344 TNFα-induced vascular hyperpermeability as the possible cause of purpura in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS)

DIHS/DRESS is a severe adverse drug reaction characterized by persistent eruption associated with reactivation of herpesviruses. In acute phase of the disease, purpura is occasionally observed mainly in limbs. We recently demonstrated that the area of purpura in the lower limbs correlates with the severity as assessed by DIHS/DRESS severity score. However, the pathogenesis of purpura has not been examined. We collected four patients with DIHS and two patients with erythema multiforme (EM). In all patients with DIHS, we observed purpura on the lower limbs at our initial examination and performed skin biopsy from purpura. To investigate whether endothelial cell death is associated with the extravasation of erythrocyte, we performed TUNEL assay combined with immunohistochemical staining with CD31 in skin biopsy specimens. In addition, we measured a total of 48 human cytokines by Bio-Plex Pro Human Cytokine Screening Panel using sera from 3 patients with DIHS to examine the level of cytokines that are involved in vascular hyperpermeability. The number of TUNEL-positive cells in the dermis observed most frequently at the 400×magnification was higher in the DIHS specimens (n=8,7,6,6), than in the EM specimens (n=3,1). The TUNEL-positive cells were not matched to CD31-positive cells. We observed higher levels of TNFα which has reported to increase vascular permeability, in the sera of patients with DIHS than those of healthy controls (65.8±15.3 vs. 42.4±5.1 pg/ml). Our results indicate that purpura in DIHS/DRESS is not caused by the vascular endothelial cell death. Instead, vascular hyperpermeability induced by inflammatory cytokines such as TNFα might be the cause of purpura. We are going to perform in vitro permeability assay using human umbilical vein endothelial cells cultured under serum administration of patients with DIHS to investigate the factors that increase vascular permeability in the serum of patients with DIHS.