Little is known concerning factors associated with the outcome of juvenile dermatomyositis (JDM), which can be variable and lethal. Previous work has documented that the association of DQA1*0501 with JDM is higher than in control groups and that the first symptoms (rash and weakness) of JDM appear to follow evidence of an infectious process--most frequently upper respiratory in nature. Preliminary data show that a long period of symptoms being left untreated before starting therapy and the TNF alpha-308A allele are associated with prolonged JDM symptoms requiring > or = 36 months of immunosuppressive therapy. A short duration of untreated disease is associated with a relative increase in CD8(+) T cells and CD56(+) natural killer (NK) cells in the untreated JDM muscle biopsy compared with a longer duration of untreated disease. The TNF alpha-308A allele is overrepresented in white children with JDM. In addition, it is associated with pathologic calcifications, increased production of TNF alpha by peripheral blood mononuclear cells in vitro and JDM muscle fibers in vivo, and occlusion of capillaries, which may be mediated in part by elevated circulating levels of thrombospondin-1, a potent anti-angiogenic factor. We speculate that DQA1*0501 is associated with JDM susceptibility to an infectious process, eliciting and activating NK cells early in the disease course. We conclude that the TNF alpha-308A allele indicates directly (or is a surrogate marker of) children with JDM who produce higher concentrations of TNF alpha in response to this undefined inflammatory stimulus, as well as increased concentrations of TSP-1 with resultant small vessel occlusion, contributing to subsequent disease chronicity.