Effect of N-acetylcysteine combined with infliximab on toxic epidermal necrolysis. A proof-of-concept study |
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| Affiliation: | 1. Department of Dermatopathology, Unilab Lg, University Hospital of Liège, 4000 Liège, Belgium;2. Burn Center, Military Hospital of Brussels, Neder-Over-Heembeek, Belgium;3. Burn Unit, University Hospital of Liège, Liège, Belgium;4. Department of Dermatology, University Hospital of Liège, Liège, Belgium;5. Laboratory of Skin Bioengineering and Imaging (LABIC), Department of Clinical Sciences, Liège University, Liège, Belgium;1. Victorian Adult Burns Service, The Alfred Hospital, Melbourne, VIC, Australia;2. Department of Dermatology, The Alfred Hospital, Melbourne, VIC, Australia;3. Department of Epidemiology & Preventive Medicine, Monash University, The Alfred Hospital, Melbourne, VIC, Australia;4. Department of Surgery, School of Medicine, Deakin University, VIC, Australia;5. Department of Medicine, Monash Health, Melbourne, VIC, Australia;6. Central and Eastern Clinical School, Department of Surgery, Monash University, VIC, Australia;1. Department of Pediatric and Adolescent Medicine, Children''s Hospital, University of Illinois Hospital & Health Sciences System, Chicago, Ill;2. Division of Hospital Medicine, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, Tenn;3. Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, Tenn;4. Division of Clinical Pharmacology, Children''s Mercy Hospitals and Clinics, Kansas City, Mo;5. Division of Infectious Diseases, Children''s Mercy Hospitals and Clinics, Kansas City, Mo;1. Department of Gastroenterology, St. John’s Medical College Hospital, Bangalore, India;3. Department of Dermatology, St. John’s Medical College Hospital, Bangalore, India;4. Hamad Medical Center, Doha, Qatar;1. Victorian Adult Burns Service, The Alfred Hospital, Melbourne, Victoria, Australia;2. Department of Dermatology, The Alfred Hospital, Melbourne, Victoria, Australia;3. Department of Surgery, School of Medicine, Faculty of Health, Deakin University, Victoria, Australia;4. School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, Monash University, The Alfred Hospital, Melbourne, Victoria, Australia;5. Department of Plastic and Reconstructive Surgery, The Alfred Hospital, Melbourne, Victoria, Australia;6. School of Medicine, Griffith University, Queensland, Australia;7. Department of Surgery, Central and Eastern Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Australia;1. University of Michigan Medical School, 1125 Freesia Street, Ann Arbor, MI 48105, USA;2. Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA;3. Department of Ophthalmology, Boston Children''s Hospital, Harvard Medical School, 300 Longwood Ave, Boston, MA 02115, USA;4. Department of Obstetrics and Gynecology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA;5. Division of Burns, Department of Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA |
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| Abstract: | IntroductionThe 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.MethodsA total of 10 TEN patients were enrolled to be treated at admission in burn units with the antioxidant N-acetylcysteine [NAC, 150 mg/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 5 mg/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 48 h 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.ResultsNo unexpected drug-induced adverse event was noticed. After 48 h 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.ConclusionsIn this proof-to-concept attempt, NAC treatment or its combination with infliximab did not appear to reverse the evolving TEN process. |
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| Keywords: | Toxic epidermal necrolysis Infliximab N-acetylcysteine Immunohistochemistry Keratinocyte Calcium |
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