Vemurafenib and cobimetinib‐induced toxic epidermal necrolysis in a patient with metastatic melanoma

Combination therapy in the treatment of metastatic melanoma has been associated with more durable response rate compared to monotherapy. However, previous studies have shown that combined target therapy commonly causes a wide spectrum of adverse events. These adverse reactions are usually manageable, however, it is always necessary to compare drug efficacy with its potential adverse effects. Toxic epidermal necrolysis represents severe mucocutaneous reaction, usually triggered by medications and characterized by extensive necrosis and detachment of the epidermis. Here we present a first case of toxic epidermal necrolysis induced by combined target therapy (vemurafenib plus cobimetinib). The case was observed in a young patient with BRAF mutant melanoma who was started on first‐line metastatic immunotherapy with pembrolisumab.     

Acetaminophen-induced toxic epidermal necrolysis in a child

Toxic epidermal necrolysis (TEN) is a severe, life-threatening disorder that usually affects adults. It is often drug induced. We report an instance of a severe case of TEN in a 6-year-old boy, probably induced by acetaminophen, and less likely by codeine. A lymphocyte stimulation test could not identify the culprit drug. Treatment with intravenous immunoglobulin seemed to halt the disease progression.     

Plasmapheresis in toxic epidermal necrolysis

Background The treatment of toxic epidermal necrolysis (TEN) is usually based on the removal of the offending drug(s), fluid replacement, nutritional support, and local management. The mortality and morbidity, however, remain high and the death rate may be reduced to 10% only in special centers that use biologic dressings. Plasma exchange (PE) was proven efficacious in small series of patients and of no particular value in others. Methods Seven patients suffering from severe TEN covering 30%–80% of body surface area and having two or four mucous membranes involved, were included in this open study. Malignancy (Hodgkin's disease, brain tumor) and a variety of medicaments (carbamazepine, allopurinol, diphenylhydantoin, cefaclor, amoxicyllin with clavullanic acid) were considered as causally implicated. One to four PEs of 2.5 L were given on alternate days in six patients and on a daily basis in the seventh. Results All patients recovered successfully from their disease. No new lesions appeared after the first PE in four patients. Neither adverse reactions from this therapy nor sequelae from TEN were observed after a long follow-up lasting up to 8 years. Conclusions Although PE is expensive and requires easy venous access to be performed, it could be listed in the first line of TEN therapy. The method is safe and efficacious, providing prompt relief from pain and rapid cessation of necrolysis. The alternate day PEs are considered preferable to the everyday regimen.     

卡马西平致中毒性表皮坏死松解症伴HLA-A*31:01阳性一例

【摘要】 目的 探讨1例卡马西平致中毒性表皮坏死松解症（TEN）的易感基因类型。方法 收集1例由卡马西平诱发的TEN患者临床资料,抽外周血提取DNA,应用荧光染色原位杂交技术检测卡马西平易感基因位点HLA-A*31:01（rs1633021）、HLA-B*58:01（rs3095318）、HLA-B*15:02（rs3909184）和HLA-B*15:02（rs2844682）。结果 患者女,40岁,汉族,因口周红斑水疱7 d,泛发全身4 d就诊。患者出现皮损前曾应用卡马西平1个月。基因检测显示,HLA-B*15:02阴性,HLA-A*31:01阳性。结论 本例中国汉族卡马西平致TEN患者HLA-A*31:01阳性。     

Management of toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN) is a medical emergency requiring the combined efforts of specialists from multiple disciplines. A basic guide to the management of the seriously ill patient with this disorder is provided.     

Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis

Toxic epidermal necrolysis is an extremely severe drug reaction, manifesting itself by widespread apoptosis of keratinocytes, generally considered to result from Fas/CD95-FasLigand interaction, but of unknown primary mechanism. We looked at the role of cells present in the skin blisters as probable effectors of this immune reaction. In a patient suffering from cotrimoxazole-induced toxic epidermal necrolysis, blister fluid cells were phenotyped by FACS and tested without prior restimulation for cytotoxicity on autologous and allogeneic cells in the presence of the drug. Blister fluid lymphocytes were predominantly CD8+, DR+, CLA+, CD56+ T lymphocytes, perforin positive and expressing preferentially two Vbeta chains of the T cell receptor repertoire. These lymphocytes were cytotoxic only in the presence of the drug towards autologous EBV transformed lymphocytes and towards allogeneic cells sharing HLA-Cw4. Cytotoxicity occurred in the presence of either cotrimoxazole, sulfamethoxazole, or the nitroso metabolite of sulfamethoxazole, but not with the hydroxylamine metabolite of sulfamethoxazole. The lysis was blocked by an anti-MHC class I monoclonal antibody. It was abolished by EGTA and CMA, but neither by anti-fas, brefeldin A, nor by anti-TRAIL receptor monoclonal antibodies, strongly suggesting perforin/granzyme-mediated cytotoxicity, without implication of Fas or TRAIL at this stage. This is direct evidence that T lymphocytes present within the lesions of toxic epidermal necrolysis may exhibit, without any re-stimulation, a drug-specific cytotoxicity against autologous cells. Harboring the markers of classical CTL and MHC class I restriction these lymphocytes reacted against the parent drug and one of its reactive metabolites. These results challenge several current concepts and could support new therapeutic approaches.