title: Effect of N-acetylcysteine combined with infliximab on toxic epidermal necrolysis. A proof-of-concept study.
abstract: BACKGROUND
  The pathophysiology of toxic epidermal necrolysis (TEN) is thought to be related to a drug-induced oxidative stress combined with TNFα overexpression by keratinocytes. None of the current treatments for TEN including systemic corticosteroids, cyclosporine and intravenous administration of immunoglobulins has proven superior over supportive care only.
  
  
  METHODS
  A total of 10 TEN patients were enrolled to be treated at admission in burn units with the antioxidant N-acetylcysteine [NAC, 150mg/kg in a 20-h intravenous (IV) administration], or the combination of the same IV NAC perfusion with the anti-TNFα antibody infliximab (Remicade(®)), administered at a 5mg/kg dosage as a single 2-h IV administration. TEN was confirmed by a skin biopsy taken from a bullous lesion. At entry in the trial and 48h later, the illness auxiliary score (IAS) of clinical severity was determined and the extent in altered skin area (erythema and blisters) was assessed as a relative body area. Skin biopsies of both clinically uninvolved and erythematous areas were collected and immunohistochemistry was performed for assessing the density of inflammatory cells (CD8+ T cells, CD68+ macrophages) and keratinocytes enriched in intracellular calcium (Ca(++)) identified by the Mac387 anti-calprotectin antibody.
  
  
  RESULTS
  No unexpected drug-induced adverse event was noticed. After 48h of both treatment modalities, improvements were not observed in the extent of skin involvement and in IAS. Immunohistopathology showed the absence of reduction in the amount of intraepidermal inflammatory cells. An increased intracellular Ca(++) load in clinically uninvolved keratinocytes and in erythematous epidermis was noticed. This latter finding suggested the progression in the way of the apoptotic process. On burn unit discharge, the survival in each modality of treatment was not improved compared to the expected outcomes determined from the IAS at admission.
  
  
  CONCLUSIONS
  In this proof-to-concept attempt, NAC treatment or its combination with infliximab did not appear to reverse the evolving TEN process.
authors.affiliation: Department of Dermatopathology, Unilab Lg, University Hospital of Liège, 4000 Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Paquet
authors.affiliation: Burn Center, Military Hospital of Brussels, Neder-Over-Heembeek, Belgium.
authors.forename: Serge
authors.initials: S
authors.lastname: Jennes
authors.affiliation: Burn Unit, University Hospital of Liège, Liège, Belgium.
authors.forename: Anne Françoise
authors.initials: AF
authors.lastname: Rousseau
authors.affiliation: Department of Dermatology, University Hospital of Liège, Liège, Belgium.
authors.forename: Florence
authors.initials: F
authors.lastname: Libon
authors.affiliation: Department of Dermatopathology, Unilab Lg, University Hospital of Liège, 4000 Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: Laboratory of Skin Bioengineering and Imaging (LABIC), Department of Clinical Sciences, Liège University, Liège, Belgium. Electronic address: gerald.pierard@ulg.ac.be.
authors.forename: Gérald E
authors.initials: GE
authors.lastname: Piérard
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis; D002056:Burns / Q000150:complications*; D003879:Dermatologic Agents / Q000627:therapeutic use*; D005260:Female; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D006801:Humans; D007150:Immunohistochemistry; D000069285:Infliximab; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013262:Stevens-Johnson Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D003879:Dermatologic Agents; D016166:Free Radical Scavengers; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000111:Acetylcysteine
keywords: Calcium; Immunohistochemistry; Infliximab; Keratinocyte; N-acetylcysteine; Toxic epidermal necrolysis