Polymyositis and dermatomyositis: novel insights into the pathogenesis and potential therapeutic targets

Polymyositis (PM) and dermatomyositis (DM) are the two major forms of inflammatory muscle diseases. They are characterized clinically primarily by proximal muscle weakness. The disease mechanisms that cause muscle damage and dysfunction are not fully understood. However, because of the association with other autoimmune diseases, the presence of autoantibodies, and response to immunosuppressive medication, they are believed to be autoimmune in origin. Recent studies have highlighted the importance of the innate immune system and non-immune mechanisms and described novel adaptive immune-based pathways in the pathogenesis of polymyositis and dermatomyositis. Stimulation of Toll-like receptors (TLRs) by endogenous antigens, e.g., aminoacyl-tRNA synthetase enzyme, may trigger activation of signaling pathways and thereby induces expression of multiple genes involved in the inflammatory response. High-mobility group box-1 (HMGB1) might interact with the same receptors and cause skeletal muscle inflammation. In addition, this protein may be involved in T lymphocyte survival in muscle tissue. A newly described T cell subset, CD28(-) T cells, may have strong myotoxic properties and comprises the predominant muscle-infiltrating T cell phenotype. Future studies should focus more on understanding the relative contribution of each pathway to the pathogenesis of inflammatory myopathies. Given the connections between the pathways, targeting multiple pathways through combination therapies may be beneficial.