Clinical and Experimental Dermatology 1992; 17: 264-265.
Toxic epidermal necrolysis treated with cyclosporin J . H E W I T T AND A.D.ORMEROD Deparlment of Dermatology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB Scotland, UK Accepted for publication 23 September 1991
Summary
day of onset of an acute erythematous eruption on her face and trunk. This followed an upper respiratory tract Toxic epidermal necrolysis (TEN) is a severe lifeinfection with cough, sore throat and rhinorrhoea for threatening disorder which has many features in common which she had been taking dequacaine lozenges (containwith graft-versus-host disease. However, immunosup- ing dequalinium chloride and benzocaine) and pholcopression with steroids gives disappointing results and is deine linctus. possibly detrimental. We treated two patients who had In the first 24 hours, the eruption became confluent TEN with a combination of cyclosporin and steroids over her back with target lesions and large tense blisters which resulted in an apparent halt to the evolution ofthe over the trunk and limbs and a positive Nikolsky's sign in disease, and a further relapse was aborted using cyclos- these areas. Although lacking mucosal involvement, 35% porin in one of these patients. We feel that the use of this of the skin surface was affected at this stage; she was drug in the early treatment of TEN where it is used as a pyrexial (39-5°C) and a skin biopsy was consistent with specific therapy aimed at the primary immunopathologi- TEN with a sub-epidermal split. She was transferred to a cal events and is used in conjunction with the supportive burns unit and was treated with prednisolone 60 mg/day, care patients require, needs to be further evaluated. IV benzyl-penicillin, flucloxacillin and supportive measures but during the next 36 hours the TEN continued to extend to the uninvolved skin. CSA was Toxic epidermal necrolysis (TEN) is a severe life- commenced in a dose of 3-6 mg/kg/24 h. threatening reaction for which the current treatment still Over the following 36 hours the progression of disease, yields a significant mortality rate of around 30%. extension of rash and blister formation halted. The Suppression with high-dose steroids remains controverpreviously affected areas improved markedly and within 4 sial'-^ and may adversely infiuence mortality.^ A celldays she was transferred to the open ward. Because of mediated cytotoxic immunopathogenesis is postulated concern of a relapse of psoriasis induced by Koebner's with many similarities to acute graft-versus-host disearesponse and steroid rebound, CSA was tailed off over 10 se(GVHD).'''* This view is supported by immunohistodays and steroids over 1 month although her skin logy,^ the presence of high levels of interleukin I in blister remained clear. fluid' and the occurrence ofthe syndrome in animal** and Investigations during this illness showed only a moderhuman GVHD^. Cyclosporin A (CSA) has been shown to ate neutrophil leucocytosis of 17-3 x 10^/1 which resolved be effective in the prevention and treatment of acute and and raised aspartate transaminase 80 U/1 and y-glutamyl chronic GVHD.' This has led to the suggestion of using transferase of 250 U/1 which were both raised prior to the CSA in the treatment of TEN* and the subsequent illness due to alcohol. reports of its efficacy in one patient with TEN** and in bullous erythema multiforme.'" We report the successful treatment of three episodes in two patients with TEN using CSA in combination with prednisolone. Although Case 2 there was no control to compare with, there was striking A 37-year-old lady, developed an acute erythematous improvement on each occasion. maculopapular eruption following treatment with amoxycillin for an upper respiratory tract infection. Within 24 hoursflaccidblisters appeared on her face and Case reports neck. She was admitted on the 3 days later, extremely ill and dehydrated with skin loss and blisters affecting the Case I lips, oral cavity, face and neck and with a mucopurulent A 34-year-old woman with a past history of psoriasis conjunctivitis. In the initial 12 hours in hospital there was treated with PUVA 6 months earlier, was admitted on the considerable progression with a confluent erythema over 264
