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Toxic epidermal necrolysis: Review of pathogenesis and management
Toxic epidermal necrolysis: Review of pathogenesis and management Andrew Downey, MBBS,a Chris Jackson, PhD,b Nadia Harun, PhD,c and Alan Cooper, MBBS, FACDd Sydney, New South Wales, Australia Toxic epidermal necrolysis (TEN) is a severe cutaneous drug reaction with a mortality rate of approximately 30%. The hallmark of TEN is widespread epidermal sloughing due to keratinocyte apoptosis. Multiple genetic associations between TEN and specific ethnic populations have been determined. The pathophysiology of TEN has yet to be fully elucidated; however, current pathogenic models implicate Fas ligand, granulysin, and reactive oxygen species. The value of current therapies, such as intravenous immunoglobulin and corticosteroids, remains under evaluation. ( J Am Acad Dermatol 2012;66:995-1003.)
INTRODUCTION Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction involving widespread keratinocyte death. Inappropriate immune activation is triggered in response to certain drugs or their metabolites. Separation of the epidermis from the dermis results in the formation of bullae and epidermal sloughing. While TEN is rare, with an incidence of 2 per million per year,1 it is a devastating condition, with a mortality rate of 30%.2 Patients with TEN are ideally treated in a burn intensive care unit where vital organ function is supported during the process of re-epithelialization. Various immune therapies which target the underlying disease process have been used for the treatment of TEN. Understanding the benefits of these treatments has proved challenging and is complicated by the ill-defined pathogenesis of TEN.
CLINICAL MANIFESTATIONS OF TEN The cutaneous involvement in TEN is preceded by a prodrome including fever, cough, rhinorrhea, conjunctivitis, anorexia, and malaise. A painful macular exanthem appears in a symmetrical distribution From The University of Sydney,a Kolling Institute of Medical Research,b Westmead Millennium Institute,c and Royal North Shore Hospital, St Leonards.d Funding sources: None. Conflicts of interest: None declared. Accepted for publication September 24, 2011. Reprint requests: Andrew Downey, MBBS, The University of Sydney, University Rd, University of Sydney NSW, Australia. E-mail: [email protected]. Published online December 12, 2011. 0190-9622/$36.00 Ó 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2011.09.029
Abbreviations used: CTL: IVIg: NK: ROS: SJS: TEN: TNF:
cytotoxic T lymphocyte intravenous immunoglobulin natural killer (cell) reactive oxygen species Stevens-Johnson syndrome toxic epidermal necrolysis tumor necrosis factor
on the face and trunk, spreading to the extremities. The skin develops the Nikolsky sign, whereby gentle lateral pressure causes the epidermis to slide over the basal layer. Blisters evolve and large sheets of epidermis slough off, leaving an exposed, weeping dermis (Fig 1). Epidermal detachment may progress for 5 to 7 days after which time a variable period of re-epithelialization occurs (typically 1-3 weeks).3 Gastrointestinal, respiratory, and genitourinary mucosal denudation also features widely and complete restoration may take months. Ocular involvement with adhesions and ulceration can result in photophobia, pain, and loss of vision. TEN occurs in all age groups and is more commonly seen in the setting of immunosuppression, HIV infection,4 systemic lupus erythematosus,5 collagen vascular disease, and malignancy.3 Histologically, sections of skin from TEN exhibit widespread keratinocyte apoptosis (Fig 2). There is separation at the dermoepidermal junction and a mild mononuclear infiltrate is seen in the dermis.6 Late lesions show evidence of necrosis.7
CLASSIFICATION Classically, TEN is considered part of a group of cutaneous hypersensitivity reactions with a spectrum 995
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of severity; erythema multiforme, followed by include aromatic anticonvulsants, sulfonamide antiStevens-Johnson syndrome (SJS) and TEN. Despite biotics, allopurinol, oxicam nonsteroidal antithis historical categorization, erythema multiforme is inflammatory drugs, and nevirapine (Table I).13 There are also case reports of vaccination and M probably a distinct clinical entity occurring after pneumoniaeeinduced TEN.14,15 infection with herpes simplex virus or Mycoplasma pneumoniae. Recent evidence supports the notion that SJS is the same clinical syndrome as TEN, only a GENETIC ASSOCIATIONS IN TEN less severe variant, since paA landmark paper in thology and clinical evidence 2004 from Chung et al16 CAPSULE SUMMARY differentiate the two solely described the association of on the basis of disease severcarbamazepine-induced SJS/ Toxic epidermal necrolysis is a lifeity.3 SJS involves less than TEN with the HLA-B*1502 threatening adverse drug reaction 10% of the total body surface allele among Han Chinese involving widespread keratinocyte area, whereas TEN involves (odds ratio [OR] 895; P \ apoptosis. more than 30% of the total .001). This is the strongest The pathophysiology of toxic epidermal body surface area. Total known HLA-disease associanecrolysis is incompletely understood; body surface area involvetion so far described and it has current theories involve apoptosis due to ment between 10% and 30% been confirmed in other Fas-mediated mechanisms, granulysin, is known as SJS-TEN overlap Southeast Asian populaand reactive oxygen species. (Fig 3). tions.17-19 The US Food and Drug Administration has since Treatment involves early cessation of the recommended genetic screenPROGNOSIS causative drug and supportive care in a ing for all patients requiring The prognosis of TEN reburn intensive care unit. Intravenous lates to the degree of epidercarbamazepine whose ancesimmunoglobulin should be considered mal involvement.8 This try has high rates of HLAthe first line adjunct to supportive care pattern is reflected by the B*1502.20 Recommendations and corticosteroids should be avoided. have been made to avoid relower mortality rate seen in lated drugs as they may also be SJS compared with TEN (1%harmful.21 Many other SJS/TEN-drug associations 3% compared with 30%, respectively).2,9 However, have recently emerged; HLA-A*3101 and modern advances in intensive care and burn manHLA-B*1511 with carbamazepine, HLA-B*1502 with agement mean that reported mortality rates are potentially overestimated.10 Infection is the most phenytoin,18 HLA-B*5801 with allopurinol,17,22-24 8 HLA-B*38 with sulfamethoxazole or lamotrigine and common cause of death in TEN. Other fatal complications include pulmonary embolism, adult HLA-B*73 with oxicam nonsteroidal antiinflammatory drugs.23 An accurate and specific respiratory distress syndrome, gastrointestinal hemknowledge of risks associated with various HLAs orrhage, as well as cardiac and renal failure.11 The could eventually enable genetic databases which SCORTEN developed by Bastuji-Garin et al12 is a allow prescriptions to be tailored to an individual’s validated measure of disease severity, which may be genetic risk. used to estimate prognosis. It incorporates 7 clinical variables: age, malignancy, body surface area, heart rate, serum urea, bicarbonate, and glucose. The PATHOPHYSIOLOGY OF TEN SCORTEN has proved to be a reliable tool for TEN was traditionally thought to be the result of determining an individual’s prognosis and has been either a Fas or a granulysin-mediated apoptotic used as a control for studies lacking adequate numpathomechanism. Recently, reactive oxygen species (ROS) formed within keratinocytes have also been bers.12 Recently, hypernatremia has been proposed as a contributing factor to mortality in TEN despite its implicated. Intracellular damage by ROS is thought exclusion from SCORTEN calculations. It is unclear to precede the activation of these other wellwhether patients with more severe disease have described pro-apoptotic systems. greater epidermal water loss leading to hypernatremia, or if hypernatremia in itself contributes to FAS-MEDIATED APOPTOSIS— mortality. KERATINOCYTE SUICIDE OR MURDER? Fas is a ubiquitous membrane-bound protein, CAUSES OF TEN which upon activation causes programmed cell Numerous medications have been implicated as death, or apoptosis, through a cascade of intracellucauses of TEN, the most frequently associated drugs lar events culminating in the activation of caspases d
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Fig 1. TEN. Blistering and epidermal sloughing characteristic of toxic epidermal necrolysis. A, Lesion 1 day after admission with positive Nikolsky sign. B, Widespread epidermal loss with erythematous areas of expansion 3 days following admission. This patient progressed to have more than 90% total body surface area involved.
