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

Objective: Axial spondyloarthritis (axSpA) is an inflammatory disease in which overactive interleukin (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 patients with axSpA 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 patients with axSpA 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 fluorescent‐activated cell sorting 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 healthy controls before secukinumab treatment (P < 0.01). SEC‐NR had a significant increase of CXCR3+ CD4+ T cells before secukinumab treatment compared to SEC‐R (P < 0.01). Differentially expressed gene analysis revealed up‐regulation of type 1 interferon (IFN)‐regulated genes in SEC‐NR patients compared to SEC‐R patients after receiving the biologic. SEC‐R patients had an up‐regulated cytotoxic CD4+ T cell gene signature before receiving secukinumab treatment compared to SEC‐NR patients. Conclusion: 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. [ABSTRACT FROM AUTHOR]