Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening cutaneous adverse drug reactions. It is difficult to distinguish erythema multiforme (EM) and SJS/TEN in early stage. Although keratinocytes have been suggested to die as apoptosis, our recent study revealed that necroptosis, programmed necrosis, also contribute to keratinocyte death in SJS/TEN.  We hypothesized that analyzing the form of keratinocyte death is useful for early diagnosis of SJS/TEN. 
The skin samples were obtained from non-bullous erythematus lesion of the patient who suspected drug eruption in the acute phase. We included 4 patients diagnosed as SJS/TEN and 10 patients diagnosed as EM. Anti-phosphorylated MLKL (pMLKL) antibody was used to detect necroptosis, and anti-cleaved caspase8 (cCas8) antibody was used to detect apoptosis.
Both of pMLKL(+) cell (3.78±2.70%) and cCas8(+) cell (17.8±4.94%) were shown in the 4 SJS/TEN patients. In EM patients, pMLKL(+) cell was shown in 4 patients (1.47±2.56%) and cCas8(+) cell was shown in 2 patients (1.09±2.15%). In 4 all cases diagnosed as SJS/TEN, both of pMLKL and cCas8 cell were positive. In contrast, it was only 1 case that both pMLKL and cCas8 were positive and either pMLKL or cCas8 was positive in 4 cases in EM. The number of pMLKL(+) plus cCas8(+) cell were statistically higher than the number of death keratinocyte detected by HE staining (SJS/TEN: 13.42±5.39%)(EM: 1.02±1.38%).
The results revealed that both of necroptosis and apoptosis are occurred in keratinocyte death in SJS/TEN. Although, in EM, both of necroptosis and apoptosis are shown, the amount of cell death is lower than SJS/TEN. It is suggested that the frequency of cell death is important for differentiation between SJS and EM. pMLKL and cCas8 may be able to detect earlier stages of cell death than HE staining, and it is expected that pMLKL and cCas8 can be the marker of SJS/TEN.

Phosphorylated MLKL and cleaved caspase8 are useful for early diagnosis of Stevens-Johnson syndrome and toxic epidermal necrolysis.