Fig 3. The classification of SJS, SJS-TEN and TEN based on total body surface area involvement.
Fig 2. Histologic appearance of TEN. Prominent keratinocyte death, separation at the dermoepidermal junction (black arrows) and mild dermal lymphocytic infiltration (LI ). Hematoxylin and eosin stain. Image courtesy of Dr Antony Kaufman, PaLMS Royal North Shore Hospital.
(the effectors of apoptosis). Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells produce Fas ligand (FasL) which binds Fas on target cells. Although CTL and NK cells are the classic producers of membrane-bound FasL, the paucity of dermal mononuclear cells in histologic sections of TEN skin make them unlikely candidates for activating apoptosis in TEN.25 Keratinocytes, however, are a lesser known source of FasL. These cells are potentially responsible for their own destruction via autocrineor paracrine-mediated Fas mechanisms. In 1998, Viard et al26 produced compelling evidence for a role of FasL in TEN pathogenesis. Patients’ sera were found to have high levels of soluble FasL (sFasL). While investigating the source of sFasL, they found dense keratinocyte localization of FasL on immunostained skin sections from these patients. Keratinocyte-bound FasL was inferred to be the source of the sFasL and the cause of keratinocyte apoptosis (keratinocyte suicide). They also
demonstrated that the lytic activity of keratinocytebound FasL could be blocked by addition of FasL-binding monoclonal antibody or intravenous immunoglobulin (IVIg), containing Fas-binding antibodies. Viard et al extrapolated their results to a clinical pilot study where 10 patients treated with IVIg showed accelerated clinical recovery from TEN with no deaths. Abe25 and Abe et al27 challenged the keratinocyte suicide theory, instead favoring a role for soluble FasL (sFasL). Abe et al did not detect keratinocytebound FasL. However, they confirmed the presence of raised levels of sFasL in the sera of patients with TEN. The sFasL was produced by peripheral blood mononuclear cells and its lytic activity was confirmed. The levels of apoptosis decreased in a dose-dependent manner upon addition of anti-Fas monoclonal antibodies. Although Abe et al contradict Viard et al regarding the source of FasL, they both concur that the blockade of Fas prevents keratinocyte apoptosis. Considering the dose dependent apoptosis after addition of TEN patient sera to keratinocytes observed by Abe et al, it is reasonable to extrapolate that higher levels of FasL would produce a more severe clinical state. However, a correlation between FasL levels and disease severity has not been established.25,28 Four possible explanations include (1) initial keratinocyte damage caused by ROS may establish the degree of clinical
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Table I. Drugs associated with risk of SJS/TEN according to the 2008 Euro-SCAR study13 Confirmed high risk
Nevirapine Lamotrigine Carbamazepine Phenytoin Phenobarbital Cotrimoxazole 1 other anti-infective sulfonamides Sulfasalazine Allopurinol Oxicam-NSAIDs — —
Low risk
Potential risk (requiring further investigation)
No determined risk
Sertraline Acetic acid NSAIDs Macrolides Quinolones Cephalosporins Tetracyclines
Pantoprazole Corticosteroids Pyrazolones Acetylsalicylic acid Tramadol Nimesulfide
Statins Sulfonamide-related diuretics/antidiabetics Beta blockers ACE inhibitors Calcium channel blockers Thiazide diuretics
Aminopenicillins — — — —
Paracematol Ibuprofen — — —
Furosemide Insulin Propionic acid NSAIDs Non-pantoprazole proton pump inhibitors Non-sertraline SSRIs
ACE, Angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory druga; SJS, Stevens-Johnson syndrome; SSRI, selective serotonin reuptake inhibitor; TEN, toxic epidermal necrolysis.
involvement whereas the contribution of Fas may be a less important consequence; (2) variations in individuals’ underlying genetic susceptibilities to Fas pathway activation. For example, in African American patients with systemic lupus erythematosus (SLE), variation in single nucleotide polymorphisms (SNP) at nucleotide position e844C in the 59 promoter of the FasL gene have been linked to overactivity of the Fas death receptor pathway.5 (3) The timing of sample collection could impinge on accurate assessments of biological function. Abe et al25 described a rapid but transient rise in sFasL in the first days after disease onset. (4) In an isolated report Tohyama et al29 proposed that sFasL is a mere byproduct of hepatocyte damage and should not be used as a marker of disease severity. They suggest that sFasL is not specific for SJS/TEN because elevated levels have also been detected in maculopapular eruption and drug-induced hypersensitivity syndrome.30
GRANULYSIN CELL-MEDIATED APOPTOSIS Granulysin is a pro-apoptotic protein which permits cell-mediated cytotoxicity without direct cell-tocell contact. In 2009, Chung et al31 detected granulysin in TEN blisters. Theories involving cellmediated immunity had previously been disregarded based on the cell-poor infiltrates seen in TEN biopsy specimens. The findings by Chung et al31 are consistent with the classic paucicellular histology of TEN. The 9-kd granulysin molecule is one of several cytotoxic proteins secreted in granules by CTL and NK cells. In addition to its role in initiating apoptosis, it also has antitumor, antimicrobial, chemotactic, and proinflammatory properties.32 Chung
et al31 investigated the 15-kd granulysin molecule, the precursor for the well-studied 9-kd fragment. Both molecules have cytotoxic activity31; however, the 15-kd molecule is released in a non-granule exocytic manner that does not require direct cellular apposition. Furthermore, Chung et al reported the predominant cells within the blister fluid from patients with SJS/TEN to be CTL, NK, and natural killer T cells.31 Natural killer T cells are those which share NK and CTL phenotype. These cells expressed large amounts of granulysin above the amounts produced by peripheral blood mononuclear cells. Other inflammatory molecules expressed were FasL, granzyme B, and perforin; however, these molecules were produced in smaller amounts. The severity of the cutaneous lesions correlated with granulysin levels. Furthermore, granulysin demonstrated a dose-dependent cytotoxicity in vitro. Recombinant sFasL, perforin, and granzyme B, however, showed little cytotoxic activity. Granulysin depletion, and not sFasL, perforin, or granzyme B depletion also increased cellular viability. In addition, granulysin was highly expressed in SJS/TEN lesions and only weakly expressed or undetectable in various other dermatoses and controls. Furthermore, intradermal injection of granulysin produced lesions resembling SJS/ TEN.31 If successful, the development of such an animal model would be invaluable in advancing the understanding of TEN and other similar cutaneous disorders.
