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Dermatomyositis (DM) is a systemic autoimmune disease characterized by chronic inflammation in proximal skeletal muscles, skin and other target organs. Many physicians focus on the weakness and the resulting physical dysfunction as the most disabling features of DM and therapeutic trials often have been directed at improving these manifestations. Subsequently, the skin disease is often neglected by treating physicians as a less severe manifestation of illness and is often not the focus of therapy.
Nonetheless, despite the second-hand status often afforded the skin disease of DM, it can be as debilitating as the muscle disease. Patients with adult and juvenile DM often experience a variety of both sun-exposed and non-sun-exposed skin rashes, including erythematous and vasculopathic lesions (1;2). Pruritus is a frequent manifestation of active DM skin disease that adversely impacts quality of life (3). Incompletely treated cutaneous manifestations can lead to dystrophic calcification in the skin and subcutaneous tissues in up to 25% of juvenile-onset DM patients and 15% of adults with DM (4). Skin atrophy, dyspigmentation and lipodystrophy, the loss of subcutaneous tissue resulting in metabolic sequelae of insulin resistance and hyperlipidemia, are common outcomes of prior inflammation in the skin and subcutaneous tissue (4;5).
Discordance in the presentation of skin and muscle symptoms and their different impact on outcomes are becoming evident. The characteristic DM skin rashes of Gottron’s papules and the heliotrope rash predate the onset of muscle symptoms in almost half of the patients (6). Periungual nailfold capillary changes, an almost universal feature of DM, correlate more with skin than muscle disease activity (7). Persistence of Gottrons papules, other skin rashes, and periungual nailfold capillary changes are associated with a longer time to remission in patients with juvenile DM and a monocyclic illness course (7;8). Thus, we can no longer neglect the skin as an important manifestation of DM, as skin disease significantly impacts the outcome of this illness and clearly deserves its own focus for therapy.
The pathologic changes in the affected skin, including perivascular inflammation at the dermal-epidermal junction and resulting small vessel vasculopathy and capillary loss, appear to parallel similar changes present in the affected muscles (9). Corresponding information on the pathogenesis of the skin disease and a fuller elucidation of the role of plasmacytoid dendritic cells and the type I interferon response in the affected skin, however, has been lagging.
In this issue of Arthritis and Rheumatism, Shrestha and colleagues (10) describe several novel findings related to the pathogenesis of the skin disease of patients with juvenile DM, and extend observations on the type I interferon pathway, in a carefully conducted study that not only controls for disease state and treatment, but also pairs skin and muscle tissue in simultaneous examinations. These authors also confirm that mature dendritic cells (DC-LAMP positive), which are plasmacytoid in origin (BDAC2 positive), are increased in the affected muscle of newly-diagnosed, untreated patients with juvenile DM compared to control children. These cells are primarily found in perivascular and perifascicular areas, which are the regions of greatest pathologic change (11;12). The majority of juvenile DM muscles also express increased MxA protein, a product of type I interferon signaling, in perifascicular myofibers and in the perivascular inflammatory infiltrates. In skin biopsies, taken from an overlying muscle biopsy site and not always involving an active rash, mature dendritic cells, which are apparently of plasmacytoid origin and express the MxA protein, are present throughout the epidermis and dermis, as well as at the periphery of blood vessels. The frequency of these cells and the intensity of staining are higher in the skin of juvenile DM patients than that of the control subjects. Also the expression of all dendritic cell markers and the type I interferon-induced MxA protein is stronger in the skin than muscle tissue.
These authors also report that the number of mast cells is increased throughout the dermis of patients with juvenile DM compared to controls without an inflammatory condition, that these cells appear to be degranulated and thus activated, and that their frequency is similar in both lesional and non-lesional DM skin. There is no difference in the numbers of mast cells, however, in the affected muscle tissues of juvenile DM patients compared to muscle tissues from control subjects. Their findings point to several novel pathways in the pathogenesis of DM skin disease and, while suggesting certain similarities between the skin and muscle disease, they also show us certain distinctions in the pathogenesis of DM skin and muscle disease.
A series of gene expression profiling and immunohistochemistry studies have revealed a prominent type I interferon signature in the affected muscle tissue, which is particularly prominent in adult and juvenile DM compared to other forms of myositis such as polymyositis and inclusion body myositis (13). This type I interferon signature appears to correlate with the infiltration of plasmacytoid dendritic cells in the skeletal muscle and to be a central aspect of the disease pathogenesis (12;14). The type I interferon signature is also present in peripheral blood mononuclear cells, and correlates with myositis disease activity (15;16). One study in juvenile patients suggests that MxA production, a type I interferon inducible gene product, correlates better with skin than muscle disease activity (17). Studies of adult DM skin biopsies have revealed the presence of the MxA protein and other type I interferon-induced proteins throughout the epidermis and perivascular infiltrate of affected DM skin tissue, corresponding to the infiltration of plasmacytoid dendritic cells (9;18). MxA expression is also prominent in the affected endothelial cells of adult DM skin tissue, and the plasmacytoid dendritic cells are not uniformly present in areas of MxA expression (9). The presence of MxA and plasmacytoid dendritic cells in the dermisand epidermis in the juvenile-onset DM patients of Shrestha et al. (10) may relate to the inclusion of non-lesional skin tissue in their juvenile study and not in the studies of adult DM, to differences of disease duration and therapy (the juvenile study was in new-onset patients and the adult DM studies included treated patients), or to true differences in the pathogenesis of adult versus juvenile DM.
