From diagnosis to prognosis: Revisiting the meaning of muscle ISG15 overexpression in juvenile inflammatory myopathies

Objectives Juvenile idiopathic inflammatory/immune myopathies (JIIM) constitute a highly heterogeneous group with diagnostic difficulties and prognostic uncertainties. Circulating myositis-specific autoantibodies (MSAs) were first recognized as reliable tools for patient sub-stratification. Considering the key role of type 1 interferon (IFN-I) up-regulation in JIIM, we investigated whether the IFN-stimulated gene 15 (ISG15) could be reliable biomarker for stratification and diagnosis while shedding light on its role in JIIM pathophysiology. Methods We included 56 patients, 24 Juvenile Dermatomyositis (JDM), 12 Juvenile Overlap Myositis (JOM), 10 patients with Duchenne Muscular Dystrophy (DMD) and 10 patients with Congenital Myopathies (CM). Muscle biopsies have been studied using immunohistochemistry, immunoblotting, and real-time quantitative PCR. The negative (ISG15, USP18) and positive regulators (DDX58, and IFIH1) of IFN-I were analyzed. Results ISG15 expression discriminated JIIM from non-immune myopathies, and among JIIM, JDM from JOM. Among JDM patients, IFN-I positive upregulation (DDX58, IFIH1) was similar whatever MSAs. In contrast, the highest level of ISG15, which is a negative regulator of IFN-I was observed in MDA5(+) patients compared to others. Finally, ISG15 level was inversely correlated with the severity of muscle histological injuries, and was positively correlated with motor performance (CMAS, MMT). Conclusions Muscle ISG15 expression is strongly associated with diagnosis of JDM. Patients present a different muscle signature of ISG15 according to their MSAs class. JDM MDA5(+) patients have a higher expression of ISG15 (gene and protein) compared to the other subgroups. Moreover, our data showed that the IFN-I negative regulation correlates with milder muscle involvement.