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Pathogenesis, classification and treatment of inflammatory myopathies

Abstract

The inflammatory myopathies—collectively, myositis—are a heterogeneous group of chronic muscle disorders that differ in response to immunosuppressive treatment. Insufficient knowledge of the molecular pathways that drive pathogenesis (and underlie the clinical differences between subtypes) has hindered accurate classification, which in turn has been detrimental for clinical research. Nevertheless, new insights into pathogenesis are paving the way for improvements in diagnosis, classification and treatment. Accumulating data suggest that both immune and nonimmune mechanisms cause muscle weakness. Phenotyping of the T cells that accumulate in muscle tissue has identified proinflammatory, apoptosis resistant and cytotoxic CD4+ and CD8+ CD28null populations. Several myositis-specific autoantibodies have been identified, associated with distinct clinical phenotypes. Thus, adaptive immunity is involved in pathogenesis, and both T and B cells are interesting targets for therapy. Furthermore, genotyping has revealed activation of the type I interferon pathway in patients with dermatomyositis or with expression of particular autoantibodies. Decreased release of Ca2+ from the sarcoplasmic reticulum, as a consequence of release of proinflammatory cytokines and high mobility group protein B1, might contribute to muscle weakness, and nonimmune mechanisms potentially include a role for endoplasmic reticulum stress, autophagy and hypoxia. Deeper understanding, careful phenotyping of patients—and new classification criteria—will expedite clinical research.

Key Points

  • Myositis is a heterogeneous group of chronic inflammatory muscle disorders, the origins of which are not yet clear and for which efficient treatment is largely lacking

  • Recent findings suggest that both immune and nonimmune mechanisms are involved in the pathogenesis of myositis, and that different molecular pathways might predominate in different subsets of myositis

  • The immune mechanisms involve immune cells—T cells, B cells, dendritic cells and macrophages—and their products, such as cytokines and antibodies

  • Myositis-specific autoantibodies are helpful in the diagnosis of myositis, they identify different clinical subsets of myositis, and they might be important for differentiating pathogenic mechanisms between patients with myositis

  • Among nonimmune pathogenic mechanisms, there seem to be roles for endoplasmic reticulum stress, hypoxia and autophagy, contributing to the cause of muscle weakness

  • New classification criteria are needed to identify more homogenous subsets of patients, and subsets that are likely to share molecular pathways

  • Studying the outcomes of targeted therapies will facilitate understanding of disease mechanisms

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Figure 1: Potential immune mechanisms in myositis pathogenesis.
Figure 2: Localization of MHC class I antigens in muscle tissue of a patient with myositis.
Figure 3: Potential nonimmune mechanisms in myositis pathogenesis.

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M. Zong and I. E. Lundberg contributed equally to all aspects of the preparation of this manuscript.

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Correspondence to Ingrid E. Lundberg.

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Zong, M., Lundberg, I. Pathogenesis, classification and treatment of inflammatory myopathies. Nat Rev Rheumatol 7, 297–306 (2011). https://doi.org/10.1038/nrrheum.2011.39

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