Mast cells, which do not usually circulate in the blood but acquire their phenotype in the tissues where they reside, are central mediators of a wide variety of stimuli. Shrestha and colleagues (10) are the first to directly implicatemast cells in the pathogenesis of human DM skin disease, although mast cells have been reported as a prominent infiltrating cell of the skin lesions of dogs with DM (19). Increased numbers of mast cells have been reported in polymyositis patients in the muscle tissue, particularlyin areas of necrosis and regeneration (20)and as part of the interstitial inflammatory infiltrate (21), although an increased number of mast cells was not found to be present in juvenile DM muscle biopsies (10).
Over the past decade an expanded role for mast cells has emerged, not only as the cell critical in the response to allergens, but as a primary cell for host defense and initiation of innate immune responses in tissues located at the interface between the host and the environment, especially the skin, mucosa, gastrointestinal and respiratory tracts. Mast cells are not only activated by the high affinity IgE receptor, but also by Fc gamma receptors, complement receptors and toll-like receptors after interaction with bacterial products and viral RNA, and even by physical stimuli including ultraviolet B irradiation (22;23). Notably, ultraviolet B irradiation and viruses have been implicated as some of the possible environmental risk factors for DM (6;24). Activated mast cells secrete a number of pro-inflammatory mediators including type I interferons, TNF-α, IL-6, and IL-1β and result in the influx of TH2 T lymphocytes and dendritic cells, all of which are thought to be critical factors in the pathogenesis of DM (22;23;25). Mast cells then may be an early key initiator of the pathogenic sequence of events in DM, at least in the skin tissue.
Mast cells are emerging as a critical player inmediating a number of systemic and organ-specific autoimmune diseases. In a K/BxN mouse model of rheumatoid arthritis, knock out of mast cells by two different pathways (deficiency of stem cell factor and of c-kit, a mast cell differentiation factor) leads to abrogation of disease, whereas engraftment of mast cells restores joint inflammation (26). Agents that inhibit mast cell degranulation, such as salbutamol, slow the progression of collagen-induced arthritis (27). In the MRL/lpr mouse model of lupus, a dense mast cell infiltrate is present in the dermis of the affected skin lesions in animals older than 4 months of age; and, this correlates with decreased histamine methyltransferase activity and prolonged activation of histamine in the affected skin tissue (28). Mast cells are also increased in the affected skin of patients with chronic cutaneous lupus (28). Activated mast cells have also been reported in the skin of patients with systemic sclerosis, and mast-cell targeted therapies improve the skin disease of the tight-skin mouse model of scleroderma (22). Mast cell deficient mice either do not develop disease, as in bullous pemphigoid, or have less severe and delayed disease, as in the experimental autoimmune encephalomyelitis model of multiple sclerosis (22;27). Mast cells likely play a role in the pathogenesis of a number of other autoimmune disorders, including Graves’ disease, systemic vasculitis, insulin-dependent diabetes, Sjogren’s syndrome, Guillain-Barre syndrome and pemphigus vulgaris, based on the findings of increased mast cell numbers in the affected tissues and/or an improvement in disease with mast cell-targeted therapies (22).
The report of Shrestha et al. (10) expands our understanding of the type I interferon response and the corresponding infiltrating plasmacytoid dendritic cells that may be generating this response in the skin and muscle tissue, refines the parallels and distinctions of the pathogenesis of skin and muscle disease in DM, and calls upon a new pathway of mast cell activation that may be critical to the pathogenesis of the skin disease in DM. As is the case with many important novel observations, it raises new questions for investigators and new implications for rheumatologists in the care of their patients. What is it that is attracting mast cells to the skin - is it viral RNAs activating toll-like receptors, ultraviolet light, and/or immune complexes activating Fc gamma receptors? What is the inter-relationship of mast cells and plasmacytoid dendritic cells to the type I interferon response, and which cells are the initiators of the type I interferon response? Are mast cells among the critical cells that first become activated and generate pro-inflammatory cytokines to initiate the pathogenesis of DM? Will use of the growing number of mast cell-directed therapies (29) be helpful in the treatment of both DM skin and muscle disease? Will such therapies decrease the skin rashes, as well as the associated pruritus that adversely impacts the quality of life of many DM patients?
In short, we now need to refine our therapeutic approaches to treating patients with myositis, directing therapies more specifically to the precise pathogeneses and particular manifestations of the illness whether they involve the skin, muscle or other tissues. The observations of Shrestha et al. (10) should renew focus on the skin disease of DM, and direct studies to answer the questions they raise to advance our understanding of the pathogenesis and treatment of myositis and other systemic autoimmune diseases in children and adults.
This work was supported by the NIEHS, NIH intramural research program.
Author contributionsDrs. Rider and Miller were involved in drafting the article or revising it critically for important intellectual content, and both authors approved the final version to be published.