Epidermal programmed cell death‐ligand 1 expression in TEN associated with nivolumab therapy

Nivolumab is a programmed cell death receptor‐1 (PD‐1) antibody used in the treatment of metastatic or unresectable melanoma. Cutaneous reactions are the most common adverse events reported with these agents and are rarely severe or life‐threatening. Here we present a case report describing the clinicopathological findings of a patient with a fatal toxic epidermal necrolysis (TEN) eruption associated with use of nivolumab for treatment of metastatic melanoma. The patient developed a pruritic, morbiliform eruption, which slowly progressed over 3 months to a tender, exfoliative dermatosis. Histology initially showed interface dermatitis and subsequently revealed full thickness epidermal necrosis. The diagnosis of TEN was made. From initial biopsy to TEN presentation, there was an increase in the number of CD8+ lymphocytes within the dermal–epidermal junction and an increase of programmed death ligand 1 (PD‐L1) expression in both lymphocytes and keratinocytes. Despite treatment with infliximab, high‐dose steroids and intravenous immunoglobulin, the patient expired. Herein we describe what we believe is the second case of TEN associated with anti‐PD1 therapy reported in the literature. Increased expression of PD‐L1 by immunohistochemistry was observed as the eruption progressed to TEN. Early diagnosis and treatment is necessary in these fatal TEN reactions secondary to the anti‐PD‐1 antibody therapies.     

Epidermotropic metastatic melanoma simulating multiple primary melanomas

Epidermotropic metastatic melanoma is usually distinguished from primary melanoma by the limitation of the epidermal involvement of the metastasis to an area overlying the dermal tumor. We report a case demonstrating multiple epidermotropic melanoma metastases with more extensive epidermal involvement simulating primary melanoma that occurred 20 years after excision of the primary tumor.     

Toxic epidermal necrolysis successfully treated with etanercept

Toxic epidermal necrolysis (TEN) is a rare and acute severe adverse reaction to drugs, characterised by massive apoptosis and widespread epidermal and mucosal detachment. Although no gold standard therapy exists, human i.v. immunoglobulins have recently been described as an effective treatment for this disease. We report a case of phenobarbital-induced TEN in a 59-year-old white woman where the epidermal detachment stopped 48 h after beginning the etanercept treatment with complete healing after 20 days. To the best of our knowledge, this is only the second reported case of TEN successfully treated with etanercept.     

A 2-year-old girl with Stevens--Johnson syndrome/toxic epidermal necrolysis treated with intravenous immunoglobulin

Toxic epidermal necrolysis and Stevens-Johnson syndrome are severe skin reactions, usually to drugs, associated with a widespread destruction of the epidermis. Widespread purpuric macules and epidermal detachment of less than 10% of the body surface is indicative of Stevens-Johnson syndrome, whereas epidermal detachment between 10% and 30% is called Stevens-Johnson-toxic epidermal necrolysis overlap. Epidermal detachment involving more than 30% of the total body surface is designated as toxic epidermal necrolysis. These generalized reactions are known to occur in association with various drugs. Treatment is primarily supportive care, and there are no specific therapy regimens. Therapeutic modalities such as corticosteroids, cyclosporin, thalidomide, cyclophosphamide, and plasmapheresis, usually based on a symptomatic approach, have been tried in single patients or in small series. Intravenous immunoglobulin has recently been shown to provide rapid improvement in all three of these skin reactions. We report a 2-year-old girl who developed Stevens-Johnson syndrome-toxic epidermal necrolysis overlap after receiving ampicillin-sulbactam for an upper respiratory tract infection. She was treated successfully with a 4-day course of intravenous immunoglobulin.     

