Abstract
The classification of idiopathic inflammatory myopathies (IIM) is based on clinical, serological and histological criteria. The identification of myositis‐specific antibodies has helped to define more homogeneous groups of myositis into four dominant subsets: dermatomyositis (DM), antisynthetase syndrome (ASyS), sporadic inclusion body myositis (sIBM) and immune‐mediated necrotising myopathy (IMNM). sIBM and IMNM patients present predominantly with muscle involvement, whereas DM and ASyS patients present additionally with other extramuscular features, such as skin, lung and joints manifestations. Moreover, the pathophysiological mechanisms are distinct between each myositis subsets. Recently, interferon (IFN) pathways have been identified as key players implicated in the pathophysiology of myositis. In DM, the key role of IFN, especially type I IFN, has been supported by the identification of an IFN signature in muscle, blood and skin of DM patients. In addition, DM‐specific antibodies are targeting antigens involved in the IFN signalling pathways. The pathogenicity of type I IFN has been demonstrated by the identification of mutations in the IFN pathways leading to genetic diseases, the monogenic interferonopathies. This constitutive activation of IFN signalling pathways induces systemic manifestations such as interstitial lung disease, myositis and skin rashes. Since DM patients share similar features in the context of an acquired activation of the IFN signalling pathways, we may extend underlying concepts of monogenic diseases to acquired interferonopathy such as DM. Conversely, in ASyS, available data suggest a role of type II IFN in blood, muscle and lung. Indeed, transcriptomic analyses highlighted a type II IFN gene expression in ASyS muscle tissue. In sIBM, type II IFN appears to be an important cytokine involved in muscle inflammation mechanisms and potentially linked to myodegenerative features. For IMNM, currently published data are scarce, suggesting a minor implication of type II IFN. This review highlights the involvement of different IFN subtypes and their specific molecular mechanisms in each myositis subset.
Highlights
Inflammatory idiopathic myopathies (IIM) are a group of rare autoimmune diseases involving muscle tissue and other organs. They are categorised into four dominant subsets: dermatomyositis (DM), antisynthetase syndrome (ASyS), inclusion body myositis (IBM) and immune-mediated necrotising myopathy (IMNM) based on clinical manifestations, the presence of myositis- specific autoantibodies (MSA) and myopathological findings
ASyS harbours a perifascicular pathology characterised by perifascicular necrosis, and the majority of patients have interstitial lung disease while this latter feature rarely occurs in DM patients
ASyS is defined by the presence of one of the anti-histidyl RNA-t-synthetase antibodies [5, 6], and DM is associated with a different set of MSAs: anti-Mi2 [7], anti-SAE1 [8], anti-TIF1γ [9], anti-NXP2 [10] and anti-melanoma differentiation-associated protein 5 (MDA5) (11–13)
Summary
In the V154M knock-in model, mice developed interstitial pulmonary disease reproducing the phenotype of SAVI, similar to that in anti-MDA5+ DM patients. Later Greenberg et al reported on the activation of IFN pathways in muscle biopsies from adult DM patients [60]. This IFN signature was not observed in other subsets of inflammatory myopathies such as polymyositis [60]. Ono et al showed a correlation between IFN signature in blood and skin and vasculopathy features They confirmed IFN pathway involvement at a protein level with MxA staining in the blood vessels and interstitial fibroblasts of DM patients.
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