INTRACELLULAR KERATINOCYTE DAMAGE—REACTIVE OXYGEN SPECIES Oxidative stress may also be involved in the etiology of TEN.33 GST-p is a marker of oxidative stress in keratinocytes. It is expressed in greater
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abundance in TEN compared to other cutaneous adverse drug reactions.34 Electrophilic xenobiotics may impair detoxification pathways resulting in the production of reactive oxygen species (ROS).35 Resultant damage to intracellular machinery and membranes occurs and triggers pro-apoptotic processes including FasL expression and inflammatory cytokine production such as tumor necrosis factor alpha (TNF-a). TNF-a is found in the epidermis and within inflammatory cells of TEN patients.36-39 TNF-a may contribute to the apoptosis seen in TEN by activating caspases and increasing the expression of Fas and FasL.40,41 TNF-a stimulates nitric oxide production,42 which in turn inhibits the electron transport chain, further increasing the production of ROS.43 The aforementioned events are proposed to cause apoptosis in the short term; however, the loss of mitochondrial integrity and permeability pores lead to cellular swelling and subsequent necrosis.7 This correlates with the early apoptosis and late necrosis seen histologically in TEN. Current therapies may not target the initiating events in TEN but rather abrogate later events once a process of epidermal destruction has already begun. If the initial apoptotic stimulus could be identified and blocked, a dramatic improvement in outcomes may be seen.
PROPOSED ALTERNATIVE CELLMEDIATED APOPTOSIS PATHWAYS IN TEN Morel et al44 have described a novel mode of activation of CTL and NK via CD94/NKG2C recognition of keratinocyte-bound HLA-E. Patients with SJS/ TEN were found to have large counts of cytotoxic lymphocytes expressing the CD94/NKG2C receptor. This receptor is activated by HLA-E, which is up regulated by keratinocytes in TEN patients. A role for close-contact cell-mediated apoptosis is also supported by observations of drug-specific major histocompatibility complex (MHC) class 1erestricted T cells within TEN blisters.45 These cells show strong immunoreactivity for the cytotoxic protein granzyme. A role for defective regulatory T cells has been proposed.46 Novel work by Takahashi et al47 has shown that regulatory T cells are present in normal numbers but are functionally ineffective in the acute stage of TEN. Following disease resolution, these cells regain their function. Recent investigation into alarmins has raised the possibility that the innate immune system plays a role in the pathogenesis of drug hypersensitivity syndromes.48 Alarmins are endogenous molecules produced in response to tissue damage which recruit and activate the innate immune system. Gene expression patterns strongly
favoring production of alarmins have been described in patients with SJS/TEN.48
CYTOKINE-INDUCED AMPLIFICATION OF APOPTOTIC PATHWAYS Following an initial apoptotic stimulus, it is likely that apoptotic signals are amplified by cytokines. De Araujo et al49 recently proposed a mechanism whereby drug-specific CTLs elaborate interferon gamma (IFN-g), which promotes CTL cytotoxicity. Macrophages, monocytes, and dendritic cells are recruited by the IFN-g gradient and subsequently produce other proinflammatory cytokines, such as TRAIL (TNF-related apoptosis-inducing ligand) and TWEAK (TNF-related weak apoptosis inducer). They showed that TRAIL was produced by CD8, CD1a, and CD14 cells and that TWEAK was produced by CD1a and CD14 cells, which were all present in TEN blister fluid. This process culminates in a cooperative keratinocyte killing process through an MHCdependent pathway. Dermal endothelial damage has also recently been described in TEN.50 Perivascular expression of granzyme B and TNF-a occurred. Dermal vascular damage may further contribute to the poor viability of epidermis in TEN.
GENERAL MANAGEMENT Two firmly established principles consistently shown to improve survival in the management of TEN are the early withdrawal of the offending drug51 and prompt referral to a burn unit.52,53 Early drug withdrawal reduces the initiating stimulus for apoptosis; however, metabolites of drugs with longer half-lives can persist, conferring a decreased survival.51 In addition to specialized skin care, patients with TEN require careful management of fluid balance, electrolyte disturbances, respiratory function, nutrition, infection, and pain. Consideration must be given to all epidermal and mucosal surfaces; respiratory, gastrointestinal, ocular, vulvovaginal and preputial. Regular manual lysis is also required to prevent adhesions within these tissues. The hypercatabolic state induced by TEN necessitates nutritional correction to aid the healing process. Enteral feeding should be instituted early and parenteral feeding should only be used where enteral feeding is not possible. Enteral feeding has been associated with a survival advantage, and animal experiments have demonstrated benefits in treating large wounds.53
SPECIFIC WOUND CARE There is no ‘‘gold standard’’ approach to wound care and most centers follow local trends in burn care. In general, devitalized epidermis should be
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urgently removed and covered with a non-adherent dressing. Frequent dressing changes and aggressive wound debridement should be avoided as they may interfere with re-epithelialization. Various treatments exist to cover denuded epidermis: biological, biosynthetic, silver- or antibioticimpregnated dressings.54-57 Infections in TEN are common and carry a high mortality rate. Staphylococcus aureus is frequently involved and cases of Pseudomonas infection may occur after prolonged admission.58 Active infection surveillance should occur; however, empiric prophylactic antibiotics are not recommended since no survival advantage has been established.53 In addition, unnecessary catheters and invasive devices should be avoided.10
SYSTEMIC CORTICOSTEROIDS Although historically considered a first-line treatment for TEN, steroids have been associated with increased mortality,59,60 higher rates of sepsis, and prolonged hospital admissions.59 This association is presumably due to an increased risk of infection and poorer wound healing. A recent retrospective casecontrol study in Europe, however, did not detect increased mortality from steroid treatment.61 There has been interest in brief high-dose steroid therapy early in the disease course, such as less than 48 hours’ use before significant epidermal loss.62 Follow-up in this area may be warranted; however, the use of systemic corticosteroids should be discouraged outside of trials.
INTRAVENOUS IMMUNOGLOBULIN (IVIg) To date, IVIg has been the major focus of therapeutic trials for TEN. It is thought that anti-Fas antibodies or other inhibitory antibodies within IVIg may prevent apoptosis. Numerous studies describe favorable outcomes following the use of IVIg.63-69 Brown et al70 and Bachot et al,71 in contrast, reported poorer outcomes following treatment with IVIg. Several limitations of these two studies have been put forward. In the study by Brown et al,70 the IVIg group had an average delay of 9.2 days between onset of symptoms and treatment compared with 5.6 days for the control group. Additionally, the IVIg doses used were relatively lower than many other studies. In the study by Bachot et al,71 32 of 34 patients were treated with IVIg from the same batch. High variability of anti-Fas activity between batches has been described.65,72 There is a subsequent risk in treating numerous patients from a single batch as there may be poor anti-Fas activity in a particular batch.
