Spatial transcriptomics in immune-mediated necrotising myopathy uncovers a specific necrotic signature related to immune-driven fibrosis

Immune-mediated necrotising myopathies (IMNM) are characterised by muscle fibre necrosis, complement deposits around non-necrotic fibres, and macrophage infiltrates. Patients experience muscle damage with fibro-fatty replacement, leading to poor strength recovery, but the pathogenesis remains unclear. To investigate IMNM pathogenesis, we applied spatial transcriptomics on myositis muscle biopsies and integrated the results with published single-nucleus transcriptomic data. This combined approach enabled analysis of gene expression with spatial localisation in the muscle. Inflammatory, fibrotic, regenerative, and lipid metabolism-related signatures were identified in IMNM, distinct from other myositis, with specific distribution in necrotic and peri-necrotic regions. A unique subtype of immune-driven fibroblasts expressing SFRP4 was enriched in IMNM necrotic areas. These cells carried a strong proportion of IMNM-enriched pathological signatures, notably a complement-linked 'tumour-like' inflammatory fibroblast signature and a specific interferon response, characterised by the expression of metallothioneins. Peri-necrotic areas were characterised by pathological muscle signatures carrying interferon response and FABP4+ metabolically dysfunctional signatures. In conclusion, IMNM necrotic muscle areas are linked to a specific SFRP4-expressing fibroblast subtype interacting with macrophages, potentially driving the pathological muscle phenotype and contributing to inflammation, fibro-fatty replacement, and strength loss.