IFN-α levels correlate with muscle disease activity only in juvenile dermatomyositis patients with anti-MDA5 ^þ autoantibodies

Objective: This study aimed to establish the role of myositis-specific antibodies (MSAs) in the association between type I interferon (IFN-I) plasma levels and disease activity in juvenile dermatomyositis (JDM). Methods: We prospectively obtained 400 samples from 101 JDM patients from two independent cohorts. Autoantibody levels were determined for all patients. Muscle activity was assessed using the Childhood-Myositis Assessment Scale (CMAS). Two characterized homebrew digital ELISAs measuring, respectively, all 12 IFN-α subtype protein and IFN-β were used to quantify IFN-I in patient plasma. Receiver operating characteristic (ROC) curve analysis was used to identify IFN-I thresholds associated with CMAS changes. Correlations between IFN-I levels and CMAS were assessed at recruitment using Spearman’s test, and longitudinally using mixed-effects models to account for repeated measures. Results: IFN-α levels were higher in melanoma differentiation-associated gene 5 (MDA5)-positive patients while IFN-β levels were comparable across MSA subgroups. IFN-β was found to be more effective than IFN-α in distinguishing between active and inactive muscle disease, and between severe and non-severe disease status. Over the disease course, we identified IFN-β as a reliable biomarker of muscle disease activity regardless of MSA expression. In contrast, IFN-α levels showed a specific association with CMAS only in MDA5-positive patients. Conclusion: The exclusive association of IFN-α levels with muscle clinical score in anti-MDA5-positive patients suggests a subgroup-specific pathophysiological mechanism. These findings underscore potentially distinct roles for IFN-I subtypes (IFN-α and IFN-β) as circulating biomarkers of muscle disease activity in JDM according to MSA expression.