Toxic epidermal necrolysis with severe hyperbilirubinemia: Complete re‐epithelialization after bilirubin reduction therapies

Toxic epidermal necrolysis is a life‐threatening skin disorder, and its mortality rate is estimated to be approximately 20–30%. It is characterized that more than 30% of the skin surface is eroded, however, skin lesions are usually re‐epithelialized within 2–3 weeks. Previously, we reported a fatal case of toxic epidermal necrolysis with hyperbilirubinemia, and more than 60% of body surface areas had been eroded for 9 weeks. For the reason of delayed re‐epithelialization, we hypothesized that hyperbilirubinemia was the culprit because bilirubin damaged cultured keratinocytes in vitro. In this case, we had an opportunity to treat another case of toxic epidermal necrolysis with severe hyperbilirubinemia. In order to reduce serum bilirubin levels, we performed bilirubin adsorption therapies, and skin lesions were successfully re‐epithelialized within 4 weeks. Though further studies are required, we considered that bilirubin adsorption therapies are worth trying for toxic epidermal necrolysis with hyperbilirubinemia, especially for the cases suffering from delayed re‐epithelialization.     

Stevens-Johnson syndrome limited to multiple sites of radiation therapy in a patient receiving phenobarbital

Stevens-Johnson syndrome (SJS) is a severe cutaneous eruption that most often appears as an adverse reaction to a medication. There have been 21 reported cases of atypical erythema multiforme, toxic epidermal necrolysis, and SJS arising in patients receiving radiation therapy in addition to phenytoin, phenobarbital, or carbamazepine. We report the second case of SJS resulting from concomitant phenobarbital and radiation therapy, in which the eruption was limited to the sites of radiation, which were multiple.     

Treatment of toxic epidermal necrolysis with intravenous immunoglobulin: a series of three cases

Stevens-Johnson's syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening dermatoses, that lead to keratinocyte apoptosis induced by interactions between Fas (cell death receptor) and soluble Fas-ligand, present in serum of Stevens-Johnson's syndrome / toxic epidermal necrolysis patients. Anti-Fas antibodies in intravenous immunoglobulin (IVIG) would block the apoptosis cascade. Three cases of toxic epidermal necrolysis occurred in one male and two female patients, after use of allopurinol, leprosy multidrug therapy concomitant with dipyrone, and diclofenac. The cases were treated with intravenous immunoglobulin 2-3 mg/kg and prednisone 20-50 mg/day. The interruption of new lesions outbreak and reepithelization were extremely fast after the use of intravenous immunoglobulin, without adverse effects. Controlled studies are needed to confirm the efficacy of intravenous immunoglobulin in Stevens-Johnson's syndrome / toxic epidermal necrolysis, but the results seem promising.     

FURTHER EXPERIENCES OF TOXIC EPIDERMAL NECROLYSIS INCRIMINATING ALLOPURINOL, PYRAZOLONE AND DERIVATIVES

Summary.— Four cases of toxic epidermal necrolysis, confirmed by skin biopsy, are described. The first case was due to allopurinol. The second case was caused by a pyrazolone derivative in a patient who, 15 days previously, had developed an urticarial exanthem from tetanus antitoxin. In these 2 fatal cases Stevens–Johnson syndrome coexisted. In the remaining cases toxic epidermal necrolysis occurred alone and recovery was uneventful.     

Tratamiento con inmunoglobulina intravenosa y esteroides sistémicos en pacientes con necrólisis epidérmica tóxica: Experiencia en un hospital en Ciudad de México

Toxic epidermal necrolysis is the most serious mucocutaneous adverse drug reaction. Multidisciplinary treatment and withdrawal of the causative drug are key to reducing mortality. Few studies have analyzed the use of systemic corticosteroids and intravenous immunoglobulins (IVIG) in patients with toxic epidermal necrolysis in Latin America. We describe our experience with 6 cases treated at a dermatology referral hospital in Mexico City. None of the patients died or developed complications in the short or medium term. The most widely used regimen was a combination of IVIG 1 g/kg for 3 to 5 days and methylprednisolone 1 g for 3 to 5 days. Mean hospital stay was 14.8 days. The combined use of systemic corticosteroids and IVIG seems to be a safe treatment option for patients with toxic epidermal necrolysis.     

