[en] Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25-30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to massive keratinocyte death in TEN. Dysregulations in the tumor necrosis factor-alpha (TNF-alpha) pathway, CD95 system (Fas ligand, CD95L; Fas receptor, CD95R) and calcium homeostasis in the epidermis are involved in this apoptotic process. An active role has also been ascribed to T lymphocytes, macrophages and factor XIIIa-positive dermal dendrocytes. Despite progress, treatment of TEN remains controversial. In the past, systemic glucocorticoids were used in order to target the inflammatory reaction in TEN. However, there was no evidence for improvement of the healing process, while corticosteroids worsened the prognosis by increasing the risk of septicemia. Only a few cases have been treated with other drugs including cyclophosphamide, pentoxyfilline, thalidomide, anti-TNF-alpha antibodies and cyclosporin A. In the recent past, some TEN patients were treated with intravenous human immunoglobulins (IVIG). The rationale for such a treatment was to block the CD95 system on keratinocytes. The early promising clinical results of IVIG treatment in TEN were subsequently challenged. This review compares the effectiveness and drawbacks of the major drugs presently used in TEN treatment. Some future prospects in TEN management are also discussed.
Disciplines :
Dermatology
Author, co-author :
Paquet, Philippe ; Centre Hospitalier Universitaire de Liège - CHU > Dermatopathologie
Pierard, Gérald ; Centre Hospitalier Universitaire de Liège - CHU > Dermatopathologie
Quatresooz, Pascale ; Centre Hospitalier Universitaire de Liège - CHU > Dermatopathologie
Language :
English
Title :
Novel treatments for drug-induced toxic epidermal necrolysis (Lyell's syndrome).
Roujeau JC: The spectrum of Stevens-Johnson syndrome and toxic epidermal necrolysis: A clinical classification. J Invest Dermatol 1994;102:28S-30S.
Roujeau JC: Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease which differs from erythema multiforme. J Dermatol 1997;24:726-729.
Paquet P, Piérard GE: Erythema multiforme and toxic epidermal necrolysis. A comparative study. Am J Dermatopathol 1997;19:127-132.
Guillaume JC, Roujeau JC, Revuz J, Penso D, Touraine R: The culprit drugs in 87 cases of toxic epidermal necrolysis (Lyell's syndrome). Arch Dermatol 1987;123:1166-1170.
Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern R, Anderson T, Auquier A, Bastuji-Garin S, Correia O, Locati F: Medication use and the risk of Stevens-Johnson or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-1607.
Shear NH, Spielberg SP, Grant DM, Tang BK, Kalow W: Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 1986;105:179-184.
Pirmohamed M, Graham A, Roberts P, Smith D, Chadwick D, Breckenridge AM, Park BK: Carbamazepine-hypersensitivity: Assessment of clinical and in vitro chemical cross-reactivity with phenytoin and oxcarbazepine. Br J Clin Pharmacol 1991;32:741-749.
Wolkenstein P, Tan C, Lecoeur S, Wechsler J, Garcia-Martin N, Charue D, Bagot M, Beaune P: Covalent binding of carbamazepine reactive metabolites to P450 isoforms present in the skin. Chem Biol Interact 1998;113:39-50.
Reilly TP, Lash L, Doll MA, Hein DW, Woster PM, Svensson CK: A role for bioactivation and covalent binding within epidermal keratinocytes in sulfonamide-induced cutaneous drug reactions. J Invest Dermatol 2000;114:1164-1173.
Wolkenstein P, Carriere V, Charue D, Bastuji-Garin S, Revuz J, Roujeau JC, Beaune P, Bagot M: A slow acetylator genotype is a risk factor for sulphonamide-induced toxic epidermal necrolysis and Stevens-Johnson syndrome. Pharmacogenetics 1995;5:255-258.
Dietrich A, Kowakubo Y, Rzany B, Mockenhaupt M, Simon JC, Schöpf E: Low N-acetylating capacity in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. Exp Dermatol 1995;4:313-316.
Saiag P, Cauns E, Chosidow O, Revuz J, Roujeau JC: Drug-induced toxic epidermal necrolysis (Lyell syndrome) in patients infected with the human immunodeficiency virus. J Am Acad Dermatol 1992;26:567-574.
Lee BL, Wong D, Benowitz N, Sullam PM: Altered patterns of drug metabolism in patients with acquired immunodeficiency syndrome. Clin Pharmacol Ther 1993;53:529-535.
