Multiomics analysis uncovers subtype-specific mechanisms and biomarkers in idiopathic inflammatory myopathies.

Objectives: Idiopathic inflammatory myopathies (IIM) are autoimmune disorders with distinct subtype features, but their molecular mechanisms remain unclear. This study integrated multiomics data to identify subtype-specific molecular signatures and evaluate their prognostic significance in a Han Chinese IIM cohort.

Methods: RNA sequencing, proteomics, and metabolomics were generated on muscle tissues from 203 patients with IIM (including 44 in a validation cohort) and 18 controls. Differential expression was analysed for exons, intron retentions (IRs), proteins, and metabolites, integrated via multiomics factor analysis (MOFA). Pathway enrichment, single-sample Gene Set Enrichment Analysis (ssGSEA), correlation with clinical features, receiver operating characteristic curve, and survival analyses were conducted.

Results: MOFA distinguished dermatomyositis (DM), immune-mediated necrotising myopathy (IMNM), and antisynthetase syndrome (ASyS) from controls, identifying 798, 748, and 297 subtype-specific features and pathways, respectively, which were further validated in an independent cohort. In DM, upregulated interferon (IFN) and cytokine pathways were prominent, with 11 IFN-related genes altered at exon, IR, and protein levels, alongside changes in related metabolites. IFNs and cytokine scores correlated with skin manifestations, perifascicular atrophy/necrosis, inflammation, and relapse risk. IMNM showed changes in myosin, actin, and troponin genes, with enrichment of cytoskeleton and extracellular matrix (ECM) pathways that were positively linked to muscle necrosis, regeneration, and inflammation. Protein-level of ECM-related pathways predicted a favourable prognosis. ASyS displayed distinct metabolic signatures (nucleosides, ketones, phosphatidylserine) and endothelial dysfunction, with key metabolism-regulated genes (FABP3, AKR1C2, AKR1C3) showing multiomics alterations associated with necrosis, inflammation, and prognosis.

Conclusions: This multiomics analysis elucidates distinct molecular mechanisms in IIM subtypes, identifying potential biomarkers for personalised prognosis and therapy.