Epidermal necrolysis as the presenting manifestation of pediatric lupus

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) represents the spectrum of skin lesions characterized by rashes, exfoliation, and sloughing usually following drug intake. Occasionally, TEN-like cutaneous manifestations have also been described with systemic lupus erythematosus. Recognition of lupus in a child presenting with TEN-like skin changes is clinically challenging and requires a high degree of suspicion. We describe the case of a child who had epidermal necrolysis as the presenting feature of lupus and had severe neurological complications. TEN-like skin changes in association with severe neurological complications in pediatric lupus are uncommon. Lupus must be considered in the differential diagnosis of a child presenting with epidermal necrolysis with no provocative risk factors such as a history of exposure to medications.     

Extensive Hypertrophic Scarring After Toxic Epidermal Necrolysis in a Child

Abstract: Stevens‐Johnson syndrome and toxic epidermal necrolysis are some of the most serious, usually drug‐induced, skin reactions. We report a case of severe toxic epidermal necrolysis in a child, which in addition to ophthalmic sequelae, caused extensive hypertrophic scarring of the skin. Such a course is uncommon and has rarely been described in the literature.     

Desmoplastic malignant melanoma.

A 68-year-old man sought dermatologic attention for a tumor of the arm. Biopsy specimen showed abnormal, essentially amelanotic, spindle-shaped cells in the cutis, greatly fibrotic stroma, and focal epidermal invasion. Desmoplastic malignant melanoma was diagnosed. The lesion was widely excised and axillary lymphadenectomy performed; one node showed metastasis. Nine months later, he died with widespread metastatic disease. To our knowledge, this is the first report of this entity since its delineation in 1971 and the only case in which diagnosis was established on initial biopsy and followed by definitive therapy. Desmoplastic melanoma has been confused with benign fibrosis, invasive fibromatosis, and fibrosarcoma, and is another example, with morpheaform basal cell carcinoma and sclerodermoid metastatic lesions from breast carcinoma, in which desmoplastic stroma may obscure the epithelial nature of cutaneous neoplasm.     

Allopurinol-induced Toxic Epidermal Necrolysis

ABSTRACT: An erythematous eruption with itching developed in an 84-year-old man 4 days after therapy with allopurinol was initiated. The diagnosis of toxic epidermal necrolysis, suspected when separation of the epidermis was noted, was confirmed by skin biopsy. This is the third reported case that can be attributed exclusively to allopurinol and the first patient who did not die.     

Vemurafenib‐induced toxic epidermal necrolysis: possible cross‐reactivity with other sulfonamide compounds

Vemurafenib is a newly licensed target‐directed medication. It has been proven to improve the survival of patients with metastatic melanoma and the BRAF^V600E mutation; however, adverse cutaneous reactions are frequent. Few cases of life‐threatening severe cutaneous adverse reactions (SCARs) induced by vemurafenib have been reported. Dabrafenib, another selective BRAF inhibitor, has been licensed recently as an alternative drug with the same indications. From a molecular point of view, both vemurafenib and dabrafenib contain a sulfonamide group; cross‐reactivity to sulfonamide compounds has been reported in allergic patients. We report on a patient with vemurafenib‐induced toxic epidermal necrolysis (TEN). In vitro analysis of lymphocyte reactivity to vemurafenib showed positive results, confirming drug causality. In addition, lymphocytes from the patient reacted to dabrafenib and to the antibiotic sulfonamide drug sulfamethoxazole. Moreover, lymphocytes from two patients with cutaneous adverse reactions to sulfamethoxazole also reacted to vemurafenib and dabrafenib in vitro. These data strongly suggest that there might be clinical cross‐reactivity between BRAF inhibitors and sulfonamides in some patients. Thus, precautions should be taken to avoid sulfonamide drugs as much as possible in patients showing serious hypersensitivity reactions to vemurafenib and vice versa.     