Baron JM, Merk HF: Drug metabolism in the skin. Curr Opin Allergy Clin Immunol 2001;1:287-291.
Paquet P, Nikkels A, Arrese JE, Vanderkelen A, Piérard GE: Macrophages and tumor necrosis factor-alpha in toxic epidermal necrolysis. Arch Dermatol 1994;130:605-608.
Paquet P, Piérard GE: Soluble fractions of tumor necrosis factor-α, interleukin 6 and of their receptors in toxic epidermal necrolysis. A comparison with second-degree burns. Int J Mol Med 1998;1:459-462.
Correia O, Delgado L, Leal Barbosa I, Campilho F, Fleming-Torrinha J: Increased interleukin 10, tumor necrosis factor α and interleukin 6 level in blister fluid of toxic epidermal necrolysis. J Am Acad Dermatol 2002;47:58-62.
Paquet P, Piérard GE: Keratinocyte injury in drug-induced toxic epidermal necrolysis: Simultaneous but distinct topographic expression of CD95R and calprotectin. Int J Mol Med 2002;10:145-147.
Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, Hunziker T, Saurat JH, Tschopp J, French LE: Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 1998;282:490-493.
Abe R, Shimizu T, Shibaki A, Nakamura H, Watanabe H, Shimizu H: Toxic epidermal necrolysis and Stevens-Johnson syndrome are induced by soluble Fas ligand. Am J Pathol 2003;162:1515-1520.
De Maria R, Teste R: Fas-FasL interactions: A common pathogenic mechanism in organ-specific autoimmunity. Immunol Today 1998;19:121-125.
Arnold R, Seifert M, Asadullah K, Volk HD: Cross-talk between keratinocytes and T lymphocytes via Fas/Fas ligand interaction: Modulation by cytokines. J Immunol 1999;162:7140-7147.
Correia O, Delgado L, Ramos JP, Resende C, Fleming-Torrinha JA: Cutaneous T cell recruitment in toxic epidermal necrolysis. Further evidence of CD8+ lymphocyte involvement. Arch Dermatol 1993;129:466-468.
Correia O, Delgado L, Barbosa IL, Domingues JC, Azevado R, Vaz CP, Pimentel P: CD8+ lymphocytes in the blister fluid of severe acute cutaneous graft-versus-host disease: Further similarities with toxic epidermal necrolysis. Dermatology 2001;203:212-216.
Le Cleach L, Delaire S, Boumsell L, Bagot M, Bourgault-Villada I, Bensussan A, Roujeau JC: Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells which express human natural killer (NK) inhibitory receptors. Clin Exp Immunol 2000;119:225-230.
Paquet P, Arrese JE, Beguin Y, Piérard GE: Clinicopathological differential diagnosis of drug-induced toxic epidermal necrolysis (Lyell's syndrome) and acute graft-versus-host reaction; in Cerio R (ed): Current Topics in Pathology, vol 94: Dermatopathology. Berlin, Springer, 2001, pp 65-78.
Paquet P, Paquet F, Al Saleh W, Reper P, Vanderkelen A, Piérard GE: Immunoregulatory effector cells in drug-induced toxic epidermal necrolysis. Am J Dermatopathol 2000;22:413-417.
Hermanns-Lê T, Paquet P, Piérard-Franchimont C, Arrese JE, Piérard GE: Regulatory function of factor XIIIa-positive dendrocytes in incipient toxic epidermal necrolysis and graft-versus-host reaction. A hypothesis. Dermatology 1999;198:184-186.
Kondo S, Kooshesh F, Sauder D: Penetration of keratinocyte-derived cytokines into basement membrane. J Cell Physiol 1997;171:190-195.
Paquet P, Quatresooz P, Piérard GE: Factor XIIIa-positive dendrocytes in drug-induced toxic epidermal necrolysis (Lyell's syndrome). Paradoxical activation in the skin and rarefaction in lymph nodes. Dermatology 2003;206:374-378.
Paul C, Wolkenstein P, Adle H, Wechsler J, Garchon HJ, Revuz J, Roujeau JC: Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 1996;134:710-714.
Wyllie AH: Apoptosis: An overview. Br Med Bull 1997;53:451-465.
Fulda S, Sieverb H, Frisen C, Herr I, Debatin KM: The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res 1997;57:3823-3829.
Paquet P, Piérard GE: Would cyclosporin A be beneficial to mitigate drug-induced toxic epidermal necrolysis? Dermatology 1999;198:198-202.