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In 2007, a meta-analysis of 9 IVIg trials concluded that high doses significantly improved survival.73 With each 1-g/kg increase in IVIg dose, a 4.2-fold increase in survival resulted. French, Trent, and Kerdel72 pooled the results from 8 studies and found that total doses of 2 g/kg or more had a 59% reduction in mortality between expected (SCORTEN) and observed mortality, whereas in the low-dose IVIg group (\2 g/kg total dose) only a 3% decrease in mortality was observed compared with the expected mortality using SCORTEN. They therefore concluded that doses of 3 to 4 g/kg are most likely to be effective. In summary, evidence collected thus far favors the use of high-dose IVIg for the treatment of TEN. Continued research into IVIg could involve screening batches to establish levels of anti-Fas activity.65,72 Batches with high anti-Fas activity might reveal different rates of survival compared with historical controls. Treatment with monoclonal antibodies directed at Fas could be submitted for trial once issues around availability and cost are overcome.
OTHER TREATMENTS Plasmapheresis has been used with the aim of clearing drug metabolites and cytokines. Preliminary results have shown potential survival benefits.74-78 Plasmapheresis appears safe and further prospective trials would be appropriate. Other treatments for TEN have included cyclosporine, cyclophosphamide, and anti-TNF-a antibodies.79-81 Theoretically, these treatments may provide benefit by blocking immune activation; however, currently there is not enough evidence to draw conclusions on their effects. A trial involving the anti-TNF-a agent thalidomide was ceased before the planned trial end point because of an unacceptable mortality rate in the treatment group.82 N-acetylcysteine (NAC) a precursor for glutathione (GSH) has been used in an attempt to replenish detoxification systems; however, conclusions could also not be drawn from these studies.83,84
CONCLUSION The discovery of specific genetic risks for developing TEN has been a milestone in the field of medical genetics. It has allowed the development of practical clinical guidelines based on genetic risks. The pathophysiology of TEN, however, remains incompletely understood. Current models involve an initial drug-mediated keratinocyte insult followed by up-regulation of proapoptotic systems. The early initiating events of TEN that precede the activation of proapoptotic mechanisms need to be further elucidated. By targeting early events in the disease
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process, the need for downregulation of apoptotic effector systems could be averted. Treatment of TEN over the last decade has shifted away from steroid use in preference for high-dose IVIg. IVIg should be considered the first-line adjunct to extensive supportive care in a burn intensive care unit. The development of multicenter trials will be the most effective way forward in assessing treatments for TEN. By pooling the catchment areas of numerous large referral centers, sufficient data could be collected to evaluate outcomes more efficiently. REFERENCES 1. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int 2006;55:9-16. 2. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol 2007;56:181-200. 3. Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefell DJ. Fitzpatrick’s Dermatology in general medicine. 7th ed. McGraw Hill; 2007. 4. Rzany B, Mockenhaupt M, Stocker U, Hamouda O, Schopf E. Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with the acquired immunodeficiency syndrome in Germany. Arch Dermatol 1993;129:1059. 5. Wu J, Metz C, Xu X, Abe R, Gibson AW, Edberg JC, et al. A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. J Immunol 2003;170:132-8. 6. Quinn AM, Brown K, Bonish BK, Curry J, Gordon KB, Sinacore J, et al. Uncovering histologic criteria with prognostic significance in toxic epidermal necrolysis. Arch Dermatol 2005;141: 683-7. 7. Paquet P, Pierard GE. Toxic epidermal necrolysis: revisiting the tentative link between early apoptosis and late necrosis (review). Int J Mol Med 2007;19:3-10. 8. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-85. 9. Letkko E, Papaliodis BS, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol 2005;94:419-36. 10. Imahara SD, Holmes JH 4th, Heimbach DM, Engrav LE, Honari S, Klein MB, et al. SCORTEN overestimates mortality in the setting of a standardized treatment protocol. J Burn Care Res 2006;27:270-5. 11. Mukasa Y, Craven N. Management of toxic epidermal necrolysis and related syndromes. Postgrad Med J 2008;84:60-5. 12. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149-53. 13. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR study. J Invest Dermatol 2008;128:35-44. 14. Dobrosavljevic D, Milinkovic MV, Nikolic MM. Toxic epidermal necrolysis following morbilli-parotitis vaccination. J Eur Acad Dermatol Venereol 1999;13:59-61. 15. Stevens D, Swift PG, Johnston PG, Kearney PJ, Corner BD, Burman D. Mycoplasma pneumoniae infections in children. Arch Dis Child 1978;53:38-42.
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16. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2004;428:486. 17. Hung SI, Chung WH, Liou LB, Chu CC, Lin M, Huang HP, et al. HLA-B*5801 allele as a genetic marker for severe cutaneous adverse reactions caused by allopurinol. Proc Natl Acad Sci U S A 2005;102:4134-9. 18. Locharernkul C, Loplumlert J, Limotai C, Korkij W, Desudchit T, Tongkobpetch S, et al. Carbamazepine and phenytoin induced Stevens-Johnson syndrome is associated with HLA-B*1502 allele in Thai population. Epilepsia 2008;49:2087-91. 19. Man CB, Kwan P, Baum L, Yu E, Lau KM, Cheng AS, et al. Association between HLA-B*1502 allele and antiepileptic drug-induced cutaneous reactions in Han Chinese. Epilepsia 2007;48:1015-8. 20. Information for Healthcare Professionals: Dangerous or Even Fatal Skin Reactions - Carbamazepine. United States Food and Drug Administration. Available from: http://www.fda.gov/Drugs/ DrugSafety/PostmarketDrugSafetyInformationforPatientsand Providers/ucm124718.htm. Accessed November 16, 2011. 21. Wu Y, Sanderson JP, Farrell J, Drummond NS, Hanson A, Bowkett E, et al. Activation of T cells by carbamazepine and carbamazepine metabolites. J Allergy Clin Immunol 2006;118: 233-41. 22. Kaniwa N, Saito Y, Aihara M, Matsunaga K, Tohkin M, Kurose K, et al. HLA-B locus in Japanese patients with anti-epileptics and allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis. Pharmacogenomics 2008;9:1617-22. 23. Lonjou C, Borot N, Sekula P, Ledger N, Thomas L, Halevy S, et al. A European study of HLA-B in Stevens-Johnson syndrome and toxic epidermal necrolysis related to five high-risk drugs. Pharmacogenet Genomics 2008;18:99-107. 24. Tassaneeyakul W, Jantararoungtong T, Chen P, Lin PY, Tiamkao S, Khunarkornsiri U, et al. Strong association between HLA-B*5801 and allopurinol-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in a Thai population. Pharmacogenet Genomics 2009;19:704-9. 25. Abe R. Toxic epidermal necrolysis and Stevens-Johnson syndrome: soluble Fas ligand involvement in the pathomechanisms of these diseases. J Dermatol Sci 2008;52:151-9. 26. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 1998; 282:490-3. 27. 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;162:1515-20. 28. Stur K, Karlhofer FM, Stingl G. Soluble FAS ligand: a discriminating feature between drug-induced skin eruptions and viral exanthemas. J Invest Dermatol 2007;127:802-7. 29. Tohyama M, Shirakata Y, Sayama K, Hashimoto K. The influence of hepatic damage on serum soluble Fas ligand levels of patients with drug rashes. J Allergy Clin Immunol 2009;123: 971-2; author reply 972. 30. Tohyama M, Shirakata Y, Sayama K, Hashimoto K. A marked increase in serum soluble Fas ligand in drug-induced hypersensitivity syndrome. Br J Dermatol 2008;159:981-4. 31. Chung WH, Hung SI, Yang JY, Su SC, Huang SP, Wei CY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens-Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008;14:1343-50. 32. Deng A, Chen S, Li Q, Lyu SC, Clayberger C, Krensky AM. Granulysin, a cytolytic molecule, is also a chemoattractant and proinflammatory activator. J Immunol 2005;174:5243-8.
