SAT0220 Effects of type I interferon inhibition on blood leukocyte subsets in patients treated in a phase IIB clinical study of anifrolumab in systemic lupus erythematosus (SLE). (15th June 2017)

• Record Type: Journal Article
• Authors: White, W; Casey, KA; Smith, MA; Wang, L; Sinbaldi, D; Sanjuan, MA; Illei, G
• Is Part Of: Annals of the rheumatic diseases. Volume 76(2017)Supplement 2
• Page Start: 856
• Page End: 857
• Publication Date: 2017-06-15
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2017-eular.3833
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: A Phase IIb randomized controlled study (NCT01753193 ) was conducted with anifrolumab, a fully human, anti-interferon (IFN)–α receptor (IFNAR) specific antibody in adults with moderate to severe SLE. Anifrolumab binds to subunit 1 of the IFNAR and inhibits the activity of all type I IFNs. A complete blood count analysis demonstrated that anifrolumab reversed leukopenia. However, the types of peripheral immune cells affected following treatment have not been reported. Objectives: To better understand how changes in the immune cell repertoire may be associated with SLE severity, type I IFN test status (high vs. low), and treatment with anifrolumab, we performed flow cytometry to assess peripheral blood cell types: dendritic cells (myeloid and plasmacytoid), B cells (naïve, memory, and plasma cells), neutrophils, and T cells (CD4, CD8, naïve, memory, central memory, and effector). Methods: Patients were randomized 1:1:1 to anifrolumab 300 mg, or 1, 000 mg, or placebo (PBO) every 4 weeks for 48 weeks. Peripheral blood was collected from a subset of patients (91 total) on Days 1 (prior to first dose), 85, 141, 169, 253, 337, and 365. Patients were approximately evenly distributed between treatment arms. Baseline absolute immune cell numbers were compared over treatment course in the context of SLE Disease Activity Index (SLEDAI)–2K scores, type I IFN test, and therapy response. Statistics were calculated using the Student's t -test; p-values ≤0.05 were considered statistically significant. Results: At baseline, several blood cell types were lower for patients with SLEDAI ≥10, including naïve B cells, and memory T and B cells. In IFN-high patients, neutrophils, memory T cells, and plasmacytoid dendritic cells (pDCs) were significantly decreased. Anifrolumab led to significant increases in absolute numbers of T-cell subsets in the blood of IFN-high patients. In contrast, no significant changes were observed for IFN-low patients. Observed increases were within normal reference ranges. The alterations did not appear to be secondary to tapering of oral corticosteroids, as these cell types were not significantly different in PBO groups, regardless of tapering. Patients with ≥6-point SLEDAI reductions following anifrolumab demonstrated significant increases in total CD4 and CD8 T cells, and nonsignificant decreases in memory B cells. Significant increases in pDCs were also evident. Anifrolumab did not cause significant differences in other cell types measured. Conclusions: Memory T cell numbers, among other cell types, were significantly reduced in patients with SLEDAI ≥10 and those classified as IFN high at baseline. This suggests that, for patients with more severe disease, type I IFN may be involved in cell migration into the peripheral tissues from the blood. Consistent with this, we found that neutralization of type I IFN with anifrolumab promoted immigration and/or prevented emigration of potentially pathologic immune cells between the tissues and the blood. These data suggest that some effects observed following anifrolumab treatment might be a result of altering the migration patterns of T and other immune cells, which may partially explain its biological activity. Acknowledgements: Funded by MedImmune. Medical writing support: R Plant, QXV Comms, an Ashfield company, funded by MedImmune. Disclosure of Interest: W. White Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Casey Shareholder of: AstraZeneca, Employee of: MedImmune LLC, M. Smith Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Wang Employee of: MedImmune LLC, D. Sinbaldi Shareholder of: AstraZeneca, Employee of: MedImmune LLC, M. Sanjuan Employee of: MedImmune LLC, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC