AUTHOR=Wong Wing-Yi , Leavis Helen L. , Blokland Sofie L. M. , Baloche Valentin M. D. , van Roon Joel A. G. 

TITLE=Proteins linked to type II interferon response in Sjögren’s disease: novel indicators for disease monitoring and predicting treatment response to leflunomide and hydroxychloroquine combination therapy

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1566377

DOI=10.3389/fimmu.2025.1566377

ISSN=1664-3224

ABSTRACT=ObjectiveTo identify biomarkers and endotypes predictive of treatment response, monitor disease activity, and explore pathways associated with the clinical efficacy of leflunomide and hydroxychloroquine combination therapy (LEF/HCQ) in patients with primary Sjögren’s disease (SjD).MethodsSerum proteome (Olink Immuno-oncology panel, analyzing 92 proteins) of 29 patients with SjD of the RepurpSS-I study and 8 healthy controls was analyzed at baseline and after 24 weeks of LEF/HCQ. Proteomic changes were correlated to standard and novel clinical endpoints. Transcriptome data of blood mononuclear cells and monocytes were used to assess type I and II IFN scores.ResultsAt baseline, 29 proteins were differentially expressed between SjD and HC. LEF/HCQ significantly downregulated 22 out of 27 over-expressed proteins, which was not observed in the placebo-arm. Fourteen baseline proteins and the changes of four of these proteins, CXCL10, CXCL11, TNF, and soluble CD70 concentrations, were correlated with clinical response (|r| 0.40–0.62, p<0.05). Principal Component Analysis revealed an IFN-γ-associated set of coherent proteins. At baseline, using only two proteins, CXCL10 and CXCL11 effectively distinguished patients from healthy controls and responders from non-responders (all p<0.05). Finally, in addition to changes in type I IFN signatures, type II IFN signatures were observed in monocytes that were associated with changes in disease activity.ConclusionThese data support a significant role for a type II IFN-associated immune response in SjD pathogenesis, which is targeted by LEF/HCQ. Proteins associated with type II IFN-driven immune responses hold potential to monitor disease activity and predict treatment response.