Lupus myositis, a type I interferon driven necrotizing myopathy with regional heterogeneity.

Lupus myositis (LM) is an underrecognized entity, whose pathological features significantly overlap with idiopathic inflammatory myopathies (IIMs). Currently, no standardized histopathological criteria or immunohistochemical (IHC) markers exist for the diagnosis of LM on muscle biopsy. We performed detailed histologic, immunohistochemical, ultrastructural, and spatial transcriptomic protein analyses on a stringent cohort of LM muscle biopsies, excluding patients with myositis-specific autoantibodies (MSA). Findings were compared with dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome (ASyS), and non-diseased control muscle specimens. Among 1736 patients diagnosed with systemic lupus erythematosus (SLE) between 2010 and 2023, 32 muscle biopsies were identified in myositis patients without MSA. Twenty-two cases demonstrated a necrotizing myopathy with spatial and temporal heterogeneity, MxA-positive myofiber expression, and perivascular inflammation composed of mixed T and B cells. A "pan-fascicular necrotizing myopathy" pattern was a highly recognizable feature of LM, although minority of cases demonstrated a diffuse scattered or perifascicular damage pattern. An IHC profile of MxA+/MHC I+/MHC II+ reliably distinguished LM from other IIMs. Spatial transcriptomics analysis confirmed that type I interferon pathway or MHC I related mRNAs and proteins were the most deferentially expressed in myofibers, capillaries and inflammatory cells. Electron microscopy identified frequent endothelial tubuloreticular inclusions. The remaining 10 cases demonstrated nonspecific myositis on muscle biopsy and were clinically associated with significant higher frequencies of overlapping systemic rheumatologic features such as interstitial lung disease, Sicca syndrome, systemic sclerosis, and rheumatoid arthritis, suggesting overlap myositis rather than pure LM. In conclusion, the pathological hallmark of LM is a type I interferon driven necrotizing myopathy with perivascular mixed T and B cell inflammation. A combined IHC panel including MxA, MHC I and MHC II effectively differentiates LM from other inflammatory myopathies.