Targeting interferon responses in juvenile dermatomyositis: Siglec-1 as an in vitro biomarker for JAK inhibitor efficacy.

Abstract

For IFN-driven diseases, such as juvenile dermatomyositis (JDM), there is a critical need for targeted therapies. We aimed to develop an in vitro model, using Siglec-1 as read-out, to evaluate inhibition of IFN-mediated responses with different JAK inhibitors (JAKi). Healthy donor (HD) PBMCs were cultured with type I and II IFNs, TLR agonists and plasma or serum from patients (JDM, DM, JSLE, COVID-19) and HDs. Siglec-1 expression on CD14+ monocytes was analyzed using flow cytometry. Inhibitory assays involved pre-incubation with JAKi (filgotinib, tofacitinib, baricitinib, ruxolitinib, deucravacitinib) and interferon-α/β receptor (IFNAR)-blocking antibody. Correlations between plasma-induced Siglec-1 levels and clinical disease activity were analyzed in JDM patients, as well as correlations with IFN-α and -β plasma levels. Siglec-1 was induced after 18 h of stimulation with type I IFNs and TLR-3/7/9 agonists, with minimal induction by IFN-γ. IFNAR blockade prevented type I IFN- and TLR-mediated induction. JAKi inhibited Siglec-1 induction by IFN-α and -β in a dose-dependent manner. Co-culture with plasma or serum from patients with IFN-driven diseases induced Siglec-1 expression on healthy monocytes, which could be inhibited by JAKi and IFNAR blockade. Siglec-1 levels induced by JDM plasma correlated strongly with clinical disease activity and IFN-β plasma levels. Siglec-1 is an easy and reliable in vitro marker for type I IFN responses. Its induction can be inhibited by JAKi. The type I IFN signature in JDM is likely predominantly driven by IFN-β. This assay holds promise for precision treatment strategies in JDM and other IFN-driven diseases.