Enhanced Type 1 Interferon Signature in Axial Spondyloarthritis Patients Unresponsive to Secukinumab Treatment.

ABSTRACT

OBJECTIVE: Axial spondyloarthritis (axSpA) is an inflammatory disease in which overactive IL-17A-producing cells are implicated in a central role. Therapeutically, biologics that target IL-17A, such as secukinumab, have demonstrated improved clinical outcomes. Despite this translational success, there is a gap in understanding why some axSpA patients do not respond to IL-17A blocking therapy. Our study aims to discriminate immune profiles between secukinumab responders (SEC-R) and nonresponders (SEC-NR). METHODS: Peripheral blood mononuclear cells were collected from 30 axSpA patients before and 24-weeks after secukinumab treatment. Frequency of CD4+ subsets were compared between SEC-R and SEC-NR using flow cytometry. Mature CD45RO+CD45RA-CD4+ T cells were FACS sorted, and RNA was measured using NanoString analysis. RESULTS: SEC-NR had an increased frequency of IL-17A-producing RORγt+CD4+ T cells compared to HCs at pre-secukinumab (p<0.01). SEC-NR had a significant increase of CXCR3+ CD4+ T cells pre-secukinumab compared to SEC-R (p<0.01). Differentially expressed gene analysis revealed upregulation of type 1 interferon-regulated genes in SEC-NR patients compared to SEC-R post-biologic. SEC-R patients had an upregulated cytotoxic CD4+ T cell gene signature pre-secukinumab compared to SEC-NR patients. CONCLUSIONS: The increased frequency of IL-17A-producing cells in SEC-NR patients suggests a larger inflammatory burden than SEC-R patients. With treatment, SEC-NR patients have a more pronounced type 1 IFN signature than SEC-R patients, suggesting a mechanism contributing to this larger inflammatory burden. The results point toward more immune heterogeneity in axSpA than has been recognized and highlights the need for precision therapeutics in this disease.