Interferon-Driven Tryptophan Metabolism Links Inflammation and Mental Health in Juvenile Dermatomyositis

Children with juvenile dermatomyositis (JDM) experience significant mental health burdens, including anxiety and depression. Inflammatory activation can alter tryptophan metabolism, particularly through IDO-driven kynurenine pathway induction, which has been implicated in diseases such as mood disorders and SLE. We therefore investigated skewed tryptophan metabolism and its association with disease activity and mental health symptoms in JDM. Serum samples from JDM, juvenile idiopathic arthritis (JIA), and healthy controls (HC) were analysed for tryptophan metabolites by ELISA. Interferon-regulated genes were measured using qPCR. Ability of serum to induce indoleamine 2,3-dioxygenase (IDO) was assessed by flow cytometry in presence or absence of interferon antagonists. Cluster analysis was used to identify subgroups. In JDM patients, serum tryptophan and serotonin levels were lower, while kynurenine/tryptophan ratios, kynurenic acid, and quinolinic acid levels were higher compared to healthy controls. Metabolites from the kynurenine pathway were correlated with muscle inflammation (CRP, ESR, aldolase and CK), mental health outcomes (PSC-17 and PHQ-9 scores) and disease progression (PGA scores). Further, IDO1 mRNA levels correlated inversely with serotonin levels and positively with type I interferon signature marker MX2 in PBMCs. Serum from JDM patients induced IDO protein expression in monocytes through an IFN-dependent mechanism, which was significantly inhibited by both baricitinib and anifrolumab. Four clinical subgroups were identified. Our study reveals a novel role of IFN in JDM pathogenesis, specifically in the upregulation of IDO and subsequent skewing of tryptophan metabolism towards kynurenine pathway, which may correspond to poor mental well-being and disease progression. Targeting this pathway may offer therapeutic potential for both disease activity and psychological outcomes for JDM children.