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33. Paquet P, Pierard GE. New insights in toxic epidermal necrolysis (Lyell’s syndrome): clinical considerations, pathobiology and targeted treatments revisited. Drug Saf 2010;33: 189-212. 34. Paquet P, Pierard GE. Glutathione-S-transferase pi expression in toxic epidermal necrolysis: a marker of putative oxidative stress in keratinocytes. Skin Pharmacol Physiol 2007;20:66-70. 35. Hayes JD, Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 1995;30:445-600. 36. Hermes B, Haas N, Henz BM. [Plasmapheresis and immunopathogenetic aspects of toxic epidermal necrolysis]. Hautarzt 1996;47:749-53, In German. 37. Paquet P, Nikkels A, Arrese JE, Vanderkelen A, Pierard GE. Macrophages and tumor necrosis factor alpha in toxic epidermal necrolysis. Arch Dermatol 1994;130:605-8. 38. Posadas SJ, Padial A, Torres MJ, Mayorga C, Leyva L, Sanchez E, et al. Delayed reactions to drugs show levels of perforin, granzyme B, and Fas-L to be related to disease severity. J Allergy Clin Immunol 2002;109:155-61. 39. Posadas SJ, Torres MJ, Mayorga C, Juarez C, Blanca M. Gene expression levels of cytokine profile and cytotoxic markers in non-immediate reactions to drugs. Blood Cells Mol Dis 2002; 29:179-89. 40. Arnold R, Seifert M, Asadullah K, Volk HD. Crosstalk between keratinocytes and T lymphocytes via Fas/Fas ligand interaction: modulation by cytokines. J Immunol 1999;162:7140-7. 41. Chave TA, Mortimer NJ, Sladden MJ, Hall AP, Hutchinson PE. Toxic epidermal necrolysis: current evidence, practical management and future directions. Br J Dermatol 2005;153:241-53. 42. Moncada S, Palmer RM, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991;43: 109-42. 43. Kroncke KD, Fehsel K, Kolb-Bachofen V. Nitric oxide: cytotoxicity versus cytoprotection—how, why, when, and where? Nitric Oxide 1997;1:107-20. 44. Morel E, Escamochero S, Cabanas R, Diaz R, Fiandor A, Bellon T. CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis. J Allergy Clin Immunol 2010;125:703-10, 710 e1-710 e8. 45. Nassif A, Bensussan A, Boumsell L, Deniaud A, Moslehi H, Wolkenstein P, et al. Toxic epidermal necrolysis: effector cells are drug-specific cytotoxic T cells. J Allergy Clin Immunol 2004; 114:1209-15. 46. Mizukawa Y, Yamazaki Y, Shiohara T. In vivo dynamics of intraepidermal CD81 T cells and CD41 T cells during the evolution of fixed drug eruption. Br J Dermatol 2008;158:1230-8. 47. Takahashi R, Kano Y, Yamazaki Y, Kimishima M, Mizukawa Y, Shiohara T. Defective regulatory T cells in patients with severe drug eruptions: timing of the dysfunction is associated with the pathological phenotype and outcome. J Immunol 2009; 182:8071-9. 48. Bellon T, Alvarez L, Mayorga C, Morel E, Torres MJ, Martin-Diaz MA, et al. Differential gene expression in drug hypersensitivity reactions: induction of alarmins in severe bullous diseases. Br J Dermatol 2010;162:1014-22. 49. de Araujo E, Dessirier V, Lapree G, Valeyrie-Allanore L, Ortonne N, Stathopoulos EN, et al. Death ligand TRAIL, secreted by CD1a1 and CD141 cells in blister fluids, is involved in killing keratinocytes in toxic epidermal necrolysis. Exp Dermatol 2011;20:107-12. 50. Verneuil L, Ratajczak P, Allabert C, Leboeuf C, Comoz F, Janin A, et al. Endothelial cell apoptosis in severe drug-induced bullous eruptions. Br J Dermatol 2009;161:1371-5.
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51. Garcia-Doval I, LeCleach 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;136:323-7. 52. McGee T, Munster A. Toxic epidermal necrolysis syndrome: mortality rate reduced with early referral to regional burn center. Plast Reconstr Surg 1998;102:1018-22. 53. Palmieri TL, Greenhalgh DG, Saffle JR, Spence RJ, Peck MD, Jeng JC, et al. A multicenter review of toxic epidermal necrolysis treated in U.S. burn centers at the end of the twentieth century. J Burn Care Rehabil 2002;23:87-96. 54. Endorf FW, Cancio LC, Gibran NS. Toxic epidermal necrolysis clinical guidelines. J Burn Care Res 2008;29:706-12. 55. Boorboor P, Vogt PM, Bechara FG, Alkandari Q, Aust M, Gohritz A, et al. Toxic epidermal necrolysis: use of Biobrane or skin coverage reduces pain, improves mobilisation and decreases infection in elderly patients. Burns 2008;34:487-92. 56. Dorafshar AH, Dickie SR, Cohn AB, Aycock JK, O’Connor A, Tung A, et al. Antishear therapy for toxic epidermal necrolysis: an alternative treatment approach. Plast Reconstr Surg 2008; 122:154-60. 57. Huang SH, Wu SH, Sun IF, Lee SS, Lai CS, Lin SD, et al. AQUACEL Ag in the treatment of toxic epidermal necrolysis (TEN). Burns 2008;34:63-6. 58. Revuz J, Penso D, Roujeau JC, Guillaume JC, Payne CR, Wechsler J, et al. Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987;123:1160-5. 59. Halebian PH, Corder VJ, Madden MR, Finklestein JL, Shires GT. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986;204:503-12. 60. Heimbach DM, Engrav LH, Marvin JA, Harnar TJ, Grube BJ. Toxic epidermal necrolysis. A step forward in treatment. JAMA 1987;257:2171-5. 61. Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008;58:33-40. 62. Herndon DN. 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;180:340-2. 63. Al-Mutairi N, Arun J, Osama NE, Amr Z, Mazen AS, Ibtesam el A, et al. Prospective, noncomparative open study from Kuwait of the role of intravenous immunoglobulin in the treatment of toxic epidermal necrolysis. Int J Dermatol 2004;43:847-51. 64. Campione E, Marulli GC, Carrozzo AM, Chimenti MS, Costanzo A, Bianchi L. High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis. Acta Derm Venereol 2003;83:430-2. 65. Prins C, Vittorio C, Padilla RS, Hunziker T, Itin P, Forster J, et al. Effect of high-dose intravenous immunoglobulin therapy in Stevens-Johnson syndrome: a retrospective, multicenter study. Dermatology 2003;207:96-9. 66. Shortt R, Gomez M, Mittman N, Cartotto R. Intravenous immunoglobulin does not improve outcome in toxic epidermal necrolysis. J Burn Care Rehabil 2004;25:246-55. 67. Stella M, Cassano P, Bollero D, Clemente A, Giorio G. Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: our experience. Dermatology 2001;203:45-9. 68. Trent JT, Kirsner RS, Romanelli P, Kerdel FA. Analysis of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis using SCORTEN: The University of Miami Experience. Arch Dermatol 2003;139:39-43.
