Type I interferon overactivation in sera of patients with anti‐MDA5‐positive dermatomyositis‐associated interstitial lung disease

Background Rapidly progressive interstitial lung disease (ILD) is a major complication in patients with anti‐melanoma differentiation‐associated gene 5 (MDA5)‐positive dermatomyositis (DM) and carries a poor prognosis despite aggressive immunosuppressive therapy. Emerging evidence suggests that overactivation of the type I interferon (IFN‐I) pathway may play a pivotal role in the pathogenesis of this disease. This study aimed to evaluate the activation of the IFN‐I pathway in the sera of patients with MDA5‐positive DM‐associated ILD. Methods Serum samples were collected from clinically active patients with anti‐MDA5‐positive DM‐associated ILD and anti‐aminoacyl‐tRNA synthetase (ARS)‐positive polymyositis (PM)/DM‐associated ILD and healthy controls ( n = 22, 21, and 32, respectively). Serum IFN‐I bioactivity, IFN‐stimulated gene (ISG)‐inducing activity, and nuclear factor kappa B (NF‐κB) bioactivity were determined using reporter cell lines. The relationship between these results and clinical features was analyzed. Results The sera of patients with anti‐MDA5‐positive DM‐associated ILD demonstrated significantly higher IFN‐I bioactivity and ISG‐inducing activity than those with anti‐ARS‐positive PM/DM‐associated ILD and healthy controls ( p < 0.01 for all comparisons). In contrast, no significant differences in NF‐κB bioactivity were observed. Serum IFN‐I bioactivity and ISG‐inducing activity were moderately correlated with serum ferritin levels ( r = 0.53 and 0.54, respectively). In an exploratory analysis, the serum of six patients with anti‐MDA5‐positive DM‐associated ILD demonstrated higher ISG‐inducing activity than that measured using reporter cells with a knockout of the IFNAR2 gene, and higher values of IFN‐I bioactivity, ISG‐inducing activity, and serum ferritin than the other samples, suggesting IFN‐I overactivation, especially in these patients. Conclusions This study confirmed the hypothesis that the overactivation of the serum IFN‐I pathway is strongly associated with anti‐MDA5‐positive DM‐associated ILD. In addition, anti‐MDA5‐positive DM‐associated ILD and anti‐ARS‐positive PM/DM‐associated ILD may have distinct pathomechanisms.