Lange RW, Hayden PJ, Chignell CF, Luster MI: Anthralin stimulates keratinocyte-derived pro-inflammatory cytokines via generation of reactive oxygen species. Inflamm Res 1998;47:174-181.
Ettore A, Andreassi M, Anselmi C, Neri P, Andreassi L, Di Stefano A: Involvement of oxidative stress in apoptosis induced by a mixture of isothiazolinones in normal human keratinocytes. J Invest Dermatol 2003;121:328-336.
Paquet P, Piérard GE: Differential pathomechanisms of epidermal necrolytic blistering diseases. Int J Mol Med 2002;10:695-699.
Garcia-Doval I, Le Cleach L, Bocquet H, Otero XL, Roujeau JC: Toxic epidermal necrolysis and Stevens-Johnson syndrome. Does early withdrawal of causative drugs decrease the risk of death? Arch Dermatol 2000;136:323-327.
Paquet P, Jacob E, Damas P, Piérard GE: Recurrent fatal drug-induced toxic epidermal necrolysis (Lyell's syndrome) following putative β-lactam cross-reactivity: Case report and scrutiny of antibiotic imputability. Crit Care Med 2002;30:2580-2583.
Herndon D: Toxic epidermal necrolysis: A systemic and dermatologic disorder best treated with standard treatment protocols in burn intensive care units without the prolonged use of corticosteroids. J Am Coll Surg 1995;180:340-342.
Kelemen JJ, Cioffi W, McManus W, Mason A, Pruitt B: Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995;180:273-278.
Spies M, Sanford AP, Aili Low JF, Wolf S, Herndon D: Treatment of extensive toxic epidermal necrolysis in children. Pediatrics 2001;108:1162-1168.
Ghislain PD, Roujeau JC: Treatment of severe drug reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome. Dermatol Online J 2002;8:5-15.
Arevalo JM, Lorente JA: Skin coverage with Biobrane biomaterial for the treatment of patients with toxic epidermal necrolysis. J Burn Care Rehabil 1999;20:406-410.
Trautmann A, Akdis M, Schmid-Grendelmeier P, Disch R, Brocker EB, Blaser K: Targeting keratinocyte apoptosis in the treatment of atopic dermatitis and allergic contact dermatitis. J Allergy Clin Immunol 2001;108:839-846.
Kull FC: Reduction in tumor necrosis factor receptor affinity and cytotoxicity by glucocorticoids. Biochem Biophys Res Commun 1988;153:402-409.
Beyaert R, Suffys P, Van Roy F, Fiers W: Inhibition by glucocorticoids of tumor necrosis factor-mediated cytotoxicity. Evidence against lipocortin involvement. FEBS Lett 1990;262:93-96.
Chambaut-Guerin AM, Thanopoulos P: Regulation by dexamethasone and 1,25-dihydroxyvitamin D3 of the 75 kD type A tumor necrosis factor receptor surface expression and mRNA level in human U937 cells. Eur Cytokine Netw 1991;2:355-358.
Kurtz RM, Elner VM, Bian ZM, Strieter RM, Kunkel SC, Elner SG: Dexamethasone and cyclosporine A modulation of human retinal pigment epithelial cell monocyte chemotactic protein-1 and interleukin-8. Invest Ophthalmol Vis Sci 1997;38:436-445.
Wutrich RP, Sekar P: Effect of dexamethasone, 6-mercaptopurine and cyclosporine A on intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression. Biochem Pharmacol 1993;46:1349-1353.
Robert C, Kupper TS: Inflammatory skin diseases, T cells, and immune surveillance. N Engl J Med 1999;341:1817-1828.
Bemelmans M, Abramowicz D, Gouma P, Goldman M, Buurman W: In vivo T cell activation by anti-CD3 monoclonal antibody induces soluble TNF-receptor release in mice. Effects of pentoxifylline, methylprednisolone, anti-TNF and anti-IFN-γ antibodies. J Immunol 1994;153:499-506.
Simons HW: Acute life threatening dermatologic disorders. Med Clin North Am 1981;65:227-243.
Finlay AY, Richards J, Holt PJ: Intensive therapy unit management of toxic epidermal necrolysis: Practical aspects. Clin Exp Dermatol 1982;7:55-60.
Criton S, Devi K, Sridevi PK, Asokan PV: Toxic epidermal necrolysis - A retrospective study. Int J Dermatol 1997;36:923-925.