TOXIC EPIDERMAL NECROLYSIS the back and chest with positive Nikolsky's sign and sloughing of epidermis estimated at 40% of the skin surface area. She had a sinus tachcardia 120/min and was pyrexial (38-2°C). Initial investigation showed a thrombocytopenia (95 X 10^/1), leucopenia (neutrophils 1-3 x lO'/l lymphocytes 0-3 X lO'/l), prolonged prothrombin time (21 s) and bilirubinuria. Thorough screening for infection was subsequently negative. Treatment with prednisolone (40 mg/kg/day) had been initiated 72 hours before admission. This was changed to I.V. hydrocortisone (1200 mg/day) with parenteral fluid replacement on arrival. She was transferred to a burns unit and in addition to supportive measures received CSA (3 mg/kg/day) orally in combination with methyl prednisolone (60 mg/day) intravenously. Within the next 24 hours, the progression of skin loss, blistering and erythema was halted and the degree of previous erythema was reduced. Thereafter, her skin continued to improve markedly and the CSA was stopped after 9 days. Accompanying her acute illness were profuse diarrhoea, rectal bleeding and a paralytic ileus from presumed gastrointestinal involvement. She also developed progressive cholestatic jaundice resembling sclerosing cholangitis also related to amoxycillin (this has persisted for 12 months with permanent scarring and dilatation ofthe intra-hepatic bile ducts). Six weeks after presentation, TEN threatened to recur following treatment with ciprofloxacin for a urinary infection. She was febrile and toxic with vesiculo-bullous target lesions and confluent erythema confined to areas previously spared by the TEN; skin biopsy showed erythema multiforme. At this point CSA was recommended in a dose of 5 mg/kg/day and again over a 5-day period her rash faded and cyclosporin was stopped after 14 days. Since stopping, she has continued to demonstrate a low grade, recurrent chronic erythema multiforme but because of her hepatic problems, CSA has not been reintroduced. Discussion In all three episodes of TEN and erythema multiforme we felt there was a substantial clinical improvement whenever CSA was administered and similar observations were made by Renfo et al. in TEN' and by Wilkel'" et al. in erythema multiforme. There is good reason (above) to suppose that drugs acting on the efferent limb of cell mediated immunity such as CSA and FK-506
265
(Fugisawa, Japan) should be effective. However, immunosuppression of a patient already compromised by TEN and the frequent presence of lymphopenia,' which may arise by redistribution of leucocytes, remains hazardous and extra vigilance is required to avoid infection. The burns unit treatment and intensive care of these patients remains foremost in management.'•' Whilst the role of systemic steroids alone is doubtful,' cyclosporin shows promise and may either allow sparing from more detrimental high-dose steroids or may be worth investigating as monotherapy. The hepatic disturbance in Case 2, whilst still unresolved is not consistent with cyclosporin toxicity. As a toxic hepatitis occurs in TEN' and cyclosporin is metabolised in the liver by cytochrome p450, caution in dosage is also required; CSA trough levels (parent molecule) were in the therapeutic range in both patients (98-120 ^g/1). Ideally cyclosporin A should be assessed prospectively and randomly in those centres able to collect sufficient numbers of patients. References 1. Roujeau JC, Chosidow O, Saiag P et al. Toxic epidermal necrolysis (Lyell's synAromt). Journal ofthe American Academy of Dermatology 1990; 123: 1039-1058. 2. Tegelberg-Stassen MJAM, Van-Vlotten WA, Baart de la Faille H. Management of non-staphylococcal toxic epidermal necrolysis, follow-up study of 16 case histories. Dermatologica 1990; 180: 124-129. 3. Halebain PH, Madden MR, Finkelstein JL et al. Improved burn centre survival of patients with toxic epidermal necrolysis managed without corticosteroids. Annals of Surgery 1986; 204: 503-511. 4. Merot Y, Saurat JH. Clues to the pathogenesis of toxic epidermal necrolysis. International Journal of Dermatology 1985; 24: 165168. 5. Merot Y, Gravallese E, Guillen FJ, et al. Lymphocyte subsets and Langerhans' cells in toxic epidermal necrolysis. Archives of Dermatology 1986; 122: 455-458. 6. Villada G, Roujeau JC, Cordonnier C, et al. Toxic epidermal necrolysis after bone marrow transplantation, study of nine cases. Journal ofthe American Adademy of Dermatology 1990; 23: 870875. 7. Sullivan KM, Siadak MF, Witherspoon RP. Cyclosporin treatment of chronic graft-versus-host disease following allogenic bone marrow transplantation. Transplant Proceedings 1990; 22: 13361338. 8. Heng M. Drug induced toxic epidermal necrolysis. British Journal of Dermatology 1985; H3: 597-600. 9. Renfo L, Grant-Kels JM, Daman LA. Drug induced toxic epidermal necrolysis treated with cyclosporin. International Journal of Dermatology 1989; 28: 441-444. 10. Wilkel CS, McDonald CJ. Cyclosporin therapy for bullous erythema multiforme. Archives of Dermatology 1990; 126: 397398.
