Anti-aminoacyl-tRNA synthetase-related myositis and dermatomyositis: clues for differential diagnosis on muscle biopsy

Abstract

Anti-synthetase syndrome is an autoimmune disease characterized by autoantibodies toward amino acyl-tRNA synthetases (ARS), anti-Jo 1 being the most commonly detected. Muscle damage develops in up to 90% of ARS-positive patients, characterized by a necrotizing myositis restricted to the perifascicular region. This topographic distribution of muscle damage may lead to a misdiagnosis of dermatomyositis (DM) at muscle biopsy. We compared morphological, immunohistochemical, and histoenzymatic features of muscle from ARS-positive patients (n = 11) with those of DM (n = 7) providing clues for their differential diagnosis. In addition, we evaluated markers of mitochondrial damage to provide a further distinction between these two entities. Necrosis occurred in the majority of ARS patients, mainly located in the perifascicular region. It was often limited to small foci of fibers, always associated with myocyte regeneration. This last often overwhelmed necrosis, representing occasionally the main finding. In DM, necrosis/regeneration was scarce while the peculiar feature was a diffuse atrophy of perifascicular fibers. These last showed decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion, consistent with mitochondrial dysfunction. In contrast to DM, ARS displayed scattered COX-deficient fibers, not restricted to the perifascicular region. This feature occurred in up to 91% of patients, being prominent only in two.

Mitochondrial morphology and MAVS‐IFN1 signaling pathway in muscles of anti‐MDA5 dermatomyositis

“…Interestingly, the abnormal mitochondria in the area of perifascicular region was much less to the antibody‐negative group whereas the scattered COX‐deficient fibers, not restricted to the perifascicular region were confined to anti‐MDA5 DM and broadly distributed COX‐deficient fibers across the specimen were observed in three anti‐MDA5 DM patients. Similar topographic distribution of COX negative fibers was also frequently observed in anti‐synthetase syndrome patients 2 . Therefore, we speculated the distinct mechanism of mitochondrial injury between anti‐MDA5 DM and antibody‐negative DM.…”

“…Similar topographic distribution of COX negative fibers was also frequently observed in antisynthetase syndrome patients. 2 Therefore, we speculated the distinct mechanism of mitochondrial injury between anti-MDA5 DM and antibody-negative DM. MDA5 is one of the viral RNA sensors that induce MAVS oligomerization.…”

“…1 Decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion consistent with mitochondrial dysfunction is mostly revealed in myofibers within perifascicular area. 2 Overexpression of mitochondrial apoptosis molecules or gasdermin E-dependent mitochondrial pyroptotic pathway might be pathogenesis for perifascicular atrophy in DM. 3 A number of myositis-specific autoantibodies (MSA) have been identified in DM, including autoantibodies to melanoma differentiation-associated protein 5 (MDA5), the nuclear helicase protein Mi-2 region, nuclear matrix protein 2(NXP2), transcriptional intermediary factor 1c (TIF1c), and the small ubiquitin-like modifier-activating enzyme(SAE).…”

“…The typical histopathologic features of DM muscle pathology are the infiltration of perimysial lymphocytes and macrophages, perifascicular atrophy, as well as loss of capillaries 1 . Decreased cytochrome c oxidase (COX) stain and mitochondrial DNA depletion consistent with mitochondrial dysfunction is mostly revealed in myofibers within perifascicular area 2 . Overexpression of mitochondrial apoptosis molecules or gasdermin E‐dependent mitochondrial pyroptotic pathway might be pathogenesis for perifascicular atrophy in DM 3 …”

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies

“…Out of eight patients with pathological muscle biopsy, all presented widespread up-regulation of major histocompatibility complex class I (MHC-I), five with perivascular and/or endomysial inflammatory infiltrates even invading non-necrotic muscle fibers and two with perifascicular atrophy. The patient with anti-SerRS antibody reactivity had perifascicular necrosis, which has been proposed to be specific for ASSD [29][30][31] (missing information in 5/8 pathological muscle biopsies). None of the patients suffered from Raynaud's phenomenon.…”