Imbalance of type I and II onterferon pathways is associated with pain perception in Sjogren’s disease: a real-life study

Introduction Activation of interferon (IFN) pathways is a central mechanism in the pathogenesis of Sjögren’s disease (SjD) and systemic lupus erythematosus (SLE). While type I IFN signatures have been extensively characterized, the systemic relevance of circulating type III IFNs and the clinical implications of the relative balance between IFN types I, II, and III remain insufficiently explored. Methods In this real-life, exploratory study, plasma concentrations of IFN-α2, IFN-β, IFN-γ, IFN-λ1, and IFN-λ2 were measured in patients with SjD (n = 59), SLE (n = 35), and healthy controls (n = 30). Disease activity and patient-reported outcomes were assessed using ESSDAI, ESSPRI, and SLEDAI-2K. In addition to absolute IFN concentrations, ratios between IFN subtypes were analyzed to reflect interferon pathway balance. Non-parametric statistical analyses with correction for multiple testing were applied. Results Absolute plasma concentrations of individual IFN subtypes did not differ significantly between the study groups. In SjD, exploratory correlation analyses revealed a significant association between the IFN-α2/IFN-γ ratio and pain severity assessed by ESSPRI (Spearman’s ρ = 0.48, adjusted p < 0.05). This association was independent of systemic inflammatory activity measured by ESSDAI. Furthermore, selected IFN ratios involving IFN-λ differed between SLE and SjD, suggesting disease-specific patterns of interferon balance. No significant associations were observed between IFN parameters and SLEDAI-2K scores in SLE. Conclusions These findings indicate that the relative balance between interferon pathways, rather than absolute circulating IFN levels, may be clinically relevant in SjD, particularly with respect to patient-reported pain. Interferon subtype ratios may represent exploratory biomarkers of immune dysregulation. Further studies integrating systemic, tissue-level, and transcriptomic approaches are warranted to validate these observations.