异基因外周血干细胞移植术后中毒性表皮松解症临床分析

目的总结异基因造血干细胞移植后中毒性表皮松解症(TEN)诊治经验。方法分析3例表现为TEN的造血干细胞移植后急性移植物抗宿主病(aGVHD)。结果3例TEN均发生于外周血干细胞移植后,表现为皮肤水疱及表皮松解,合并高热、肠炎或肝损害,经给予有效的免疫抑制剂,联合营养支持及相应护理措施,皮损均消退。结论TEN是皮肤GVHD最严重的类型,需采用针对aGVHD的免疫抑制为主的综合治疗。     

Use of Suprathel dressing in a young infant with TEN

Toxic epidermal necrolysis and Stevens-Johnson syndrome are potentially life-threatening skin disorders. We report that a 3-month-old infant, a patient with toxic epidermal necrolysis, who in addition to a standard resuscitation protocol for burns received treatment with Suprathel (PolyMedics Innovations GmbH, Filderstadt, Germany) and fatty gauze as topical wound dressings in the form of a whole body cover with complete recovery. This is the first case report of Suprathel being used successfully in a baby with toxic epidermal necrolysis.     

[Translated article] Use of Intravenous Immunoglobulins and Systemic Corticosteroids in Patients With Toxic Epidermal Necrolysis: Experience of a Hospital in Mexico City

Toxic epidermal necrolysis is the most serious mucocutaneous adverse drug reaction. Multidisciplinary treatment and withdrawal of the causative drug are key to reducing mortality. Few studies have analyzed the use of systemic corticosteroids and intravenous immunoglobulins (IVIG) in patients with toxic epidermal necrolysis in Latin America. We describe our experience with 6 cases treated at a dermatology referral hospital in Mexico City. None of the patients died or developed complications in the short or medium term. The most widely used regimen was a combination of IVIG 1 g/kg for 3–5 days and methylprednisolone 1 g for 3–5 days. Mean hospital stay was 14.8 days. The combined use of systemic corticosteroids and IVIG seems to be a safe treatment option for patients with toxic epidermal necrolysis.     

Basic measures and systemic medical treatment of patients with toxic epidermal necrolysis

Background: With an incidence of 1.5–1.8/1 million inhabitants per year, toxic epidermal necrolysis is a rare but life threatening disease. It is almost always drug‐induced and its lethality is pronounced with up to 50 %. Several therapeutic options are described in literature; however, there is still lack of a universally accepted and specific therapy of toxic epidermal necrolysis. Methods: This survey considers 8 cases of toxic epidermal necrolysis diagnosed and treated in our clinic from 2003 to 2007. The epidermal sloughing was > 30 % of the body surface in each case. Results: After immediately discontinuing the drug suspected of being responsible for toxic epidermal necrolysis, we treated with systemic corticosteroids in an initial dose of up to 1.5 mg/kg. Moreover, special emphasis was put on basic measures such as control of vital parameters. With this treatment we reached good results; none of the patients died. Conclusions: Immediate beginning of therapy is essential for a successful treatment of toxic epidermal necrolysis. Besides systemic therapy with corticosteroids, certain basic measures such as isolation of patients at adequate room temperature to prevent hypothermia, strict control of circulation, temperature and laboratory parameters, daily smears of skin and mucous membranes and a diet rich in calories due to the catabolic metabolic status are very important for successful outcome.     

Metastatic malignant melanoma associated with vitiligo-like depigmentation

Vitiligo-like depigmentation in patients with malignant melanoma is a poorly understood phenomenon. We report a patient who presented with a 4-month history of vitiligo-like depigmentation of the face, trunk and limbs. Physical examination revealed an enlarged left inguinal lymph node. A needle biopsy taken from the lymph nodes revealed metastatic malignant melanoma. One small nodule on the left sole was found subsequently. Despite the absence of junctional activity, it was considered to be a primary tumour with regression of the epidermal lesion. The patient died from sepsis, the main complication of immunosuppressive therapy, without evidence of distant metastasis. We report this case to highlight the importance of careful physical examination of patients with skin hypomelanoses. We also propose that, due to the favourable prognosis in patients with malignant melanomas and vitiligo-like depigmentation, the treatment plan may be more conservative to minimize the adverse effects of chemotherapy.