Stables GI, Lever RS: Toxic epidermal necrolysis and systemic corticosteroids. Br J Dermatol 1993;128:357.
Tegelberg-Stassen MJAM, Van Vloten WA, Baart de la Faille H: Management of nonstaphylococcal toxic epidermal necrolysis: Follow-up study of 16 case histories. Dermatologica 1990;180:124-129.
Guibal F, Bastuji-Garin S, Chosidow O, Saiag P, Revuz J, Roujeau JC: Characteristics of toxic epidermal necrolysis in patients undergoing long-term glucocorticoid therapy. Arch Dermatol 1995;131:669-672.
Halebian P, Corder V, Madden M, Finkelstein JL, Shires GT: Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986;204:503-512.
Prendiville JS, Hebert A, Greenwald MJ, Esterly N: Management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Pediatr 1989;115:881-887.
Jones WG, Halebran P, Madden M, Finkelstein J, Goodwin C: Drug-induced toxic epidermal necrolysis in children. J Pediatr Surg 1989;70:167-170.
Ward DJ, Krzeminska EC, Tanner NSB: Treatment of toxic epidermal necrolysis and a review of six cases. Burns 1990;16:97-104.
Khoo AKM, Foo CL: Toxic epidermal necrolysis in a burns centre: A 6-year review. Burns 1996;22:275-278.
Engelhardt SL, Schurr MJ, Helgerson RB: Toxic epidermal necrolysis: An analysis of referral patterns and steroid usage. J Burn Care Rehabil 1997;18:520-524.
Sheridan RL, Weber JM, Schulz JT, Ryan CM, Low HM, Tompkins RG: Management of severe toxic epidermal necrolysis in children. J Burn Care Rehabil 1999;20:497-500.
Schulz JT, Sheridan RL, Ryan CM, MacKool B, Tompkins RG: A 10-year experience with toxic epidermal necrolysis. J Burn Care Rehabil 2000;21:199-204.
Phan TG, Wang R, Crotty T, Adelstein S: Toxic epidermal necrolysis treated with intravenous gammaglobulin. Austr J Dermatol 1999;40:153-157.
Magina S, Lisboa C, Goncalves E, Conceicao P, Leal U, Mesquita-Guimaraes J: A case of toxic epidermal necrolysis treated with intravenous immunoglobulin. Br J Dermatol 2000;142:177-178.
Stella M, Cassano P, Bollero D, Clemente A, Giorio G: Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: Our experience. Dermatology 2001;203:45-49.
Paquet P, Jacob E, Damas P, Piérard GE: Treatment of drug-induced toxic epidermal necrolysis (Lyell's syndrome) with intravenous human immunoglobulins. Burns 2001;27: 652-655.
Tristani-Firouzi P, Ptersen M, Saffle JR, Morris SE, Zone JJ: Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 2002;47: 548-552.
Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, Mauri DN, Flynn K, Trent J, Margolis DJ, Saurat JH, French LE; TEN-IVIG Study Group: Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins. Arch Dermatol 2003;139:26-32.
Bachot N, Revuz J, Roujeau JC: Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2003;139:33-36.
Trent JT, Kirsner RS, Romanelli P, Kerdel FA: Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN. Arch Dermatol 2003;139:39-43.
Paquet P, Jacob E, Damas P, Pirson J, Piérard GE: Treatment of drug-induced toxic epidermal necrolysis by intravenous human immunoglobulins or cyclosporin A. A pilot study using analytical quantification of the inflammatory cell infiltrate and CD95R expression. Arch Dermatol Res, in press.
Renfro L, Grant-Kels J, Damman LA: Drug-induced toxic epidermal necrolysis treated with cyclosporin. Int J Dermatol 1989;28:441-444.
Zaki I, Patl S, Reed R, Dalziel KL: Toxic epidermal necrolysis associated with severe hypocalcaemia, and treated with cyclosporin. Br J Dermatol 1995;133:337-338.
Sullivan JR, Watson A: Lamotrigine-induced toxic epidermal necrolysis treated with intravenous cyclosporin: A discussion of pathogenesis and immunosuppressive management. Australas J Dermatol 1996;37:208-212.
Jarrett P, Rademaker M, Havill J, Pullon H: Toxic epidermal necrolysis treated with cyclosporin and granulocyte colony simulating factor. Clin Exp Dermatol 1997;22:146-147.
Murdoch SR, Fenton DA: Toxic epidermal necrolysis and cyclosporin. Clin Exp Dermatol 1997;22:250-256.