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69. Tristani-Firouzi P, Petersen MJ, Saffle JR, Morris SE, Zone JJ. Treatment of toxic epidermal necrolysis with intravenous immunoglobulin in children. J Am Acad Dermatol 2002;47:548-52. 70. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil 2004;25:81-8. 71. 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. 72. French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharmacol 2006;6:543-9. 73. Trent J, Halem M, French LE, Kerdel F. Toxic epidermal necrolysis and intravenous immunoglobulin: a review. Semin Cutan Med Surg 2006;25:91-3. 74. Bamichas G, Natse T, Christidou F, Stangou M, Karagianni A, Koukourikos S, et al. Plasma exchange in patients with toxic epidermal necrolysis. Ther Apher 2002;6:225-8. 75. Chaidemenos GC, Chrysomallis F, Sombolos K, Mourellou O, Ioannides D, Papakonstantinou M. Plasmapheresis in toxic epidermal necrolysis. Int J Dermatol 1997;36:218-21. 76. Egan CA, Grant WJ, Morris SE, Saffle JR, Zone JJ. Plasmapheresis as an adjunct treatment in toxic epidermal necrolysis. J Am Acad Dermatol 1999;40:458-61.
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77. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol 1985;121:1548-9. 78. Sakellariou G, Koukoudis P, Karpouzas J, Alexopoulos E, Papadopoulou D, Chrisomalis F, et al. Plasma exchange (PE) treatment in drug-induced toxic epidermal necrolysis (TEN). Int J Artif Organs 1991;14:634-8. 79. Arevalo JM, Lorente JA, Gonzalez-Herrada C, Jimenez-Reyes J. Treatment of toxic epidermal necrolysis with cyclosporin A. J Trauma 2000;48:473-8. 80. Fischer M, Fiedler E, Marsch WC, Wohlrab J. Antitumour necrosis factor-alpha antibodies (infliximab) in the treatment of a patient with toxic epidermal necrolysis. Br J Dermatol 2002;146:707-9. 81. Frangogiannis NG, Boridy I, Mazhar M, Mathews R, Gangopadhyay S, Cate T. Cyclophosphamide in the treatment of toxic epidermal necrolysis. South Med J 1996;89:1001-3. 82. Wolkenstein P, Latarjet J, Roujeau JC, Duguet C, Boudeau S, Vaillant L, et al. Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis. Lancet 1998; 352:1586-9. 83. Redondo P, de Felipe I, de la Pena A, Aramendia JM, Vanaclocha V. Drug-induced hypersensitivity syndrome and toxic epidermal necrolysis. Treatment with N-acetylcysteine. Br J Dermatol 1997;136:645-6. 84. Velez A, Moreno JC. Toxic epidermal necrolysis treated with N-acetylcysteine. J Am Acad Dermatol 2002;46:469-70.
INTRODUCTION Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction involving widespread keratinocyte death. Inappropriate immune activation is triggered in response to certain drugs or their metabolites. Separation of the epidermis from the dermis results in the formation of bullae and epidermal sloughing. While TEN is rare, with an incidence of 2 per million per year,1 it is a devastating condition, with a mortality rate of 30%.2 Patients with TEN are ideally treated in a burn intensive care unit where vital organ function is supported during the process of re-epithelialization. Various immune therapies which target the underlying disease process have been used for the treatment of TEN. Understanding the benefits of these treatments has proved challenging and is complicated by the ill-defined pathogenesis of TEN.
CLINICAL MANIFESTATIONS OF TEN The cutaneous involvement in TEN is preceded by a prodrome including fever, cough, rhinorrhea, conjunctivitis, anorexia, and malaise. A painful macular exanthem appears in a symmetrical distribution From The University of Sydney,a Kolling Institute of Medical Research,b Westmead Millennium Institute,c and Royal North Shore Hospital, St Leonards.d Funding sources: None. Conflicts of interest: None declared. Accepted for publication September 24, 2011. Reprint requests: Andrew Downey, MBBS, The University of Sydney, University Rd, University of Sydney NSW, Australia. E-mail: [email protected]. Published online December 12, 2011. 0190-9622/$36.00 Ó 2011 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2011.09.029
Abbreviations used: CTL: IVIg: NK: ROS: SJS: TEN: TNF:
cytotoxic T lymphocyte intravenous immunoglobulin natural killer (cell) reactive oxygen species Stevens-Johnson syndrome toxic epidermal necrolysis tumor necrosis factor
on the face and trunk, spreading to the extremities. The skin develops the Nikolsky sign, whereby gentle lateral pressure causes the epidermis to slide over the basal layer. Blisters evolve and large sheets of epidermis slough off, leaving an exposed, weeping dermis (Fig 1). Epidermal detachment may progress for 5 to 7 days after which time a variable period of re-epithelialization occurs (typically 1-3 weeks).3 Gastrointestinal, respiratory, and genitourinary mucosal denudation also features widely and complete restoration may take months. Ocular involvement with adhesions and ulceration can result in photophobia, pain, and loss of vision. TEN occurs in all age groups and is more commonly seen in the setting of immunosuppression, HIV infection,4 systemic lupus erythematosus,5 collagen vascular disease, and malignancy.3 Histologically, sections of skin from TEN exhibit widespread keratinocyte apoptosis (Fig 2). There is separation at the dermoepidermal junction and a mild mononuclear infiltrate is seen in the dermis.6 Late lesions show evidence of necrosis.7
CLASSIFICATION Classically, TEN is considered part of a group of cutaneous hypersensitivity reactions with a spectrum 995
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of severity; erythema multiforme, followed by include aromatic anticonvulsants, sulfonamide antiStevens-Johnson syndrome (SJS) and TEN. Despite biotics, allopurinol, oxicam nonsteroidal antithis historical categorization, erythema multiforme is inflammatory drugs, and nevirapine (Table I).13 There are also case reports of vaccination and M probably a distinct clinical entity occurring after pneumoniaeeinduced TEN.14,15 infection with herpes simplex virus or Mycoplasma pneumoniae. Recent evidence supports the notion that SJS is the same clinical syndrome as TEN, only a GENETIC ASSOCIATIONS IN TEN less severe variant, since paA landmark paper in thology and clinical evidence 2004 from Chung et al16 CAPSULE SUMMARY differentiate the two solely described the association of on the basis of disease severcarbamazepine-induced SJS/ Toxic epidermal necrolysis is a lifeity.3 SJS involves less than TEN with the HLA-B*1502 threatening adverse drug reaction 10% of the total body surface allele among Han Chinese involving widespread keratinocyte area, whereas TEN involves (odds ratio [OR] 895; P \ apoptosis. more than 30% of the total .001). This is the strongest The pathophysiology of toxic epidermal body surface area. Total known HLA-disease associanecrolysis is incompletely understood; body surface area involvetion so far described and it has current theories involve apoptosis due to ment between 10% and 30% been confirmed in other Fas-mediated mechanisms, granulysin, is known as SJS-TEN overlap Southeast Asian populaand reactive oxygen species. (Fig 3). tions.17-19 The US Food