Toxic epidermal necrolysis treated with cyclosporin J . H E W I T T AND A.D.ORMEROD Deparlment of Dermatology, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB9 2ZB Scotland, UK Accepted for publication 23 September 1991
Summary
day of onset of an acute erythematous eruption on her face and trunk. This followed an upper respiratory tract Toxic epidermal necrolysis (TEN) is a severe lifeinfection with cough, sore throat and rhinorrhoea for threatening disorder which has many features in common which she had been taking dequacaine lozenges (containwith graft-versus-host disease. However, immunosup- ing dequalinium chloride and benzocaine) and pholcopression with steroids gives disappointing results and is deine linctus. possibly detrimental. We treated two patients who had In the first 24 hours, the eruption became confluent TEN with a combination of cyclosporin and steroids over her back with target lesions and large tense blisters which resulted in an apparent halt to the evolution ofthe over the trunk and limbs and a positive Nikolsky's sign in disease, and a further relapse was aborted using cyclos- these areas. Although lacking mucosal involvement, 35% porin in one of these patients. We feel that the use of this of the skin surface was affected at this stage; she was drug in the early treatment of TEN where it is used as a pyrexial (39-5°C) and a skin biopsy was consistent with specific therapy aimed at the primary immunopathologi- TEN with a sub-epidermal split. She was transferred to a cal events and is used in conjunction with the supportive burns unit and was treated with prednisolone 60 mg/day, care patients require, needs to be further evaluated. IV benzyl-penicillin, flucloxacillin and supportive measures but during the next 36 hours the TEN continued to extend to the uninvolved skin. CSA was Toxic epidermal necrolysis (TEN) is a severe life- commenced in a dose of 3-6 mg/kg/24 h. threatening reaction for which the current treatment still Over the following 36 hours the progression of disease, yields a significant mortality rate of around 30%. extension of rash and blister formation halted. The Suppression with high-dose steroids remains controverpreviously affected areas improved markedly and within 4 sial'-^ and may adversely infiuence mortality.^ A celldays she was transferred to the open ward. Because of mediated cytotoxic immunopathogenesis is postulated concern of a relapse of psoriasis induced by Koebner's with many similarities to acute graft-versus-host disearesponse and steroid rebound, CSA was tailed off over 10 se(GVHD).'''* This view is supported by immunohistodays and steroids over 1 month although her skin logy,^ the presence of high levels of interleukin I in blister remained clear. fluid' and the occurrence ofthe syndrome in animal** and Investigations during this illness showed only a moderhuman GVHD^. Cyclosporin A (CSA) has been shown to ate neutrophil leucocytosis of 17-3 x 10^/1 which resolved be effective in the prevention and treatment of acute and and raised aspartate transaminase 80 U/1 and y-glutamyl chronic GVHD.' This has led to the suggestion of using transferase of 250 U/1 which were both raised prior to the CSA in the treatment of TEN* and the subsequent illness due to alcohol. reports of its efficacy in one patient with TEN** and in bullous erythema multiforme.'" We report the successful treatment of three episodes in two patients with TEN using CSA in combination with prednisolone. Although Case 2 there was no control to compare with, there was striking A 37-year-old lady, developed an acute erythematous improvement on each occasion. maculopapular eruption following treatment with amoxycillin for an upper respiratory tract infection. Within 24 hoursflaccidblisters appeared on her face and Case reports neck. She was admitted on the 3 days later, extremely ill and dehydrated with skin loss and blisters affecting the Case I lips, oral cavity, face and neck and with a mucopurulent A 34-year-old woman with a past history of psoriasis conjunctivitis. In the initial 12 hours in hospital there was treated with PUVA 6 months earlier, was admitted on the considerable progression with a confluent erythema over 264
