Folate receptor 3 (FOLR3) and CD163 are markers of activated macrophages, the former of which has not been characterised in SLE. Our results demonstrated greater concentrations of both FOLR3 and CD163 in IFNGS test–high than in IFNGS test–low patients and HCs, along with significant associations with SLEDAI score and anti-dsDNA concentrations. Anifrolumab reduced serum concentrations of both FOLR3 and CD163 in IFNGS test–high but not IFNGS test–low patients vs. placebo (p&lt;0.05). Moreover, cellular enumeration data demonstrated anifrolumab-induced upregulation of monocyte count in IFNGS test–high patients, which may result from reduced activation, apoptosis, and/or tissue infiltration of monocytes/macrophages. <h3>Conclusions</h3> Our results identified PRDX4 as an oxidative stress marker and FOLR3 as a macrophage activation marker associated with disease activities and type I IFNGS test status in SLE. Anifrolumab administration elicits reduced oxidative stress and decreased monocyte/macrophage activation, which may contribute to the clinical efficacy of anifrolumab in SLE patients. <h3>References</h3> [1] Furie R, et al. Arthritis Rheumatol. 2017;69:376–86. [2] Guo X, et al. Ann. Rheum. Dis. 2016;75:118. <h3>Disclosure of Interest</h3> X. Guo Shareholder of: AstraZeneca, Employee of: MedImmune, S. Wang Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Shareholder of: AstraZeneca, Employee of: AstraZeneca, L. Roskos Shareholder of: AstraZeneca, Employee of: AstraZeneca, W. White Shareholder of: AstraZeneca, Employee of: MedImmune