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On-line version ISSN 1806-4841
An. Bras. Dermatol. vol.87 no.3 Rio de Janeiro May/June 2012
Treatment of toxic epidermal necrolysis with intravenous immunoglobulin: a series of three cases*
Tratamento da necrólise epidérmica tóxica com imunoglobulina endovenosa: uma série de três casos
Cristiane ComparinI; Günter Hans FilhoII; Luiz Carlos TakitaIII; Nayara de Castro Wiziack CostaIV; Roberta Ayres Ferreira do NascimentoV; Lidiane de Oliveira Costa NanniVI
IMD - Dermatologist, Residency Preceptor of Dermatology of the Department of Dermatology, Teaching Hospital, Federal University of Mato Grosso do Sul (Universidade Federal do Mato Grosso do Sul - UFMS) - Campo Grande (MS), Brazil
IIPhD - Adjunct Professor of Dermatology, Head of the Medical Residency Program in Dermatology and of the Derpartment of Dermatology, Federal University of Mato Grosso do Sul (Universidade Federal do Mato Grosso do Sul - UFMS) - Campo Grande (MS), Brazil
IIIMSc - Pathologist, Professor of Special Anatomic Pathology and Medical Residency Program in Dermatology, Federal University of Mato Grosso do Sul (Universidade Federal do Mato Grosso do Sul - UFMS) - Campo Grande (MS), Brazil
IVMD - Dermatologist, Assistant Professor of Dermatology, Federal University of Mato Grosso do Sul (Universidade Federal do Mato Grosso do Sul - UFMS) - Campo Grande (MS), Brazil
VMD - Dermatologist - Private clinic - São José do Rio Preto (SP), Brazil
VIMD - Dermatologist - Private clinic - Bauru (SP), Brazil
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.
Keywords: drug toxicity; epidermal necrolysis, toxic; fas ligand protein; immunoglobulins, intravenous
A Síndrome de Stevens-Johnson e a Necrólise Epidérmica Tóxica são dermatoses graves, que levam à apoptose dos queratinócitos induzida pela interação entre Fas (receptor de morte celular) e Fasligante solúvel, presente no soro de pacientes com Síndrome de Stevens-Johnson e Necrólise Epidérmica Tóxica. Anticorpos anti-Fas contidos na imunoglobulina endovenosa podem bloquear esta cascata apoptótica. Três casos de Necrólise Epidérmica Tóxica são descritos, ocorrendo após uso de alopurinol, diclofenaco e poliquimioterapia para hanseníase concomitante com dipirona. Os três casos foram tratados com imunoglobulina endovenosa 2-3 mg/kg, divididos em 4 ou 5 dias e prednisona 20-50 mg/dia. A interrupção no surgimento de novas lesões e a repitelização foram extremamente rápidas, sem ocorrência de efeitos adversos. Estudos controlados são necessários para confirmar a eficácia da imunoglobulina endovenosa na Síndrome de Stevens-Johnson e Necrólise Epidérmica Tóxica, porém, seus resultados parecem ser promissores.
Palavras-chave: erupção por droga; imunoglobulinas intravenosas; necrólise epidérmica tóxica; proteína ligante fas
Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are rare life-threatening dermatoses. SJS is defined when there is <10% denuded cutaneous surface; overlapping SJS-TEN when detachment involves 10-29%, and over 30%, is considered TEN. Drugs presently used, usually antibiotics, dipyrone, allopurinol, non-steroidal anti-inflammatory and anti-seizure agents, are the cause of most cases.1 The severity-of-illness score (SCORTEN) was validated by mortality prediction in TEN.2
Experiments have demonstrated that interactions between Fas (CD95, cell death receptor) and soluble-Fas-ligand (sFas-Ligand) induced keratinocyteapoptosis in SJS/TEN. Keratinocytes experimentally exposed in vitro to soluble Fas-ligand-containing serum from TEN/SJJ-patients, entered into dosedependent apoptosis, proving causality. Keratinocytes cultured in the presence of anti-Fas-ligand antibodies also showed dose-dependent reduction in apoptotic cells. Results were reproduced by exposing keratinocytes to isolated-soluble Fas-ligand, corroborating its crucial trigger-function in their apoptosis.
These data strongly support the hypothesis that serum from TEN-patients mediates keratinocyte apoptosis, through interaction between Fas and sFas-Ligand. 3
Intravenous immunoglobulin (IVIG) is plasmaderivative from pooled plasma of many blood donors with high immunoglobulin G concentration against foreign antigens and auto-antigens, including anti-Fasantibodies, which bonded to Fas preventing its interaction with sFas-Ligand, blocking apoptosis (Figure 1). 4-6 IVIG treatment: 3-4 g/kg divided into 3 consecutive days, administered in the first 7 days, has shown great possibility of success.
Despite lack of randomized controlled studies, available data supports IVIG use to treat cases of TEN, demonstrated by 3 cases that presented exceptional response.