and Drug Administration has since Treatment involves early cessation of the recommended genetic screenPROGNOSIS causative drug and supportive care in a ing for all patients requiring The prognosis of TEN reburn intensive care unit. Intravenous lates to the degree of epidercarbamazepine whose ancesimmunoglobulin should be considered mal involvement.8 This try has high rates of HLAthe first line adjunct to supportive care pattern is reflected by the B*1502.20 Recommendations and corticosteroids should be avoided. have been made to avoid relower mortality rate seen in lated drugs as they may also be SJS compared with TEN (1%harmful.21 Many other SJS/TEN-drug associations 3% compared with 30%, respectively).2,9 However, have recently emerged; HLA-A*3101 and modern advances in intensive care and burn manHLA-B*1511 with carbamazepine, HLA-B*1502 with agement mean that reported mortality rates are potentially overestimated.10 Infection is the most phenytoin,18 HLA-B*5801 with allopurinol,17,22-24 8 HLA-B*38 with sulfamethoxazole or lamotrigine and common cause of death in TEN. Other fatal complications include pulmonary embolism, adult HLA-B*73 with oxicam nonsteroidal antiinflammatory drugs.23 An accurate and specific respiratory distress syndrome, gastrointestinal hemknowledge of risks associated with various HLAs orrhage, as well as cardiac and renal failure.11 The could eventually enable genetic databases which SCORTEN developed by Bastuji-Garin et al12 is a allow prescriptions to be tailored to an individual’s validated measure of disease severity, which may be genetic risk. used to estimate prognosis. It incorporates 7 clinical variables: age, malignancy, body surface area, heart rate, serum urea, bicarbonate, and glucose. The PATHOPHYSIOLOGY OF TEN SCORTEN has proved to be a reliable tool for TEN was traditionally thought to be the result of determining an individual’s prognosis and has been either a Fas or a granulysin-mediated apoptotic used as a control for studies lacking adequate numpathomechanism. Recently, reactive oxygen species (ROS) formed within keratinocytes have also been bers.12 Recently, hypernatremia has been proposed as a contributing factor to mortality in TEN despite its implicated. Intracellular damage by ROS is thought exclusion from SCORTEN calculations. It is unclear to precede the activation of these other wellwhether patients with more severe disease have described pro-apoptotic systems. greater epidermal water loss leading to hypernatremia, or if hypernatremia in itself contributes to FAS-MEDIATED APOPTOSIS— mortality. KERATINOCYTE SUICIDE OR MURDER? Fas is a ubiquitous membrane-bound protein, CAUSES OF TEN which upon activation causes programmed cell Numerous medications have been implicated as death, or apoptosis, through a cascade of intracellucauses of TEN, the most frequently associated drugs lar events culminating in the activation of caspases d
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Fig 1. TEN. Blistering and epidermal sloughing characteristic of toxic epidermal necrolysis. A, Lesion 1 day after admission with positive Nikolsky sign. B, Widespread epidermal loss with erythematous areas of expansion 3 days following admission. This patient progressed to have more than 90% total body surface area involved.
Fig 3. The classification of SJS, SJS-TEN and TEN based on total body surface area involvement.
Fig 2. Histologic appearance of TEN. Prominent keratinocyte death, separation at the dermoepidermal junction (black arrows) and mild dermal lymphocytic infiltration (LI ). Hematoxylin and eosin stain. Image courtesy of Dr Antony Kaufman, PaLMS Royal North Shore Hospital.
(the effectors of apoptosis). Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells produce Fas ligand (FasL) which binds Fas on target cells. Although CTL and NK cells are the classic producers of membrane-bound FasL, the paucity of dermal mononuclear cells in histologic sections of TEN skin make them unlikely candidates for activating apoptosis in TEN.25 Keratinocytes, however, are a lesser known source of FasL. These cells are potentially responsible for their own destruction via autocrineor paracrine-mediated Fas mechanisms. In 1998, Viard et al26 produced compelling evidence for a role of FasL in TEN pathogenesis. Patients’ sera were found to have high levels of soluble FasL (sFasL). While investigating the source of sFasL, they found dense keratinocyte localization of FasL on immunostained skin sections from these patients. Keratinocyte-bound FasL was inferred to be the source of the sFasL and the cause of keratinocyte apoptosis (keratinocyte suicide). They also
demonstrated that the lytic activity of keratinocytebound FasL could be blocked by addition of FasL-binding monoclonal antibody or intravenous immunoglobulin (IVIg), containing Fas-binding antibodies. Viard et al extrapolated their results to a clinical pilot study where 10 patients treated with IVIg showed accelerated clinical recovery from TEN with no deaths. Abe25 and Abe et al27 challenged the keratinocyte suicide theory, instead favoring a role for soluble FasL (sFasL). Abe et al did not detect keratinocytebound FasL. However, they confirmed the presence of raised levels of sFasL in the sera of patients with TEN. The sFasL was produced by peripheral blood mononuclear cells and its lytic activity was confirmed. The levels of apoptosis decreased in a dose-dependent manner upon addition of anti-Fas monoclonal antibodies. Although Abe et al contradict Viard et al regarding the source of FasL, they both concur that the blockade of Fas prevents keratinocyte apoptosis. Considering the dose dependent apoptosis after addition of TEN patient sera to keratinocytes observed by Abe et al, it is reasonable to extrapolate that higher levels of FasL would produce a more severe clinical state. However, a correlation between FasL levels and disease severity has not been established.25,28 Four possible explanations include (1) initial keratinocyte damage caused by ROS may establish the degree of clinical
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Table I. Drugs associated with risk of SJS/TEN according to the 2008 Euro-SCAR study13 Confirmed high risk
Nevirapine Lamotrigine Carbamazepine Phenytoin Phenobarbital Cotrimoxazole 1 other anti-infective sulfonamides Sulfasalazine Allopurinol Oxicam-NSAIDs — —
Low risk
Potential risk (requiring further investigation)
No determined risk
Sertraline Acetic acid NSAIDs Macrolides Quinolones Cephalosporins Tetracyclines
Pantoprazole Corticosteroids Pyrazolones Acetylsalicylic acid Tramadol Nimesulfide
Statins Sulfonamide-related diuretics/antidiabetics Beta blockers ACE inhibitors Calcium channel blockers Thiazide diuretics
Aminopenicillins — — — —
Paracematol Ibuprofen — — —
Furosemide Insulin Propionic acid NSAIDs Non-pantoprazole proton pump inhibitors Non-sertraline SSRIs
ACE, Angiotensin-converting enzyme; NSAIDs, nonsteroidal anti-inflammatory druga; SJS, Stevens-Johnson syndrome; SSRI, selective serotonin reuptake inhibitor; TEN, toxic epidermal necrolysis.
