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

Veldkamp, S.R.; Reugebrink, M.; Evers, S.W.; Moreau, T.R.J.; Bondet, V.; Armbrust, W.; ... ; Wijk, F. van (2025)

Article / Letter to editor

Objectives: 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).

Methods: 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-alpha/beta 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-alpha and -beta plasma levels.

Results: Siglec-1 was induced after 18 h of stimulation with type I IFNs and TLR-3/7/9 agonists, with minimal induction by IFN-gamma. IFNAR blockade prevented type I IFN- and TLR-mediated induction. JAKi inhibited Siglec-1 induction by IFN-alpha and -beta 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-beta plasma levels.

Conclusion: 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-beta. This assay holds promise for precision treatment strategies in JDM and other IFN-driven diseases.

• interferon
• JAK inhibition
• Siglec-1
• juvenile dermatomyositis
• assay
• precision treatment

• All authors: Veldkamp, S.R.; Reugebrink, M.; Evers, S.W.; Moreau, T.R.J.; Bondet, V.; Armbrust, W.; Berg, J.M. van den; Muller, P.C.E.H.; Kamphuis, S.; Schatorjé, E.; Delemarre, E.M.; Kooi, A.J. van der; Bader-Meunier, B.; Duffy, D.; Rodero, M.P.; Raaphorst, J.; Royen-Kerkhof, A. van; Jansen, M.H.A.; Wijk, F. van
• Date: 2025-06-09
• Journal: Rheumatology
• Volume: 64
• Issue: 9
• Pages: 5132 - 5141
• DOI: doi:10.1093/rheumatology/keaf227