A 55-year-old female patient developed lesions fifteen days after taking allopurinol. Admitted on day 3, she presented vesicobullous lesions, large areas of denuded skin and oral mucosa. Table 1 shows clinical parameters. Histopathology confirmed TEN. Prednisone 0.5 mg/kg/day treatment was prescribed. Seven days later she suffered acute myocardial infarction. As cutaneous detachment persisted, a total dose of 2g/kg IVIG was prescribed on day ten after admission. Three days later, her general clinical and dermatological condition improved significantly, with progressive reepithelization and complete recovery (Figures 2 and 3).
A 48-year-old woman as admitted having presented bullous lesions for 10 days, after rifampicin, clofazimine and dapsone ingestion for a month for leprosy, and dipyrone. She presented oral and genital mucosal ulcerations, blisters and epidermal detachment in > 80% of body surface area (BSA). Histopathology confirmed TEN. Prednisone 40 mg and IVIG 3 g/kg were prescribed. Her general clinical condition improved significantly, with partial reepithelization five days later and complete recovery on day 14.
A 45-year-old man patient reported skin blisters that appeared two days after taking diclofenac. The exam showed erythematous-violaceous-plaques, surmounted by blisters. Histopathology confirmed TEN. Prednisone 50mg/day therapy was established. Because of epidermal detachment progression, IVIG 2.5 g/kg was introduced on day 8. After 5 days, blisteroutbreak ceased and reepithelization on > 70% BSA was observed (Figures 4 and 5). One day after IVIG treatment ended, a few blisters developed on his arms. Prednisone 0.5 mg/kg/day was reintroduced and blisters gradually diminished, with complete recovery within 7 days.
Numerous drugs have been implicated in the pathogenesis of SJS/TEN, making detailed anamnesis fundamental to elucidate the causative drug and prevent future re-exposure. 1
Prospective open studies and case series show evidence on IVIG use in SJS/TEN. Among studies that demonstrated no benefits of IVIG, the largest included patients with chronic renal failure and age >60, factors associated with greater basal mortality, and probably, bad response to IVIG. 7 Many patients received 2 g/kg of IVIG, a dose lower than presently recommended, as also shown in other studies that obtained no benefit.
In a retrospective multicentre-study, 48 patients treated with IVIG had a survival rate of 88%, much higher than expected. Factors associated with death were: old age (average: 66.2); epidermal detachment extension (average: 65%); delay in starting IVIG (average: 10 days); lower dose (<2 g/kg); and coexistent renal, cardiac or infectious diseases and cancer.8 In a review, 11 out of 14 studies demonstrated IVIG effectiveness.4 A European guideline recommends starting IVIG treatment early after confirmation of TEN diagnosis (evidence level IIIb, recommendation grade C).9
In a study on TEN, skin biopsies evaluated by immunohistochemistry showed that most samples positive for Fas/Fas-ligand before therapy, were negative right after treatment with IVIG.10
Risk of death evaluated by SCORTEN in the first and third cases described was 58.3%, however, there was no available data about the bicarbonate level necessary for a complete evaluation (Table 1). Nevertheless, both cases showed considerable risk of death, with the possibility that IVIG might help their recovery. In the third case there were new blisters after IVIG treatment ended, favoring the protective role of IVIG against keratinocyte apoptosis. We observed delay in the resolution of exulcerations before IVIG was introduced, possibly due to successive apoptosis of new keratinocytes forming in the basal layer. Treatment with IVIG, therefore, would also promote reepithelization.
TEN is a serious, rapidly progressive systemiccutaneous condition. After connection between Fas and sFas-Ligand, the signalization chain progresses and programmed keratinocyte death proceeds. This emphasizes the importance of introducing treatment within 72 hours. However, after this time has elapsed, its use is also indicated, as it could protect non-affected areas and keratinocytes in formation. The three patients described were treated after an average period of 10 days, nevertheless, exceptional improvement could be observed. If the results of future studies corroborate these observations, early prescription of adequate doses of IVIG will be safer, bringing great benefits to patients with TEN.
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5. Viard I, Wehrli P, Bullani R, Schneider P, Holier N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998;282:490-3. [ Links ]
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7. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective noncomparative study showing no benefit on mortality or progression. Arch Dermatol. 2003;139:33-6. [ Links ]
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Serviço de Dermatologia Dr. Günter Hans Hospital Universitário - NHU/UFMS
Av. Sen. Filinto Müller, S/N. Vila Ipiranga
79090-190 Campo Grande, MS
Received on 04.06.2011.
Approved by the Advisory Board and accepted for publication on 15.08.2011.
Conflict of interest: None
Financial funding: None
* Study carried out at the Department of Dermatology, Teaching Hospital, Federal University of Mato Grosso do Sul (Universidade Federal do Mato Grosso do Sul - UFMS) - Campo Grande (MS), Brazil.