Szepietowki J, Wasik F, Szybejko-Machay G, May J: Toxic epidermal necrolysis successfully treated with cyclosporin. Report of three cases. J Eur Acad Dermatol Venereol 1997;9:169-172.
Arevalo J, Lorente JA, Gonzalez-Herrada C, Jimenez-Reyes J: Treatment of toxic epidermal necrolysis with cyclosporin A. J Trauma 2000;48:473-478.
Redondo P, Subira ML: N-acetylcysteine inhibits production of tumor necrosis factor-α and interleukin-1β. Arch Intern Med 1996;156:1238-1241.
Redondo P, De Felipe I, De la Pena A, Azamendra JM, Vanaclocha U: Drug-induced hypersensitivity syndrome and toxic epidermal necrolysis. Treatment with N-acetylcysteine. Br J Dermatol 1997;136:633-634.
Velez A, Moreno JC: Toxic epidermal necrolysis treated with N-acetylcysteine. J Am Acad Dermatol 2002;46:469-470.
Han J, Thompson P, Beutler B: Dexamethasone and pentoxifylline inhibit endotoxin-induced cachectin/tumor necrosis factor synthesis at separate points in the signaling pathway. J Exp Med 1990;172:391-394.
Strieter RM, Remick DG, Ward PA, Spengler RN, Lynch JP 3rd, Larrick J, Kunkel SL: Cellular and molecular regulation of tumor necrosis factor-α production by pentoxifylline. Biochem Biophys Res Commun 1988;155:1230-1236.
Reed WR, DeGowin RL: Suppressive effects of pentoxifylline on natural killer cell activity. J Lab Clin Med 1992;119:763-771.
Sanclemente G, De la Roche C, Escobar C, Falabella R: Pentoxifylline in toxic epidermal necrolysis and Stevens-Johnson syndrome. Int J Dermatol 1998;38:873-874.
Heng MCY, Allen SG: Efficacy of cylophosphamide in toxic epidermal necrolysis. J Am Acad Dermatol 1991;25:778-786.
Frangogiannis NG, Boridy F, Mazhar M, Mathews R, Gangopadhyay S, Cate T: Cyclophosphamide in the treatment of toxic epidermal necrolysis. South Med J 1996;89:1001-1003.
Calderon P, Anzilotti M, Phelps R: Thalidomide in dermatology. New indications for an old drug. Int J Dermatol 1997;36:881-887.
Klausner JD, Freedman VH, Kaplan G: Thalidomide as an anti-TNF-α inhibitor: Implications for clinical use. Clin Immunol Immunopathol 1996;81:219-223.
Wolkenstein P, Latarjet P, Roujeau JC: Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998;352:1586-1589.
Miyachi H, Azuma A, Hioki E, Kobayashi Y, Iwasaki S, Hashimoto Y: Inducer-specific bidirectional regulation by thalidomide and phenylphthalimides of tumor necrosis factor-α production. Biochem Biophys Res Commun 1996;224:426-430.
Pizarro A, Garcia-Tobaruela A, Herranz P, Pinilla J: Thalidomide as an inhibitor of tumor necrosis factor-α production: Word of caution. Int J Dermatol 1999;38:76-77.
Fischer M, Fiedler E, Marsch WC, Wohlrab J: Antitumour necrosis factor-α antibodies (infliximab) in the treatment of a patient with toxic epidermal necrolysis. Br J Dermatol 2002;146:707-708.
Goulden V, Goodfield MJD: Recombinant granulocyte colony-stimulating factor in the management of toxic epidermal necrolysis. Br J Dermatol 1996;135:305-306.
Inamo Y, Okubo T, Wada M, Fuchigami S, Hashimoto K, Fuchigami T, Takahashi S, Sawada S, Harada K: Intravenous ulinastatin therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis in pediatric patients. Int Arch Allergy Immunol 2002;127:89-94.
Chaidemenos G, Chrysomallis F, Sombolos K, Mourellou O, Ioannides D, Papakonstantinou M: Plasmapheresis in toxic epidermal necrolysis. Int J Dermatol 1997;36:218-221.
Egan CA, Grant WJ, Morris SE, Saffle JR, Zone JJ: Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol 1999;40:458-461.
Furubacke A, Berlin G, Anderson C, Sjoberg F: Lack of significant treatment effect of plasma exchange in the treatment of drug-induced toxic epidermal necrolysis? Intensive Care Med 1999;25:1307-1310.
