Mast cells and type I interferon responses in the skin of patients with juvenile dermatomyositis: Are current therapies just scratching the surface?

Abstract

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.