Untargeted metabolomics reveals serum metabolites related to energy metabolism and inflammation associated with juvenile dermatomyositis

INTRODUCTION: Juvenile dermatomyositis (JDM) is a rare autoimmune inflammatory myopathy characterized by muscle weakness and distinctive skin rashes. Despite advancements in the clinical understanding of JDM, metabolic disturbances underlying the disease remain poorly understood. OBJECTIVES: This study aimed to investigate serum metabolite differences in JDM compared to age- and sex-matched unaffected siblings (US) and unrelated healthy controls (HC), and to identify metabolite abundance differences associated with disease severity. METHODS: Serum samples from JDM (n = 16) and adult dermatomyositis (DM; n = 15) patients and corresponding US and HC underwent untargeted metabolomics profiling. Multivariate, univariate, and correlation analyses were employed to identify metabolites differentiating groups and correlating with Physician Global Damage (PGD) scores. RESULTS: JDM patients exhibited modest but discernible alterations in serum metabolites compared to controls, many of which also correlated with PGD. Several bioactive lipids and pyroglutamic acid were upregulated in JDM and positively correlated with PGD. Changes in xanthine, methionine and N-acetylneuraminic acid also indicated increased oxidative stress and inflammation. Markers of increased energy demand and muscle damage, including acylcarnitines, creatine, 4-guanidinobutyric acid, glutamine, and phenylacetylglutamine, were differential and correlated with PGD in some cases. A metabolite abundance gradient from JDM to US to HC groups suggests that siblings help account for genetic and environmental influences on the metabolome. DM patients did not show significant serum changes compared to US. CONCLUSION: Untargeted metabolomics revealed distinct serum metabolite alterations in JDM, providing insights into disease-related metabolic perturbations. These findings enhance understanding of JDM pathophysiology and inform future large-scale, targeted studies.