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(+) CD28(null) 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 Ca(2+) 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.