Immune-mediated Necrotizing Myopathy (IMNM): A Myopathological Challenge

This review is focused on the myopathological spectrum of immune mediated necrotizing myopathies (IMNMs) and its differentiation with other, potentially mimicking, inflammatory and non-inflammatory myopathies. IMNMs are a subgroup of idiopathic inflammatory myopathies (IIMs) characterized by severe clinical presentation with rapidly progressive muscular weakness and creatine kinase elevation, often requiring early aggressive immunotherapy, associated to the presence of muscle specific autoantibodies (MSA) against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Muscle biopsy usually shows unspecific features consisting in prominent necrosis and regeneration of muscle fibres with mild or absent inflammatory infiltrates, inconstant and faint expression of major histocompatibility complex (MHC) class I and variable deposition of C5b-9 on sarcolemma. Several conditions could present similar histopathological findings leading to possible misdiagnosis of IMNM with other IIMs or non-inflammatory myopathies (nIMs) and viceversa. This review analyses the muscle biopsy data in IMNMs through a systematic revision of the literature from the last five decades. Several histopathological variables have been considered in both SRP- and HMGCR-IMNM, and compared to other IIMs - as dermatomyositis (DM) and anti-synthethase syndrome (ASS) - or other nIMs -as toxic myopathies (TM), critical illness myopathy (CIM) and muscular dystrophy (MD) - to elucidate similarities and differences among these potentially mimicking conditions. The major histopathological findings of IMNMs were: very frequent necrosis and regeneration of muscle fibres (93%), mild inflammatory component mainly constituted by scattered isolated (65%) CD68-prevalent (68%) cells, without CD8 invading/surrounding non-necrotic fibres, variable expression of MHC-I in non-necrotic fibres (56%) and constant expression of sarcoplasmic p62, confirming those that are widely considered the major histological characteristics of IMNMs. Conversely, only 42% of biopsies showed a sarcolemmal deposition of C5b-9 component. Few differences between SRP and HMGCR IMNMs consisted in more severe necrosis and regeneration in SRP than in HMGCR (p = 0.01); more frequent inflammatory infiltrates (p = 0.007) with perivascular localization (p = 0.01) and clustered expression of MHC-I (p = 0.007) in HMGCR; very low expression of sarcolemmal C5b-9 in SRP (18%) compared to HMGCR (56%) (p = 0.0001). Milder necrosis and regeneration, detection of perifascicular pathology, presence of lymphocytic inflammatory infiltrates and myofibre expression of MxA help to distinguish DM or ASS from IMNM. nIMs can present signs of inflammation at muscle biopsy. Low fibre size variability with overexpression of both MHC-I and II, associated with C5b-9 deposition, could could be observed in CIM, while increased connective tissue should lead to consider MD, or TM in absence of C5b-9 deposition. Nevertheless, these features are not constantly detected and muscle biopsy could not be diriment. For this reason, muscle biopsy should always be critically considered in light of the clinical context before concluding for a definite diagnosis of IMNM, only based on histopathological findings. More rigorous collection and analysis of muscle biopsy is warranted to obtain a higher quality and more homogeneous histopathological data in inflammatory myopathies.