TOXIC EPIDERMAL NECROLYSIS the back and chest with positive Nikolsky's sign and sloughing of epidermis estimated at 40% of the skin surface area. She had a sinus tachcardia 120/min and was pyrexial (38-2°C). Initial investigation showed a thrombocytopenia (95 X 10^/1), leucopenia (neutrophils 1-3 x lO'/l lymphocytes 0-3 X lO'/l), prolonged prothrombin time (21 s) and bilirubinuria. Thorough screening for infection was subsequently negative. Treatment with prednisolone (40 mg/kg/day) had been initiated 72 hours before admission. This was changed to I.V. hydrocortisone (1200 mg/day) with parenteral fluid replacement on arrival. She was transferred to a burns unit and in addition to supportive measures received CSA (3 mg/kg/day) orally in combination with methyl prednisolone (60 mg/day) intravenously. Within the next 24 hours, the progression of skin loss, blistering and erythema was halted and the degree of previous erythema was reduced. Thereafter, her skin continued to improve markedly and the CSA was stopped after 9 days. Accompanying her acute illness were profuse diarrhoea, rectal bleeding and a paralytic ileus from presumed gastrointestinal involvement. She also developed progressive cholestatic jaundice resembling sclerosing cholangitis also related to amoxycillin (this has persisted for 12 months with permanent scarring and dilatation ofthe intra-hepatic bile ducts). Six weeks after presentation, TEN threatened to recur following treatment with ciprofloxacin for a urinary infection. She was febrile and toxic with vesiculo-bullous target lesions and confluent erythema confined to areas previously spared by the TEN; skin biopsy showed erythema multiforme. At this point CSA was recommended in a dose of 5 mg/kg/day and again over a 5-day period her rash faded and cyclosporin was stopped after 14 days. Since stopping, she has continued to demonstrate a low grade, recurrent chronic erythema multiforme but because of her hepatic problems, CSA has not been reintroduced. Discussion In all three episodes of TEN and erythema multiforme we felt there was a substantial clinical improvement whenever CSA was administered and similar observations were made by Renfo et al. in TEN' and by Wilkel'" et al. in erythema multiforme. There is good reason (above) to suppose that drugs acting on the efferent limb of cell mediated immunity such as CSA and FK-506
265
(Fugisawa, Japan) should be effective. However, immunosuppression of a patient already compromised by TEN and the frequent presence of lymphopenia,' which may arise by redistribution of leucocytes, remains hazardous and extra vigilance is required to avoid infection. The burns unit treatment and intensive care of these patients remains foremost in management.'•' Whilst the role of systemic steroids alone is doubtful,' cyclosporin shows promise and may either allow sparing from more detrimental high-dose steroids or may be worth investigating as monotherapy. The hepatic disturbance in Case 2, whilst still unresolved is not consistent with cyclosporin toxicity. As a toxic hepatitis occurs in TEN' and cyclosporin is metabolised in the liver by cytochrome p450, caution in dosage is also required; CSA trough levels (parent molecule) were in the therapeutic range in both patients (98-120 ^g/1). Ideally cyclosporin A should be assessed prospectively and randomly in those centres able to collect sufficient numbers of patients. References 1. Roujeau JC, Chosidow O, Saiag P et al. Toxic epidermal necrolysis (Lyell's synAromt). Journal ofthe American Academy of Dermatology 1990; 123: 1039-1058. 2. Tegelberg-Stassen MJAM, Van-Vlotten WA, Baart de la Faille H. Management of non-staphylococcal toxic epidermal necrolysis, follow-up study of 16 case histories. Dermatologica 1990; 180: 124-129. 3. Halebain PH, Madden MR, Finkelstein JL et al. Improved burn centre survival of patients with toxic epidermal necrolysis managed without corticosteroids. Annals of Surgery 1986; 204: 503-511. 4. Merot Y, Saurat JH. Clues to the pathogenesis of toxic epidermal necrolysis. International Journal of Dermatology 1985; 24: 165168. 5. Merot Y, Gravallese E, Guillen FJ, et al. Lymphocyte subsets and Langerhans' cells in toxic epidermal necrolysis. Archives of Dermatology 1986; 122: 455-458. 6. Villada G, Roujeau JC, Cordonnier C, et al. Toxic epidermal necrolysis after bone marrow transplantation, study of nine cases. Journal ofthe American Adademy of Dermatology 1990; 23: 870875. 7. Sullivan KM, Siadak MF, Witherspoon RP. Cyclosporin treatment of chronic graft-versus-host disease following allogenic bone marrow transplantation. Transplant Proceedings 1990; 22: 13361338. 8. Heng M. Drug induced toxic epidermal necrolysis. British Journal of Dermatology 1985; H3: 597-600. 9. Renfo L, Grant-Kels JM, Daman LA. Drug induced toxic epidermal necrolysis treated with cyclosporin. International Journal of Dermatology 1989; 28: 441-444. 10. Wilkel CS, McDonald CJ. Cyclosporin therapy for bullous erythema multiforme. Archives of Dermatology 1990; 126: 397398.
