Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening adverse drug reactions characterized by massive epidermal necrosis, in which the specific danger signals involved remain unclear. Here we show that blister cells from skin lesions of SJS-TEN primarily consist of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells, and both blister fluids and cells were cytotoxic. Gene expression profiling identified granulysin as the most highly expressed cytotoxic molecule, confirmed by quantitative PCR and immunohistochemistry. Granulysin concentrations in the blister fluids were two to four orders of magnitude higher than perforin, granzyme B or soluble Fas ligand concentrations, and depleting granulysin reduced the cytotoxicity. Granulysin in the blister fluids was a 15-kDa secretory form, and injection of it into mouse skin resulted in features mimicking SJS-TEN. Our findings demonstrate that secretory granulysin is a key molecule responsible for the disseminated keratinocyte death in SJS-TEN and highlight a mechanism for CTL- or NK cell--mediated cytotoxicity that does not require direct cellular contact.

This study was performed to determine the characteristics and clinical outcome of patients with cutaneous malignant melanoma in Taiwan. The medical records of patients with primary cutaneous melanoma between 1992 and 2001 at Chang Gung Memorial Hospital (CGMH) were retrieved from the cancer registry. Survival was analysed by the Kaplan-Meier method. Univariate and multivariate analyses of factors associated with survival were performed using the Cox proportional hazard model. One hundred and eighty-one cases were retrieved from the cancer registry of CGMH. The male to female ratio was 1 : 1.13. The most common age of onset was the sixth decade. The median age of onset was 61 years (2-95 years). There were 105 cases (58%) of acral lentiginous melanoma (ALM), 55 cases (30.4%) of nodular melanoma (NM), 19 cases (10.5%) of superficial spreading melanoma (SSM) and two cases (1.1%) of lentigo maligna melanoma. The median survival of the 181 patients was 3.71 years, and the 5-year survival rate was 45.63%. Five-year survival rates of patients with stages I, II, III and IV disease were 84.39%, 56.03%, 34.7% and 0%, respectively. Sex, Breslow thickness, Clark's level, pathological type and age were significant prognostic factors. There were no survival differences between ALM and NM. Both ALM and NM were associated with a poor prognosis when compared with SSM. In conclusion, ALM is the most common type of cutaneous malignant melanoma in Taiwan. The prognostic factors in Taiwan are similar to those in melanoma-prevalent countries.

Allopurinol, a common drug for treating hyperuricemia, is associated with cutaneous adverse drug reactions ranging from mild maculopapular exanthema to life-threatening severe cutaneous adverse reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, and toxic epidermal necrolysis. We have previously reported that HLA-B*58:01 is strongly associated with allopurinol-induced severe cutaneous adverse reactions in Han Chinese, but the associations of the HLA-B*58:01 genotype in an allopurinol-induced hypersensitivity phenotype remain unclear. To investigate the comprehensive associations of HLA-B*58:01, we enrolled 146 patients with allopurinol-induced cutaneous adverse drug reactions (severe cutaneous adverse reactions, n = 106; maculopapular exanthema, n = 40) and 285 allopurinol-tolerant control subjects. Among these allopurinol-induced cutaneous adverse drug reactions, HLA-B*58:01 was strongly associated with severe cutaneous adverse reactions (odds ratio [OR] = 44.0; 95% confidence interval = 21.5-90.3; P = 2.6 × 10(-41)), and the association was correlated with disease severity (OR = 44.0 for severe cutaneous adverse reactions, OR = 8.5 for maculopapular exanthema). The gene dosage effect of HLA-B*58:01 also influenced the development of allopurinol-induced cutaneous adverse drug reactions (OR = 15.25 for HLA-B*58:01 heterozygotes and OR = 72.45 for homozygotes). Furthermore, coexistence of HLA-B*58:01 and renal impairment increased the risk and predictive accuracy of allopurinol-induced cutaneous adverse drug reactions (heterozygous HLA-B*58:01 and normal renal function: OR = 15.25, specificity = 82%; homozygous HLA-B*58:01 and severe renal impairment: OR = 1269.45, specificity = 100%). This HLA-B*58:01 correlation study suggests that patients with coexisting HLA-B*58:01 and renal impairment (especially estimated glomerular filtration rate < 30ml/minute/1.73 m(2)) should be cautious and avoid using allopurinol.