involvement whereas the contribution of Fas may be a less important consequence; (2) variations in individuals’ underlying genetic susceptibilities to Fas pathway activation. For example, in African American patients with systemic lupus erythematosus (SLE), variation in single nucleotide polymorphisms (SNP) at nucleotide position e844C in the 59 promoter of the FasL gene have been linked to overactivity of the Fas death receptor pathway.5 (3) The timing of sample collection could impinge on accurate assessments of biological function. Abe et al25 described a rapid but transient rise in sFasL in the first days after disease onset. (4) In an isolated report Tohyama et al29 proposed that sFasL is a mere byproduct of hepatocyte damage and should not be used as a marker of disease severity. They suggest that sFasL is not specific for SJS/TEN because elevated levels have also been detected in maculopapular eruption and drug-induced hypersensitivity syndrome.30
GRANULYSIN CELL-MEDIATED APOPTOSIS Granulysin is a pro-apoptotic protein which permits cell-mediated cytotoxicity without direct cell-tocell contact. In 2009, Chung et al31 detected granulysin in TEN blisters. Theories involving cellmediated immunity had previously been disregarded based on the cell-poor infiltrates seen in TEN biopsy specimens. The findings by Chung et al31 are consistent with the classic paucicellular histology of TEN. The 9-kd granulysin molecule is one of several cytotoxic proteins secreted in granules by CTL and NK cells. In addition to its role in initiating apoptosis, it also has antitumor, antimicrobial, chemotactic, and proinflammatory properties.32 Chung
et al31 investigated the 15-kd granulysin molecule, the precursor for the well-studied 9-kd fragment. Both molecules have cytotoxic activity31; however, the 15-kd molecule is released in a non-granule exocytic manner that does not require direct cellular apposition. Furthermore, Chung et al reported the predominant cells within the blister fluid from patients with SJS/TEN to be CTL, NK, and natural killer T cells.31 Natural killer T cells are those which share NK and CTL phenotype. These cells expressed large amounts of granulysin above the amounts produced by peripheral blood mononuclear cells. Other inflammatory molecules expressed were FasL, granzyme B, and perforin; however, these molecules were produced in smaller amounts. The severity of the cutaneous lesions correlated with granulysin levels. Furthermore, granulysin demonstrated a dose-dependent cytotoxicity in vitro. Recombinant sFasL, perforin, and granzyme B, however, showed little cytotoxic activity. Granulysin depletion, and not sFasL, perforin, or granzyme B depletion also increased cellular viability. In addition, granulysin was highly expressed in SJS/TEN lesions and only weakly expressed or undetectable in various other dermatoses and controls. Furthermore, intradermal injection of granulysin produced lesions resembling SJS/ TEN.31 If successful, the development of such an animal model would be invaluable in advancing the understanding of TEN and other similar cutaneous disorders.
INTRACELLULAR KERATINOCYTE DAMAGE—REACTIVE OXYGEN SPECIES Oxidative stress may also be involved in the etiology of TEN.33 GST-p is a marker of oxidative stress in keratinocytes. It is expressed in greater
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abundance in TEN compared to other cutaneous adverse drug reactions.34 Electrophilic xenobiotics may impair detoxification pathways resulting in the production of reactive oxygen species (ROS).35 Resultant damage to intracellular machinery and membranes occurs and triggers pro-apoptotic processes including FasL expression and inflammatory cytokine production such as tumor necrosis factor alpha (TNF-a). TNF-a is found in the epidermis and within inflammatory cells of TEN patients.36-39 TNF-a may contribute to the apoptosis seen in TEN by activating caspases and increasing the expression of Fas and FasL.40,41 TNF-a stimulates nitric oxide production,42 which in turn inhibits the electron transport chain, further increasing the production of ROS.43 The aforementioned events are proposed to cause apoptosis in the short term; however, the loss of mitochondrial integrity and permeability pores lead to cellular swelling and subsequent necrosis.7 This correlates with the early apoptosis and late necrosis seen histologically in TEN. Current therapies may not target the initiating events in TEN but rather abrogate later events once a process of epidermal destruction has already begun. If the initial apoptotic stimulus could be identified and blocked, a dramatic improvement in outcomes may be seen.
PROPOSED ALTERNATIVE CELLMEDIATED APOPTOSIS PATHWAYS IN TEN Morel et al44 have described a novel mode of activation of CTL and NK via CD94/NKG2C recognition of keratinocyte-bound HLA-E. Patients with SJS/ TEN were found to have large counts of cytotoxic lymphocytes expressing the CD94/NKG2C receptor. This receptor is activated by HLA-E, which is up regulated by keratinocytes in TEN patients. A role for close-contact cell-mediated apoptosis is also supported by observations of drug-specific major histocompatibility complex (MHC) class 1erestricted T cells within TEN blisters.45 These cells show strong immunoreactivity for the cytotoxic protein granzyme. A role for defective regulatory T cells has been proposed.46 Novel work by Takahashi et al47 has shown that regulatory T cells are present in normal numbers but are functionally ineffective in the acute stage of TEN. Following disease resolution, these cells regain their function. Recent investigation into alarmins has raised the possibility that the innate immune system plays a role in the pathogenesis of drug hypersensitivity syndromes.48 Alarmins are endogenous molecules produced in response to tissue damage which recruit and activate the innate immune system. Gene expression patterns strongly
favoring production of alarmins have been described in patients with SJS/TEN.48
CYTOKINE-INDUCED AMPLIFICATION OF APOPTOTIC PATHWAYS Following an initial apoptotic stimulus, it is likely that apoptotic signals are amplified by cytokines. De Araujo et al49 recently proposed a mechanism whereby drug-specific CTLs elaborate interferon gamma (IFN-g), which promotes CTL cytotoxicity. Macrophages, monocytes, and dendritic cells are recruited by the IFN-g gradient and subsequently produce other proinflammatory cytokines, such as TRAIL (TNF-related apoptosis-inducing ligand) and TWEAK (TNF-related weak apoptosis inducer). They showed that TRAIL was produced by CD8, CD1a, and CD14 cells and that TWEAK was produced by CD1a and CD14 cells, which were all present in TEN blister fluid. This process culminates in a cooperative keratinocyte killing process through an MHCdependent pathway. Dermal endothelial damage has also recently been described in TEN.50 Perivascular expression of granzyme B and TNF-a occurred. Dermal vascular damage may further contribute to the poor viability of epidermis in TEN.
GENERAL MANAGEMENT Two firmly established principles consistently shown to improve survival in the management of TEN are the early withdrawal of the offending drug51 and prompt referral to a burn unit.52,53 Early drug withdrawal reduces the initiating stimulus for apoptosis; however, metabolites of drugs with longer half-lives can persist, conferring a decreased survival.51 In addition to specialized skin care, patients with TEN require careful management of fluid balance, electrolyte disturbances, respiratory function, nutrition, infection, and pain. Consideration must be given to all epidermal and mucosal surfaces; respiratory, gastrointestinal, ocular, vulvovaginal and preputial. Regular manual lysis is also required to prevent adhesions within these tissues. The hypercatabolic state induced by TEN necessitates nutritional correction to aid the healing process. Enteral feeding should be instituted early and parenteral feeding should only be used where enteral feeding is not possible. Enteral feeding has been associated with a survival advantage, and animal experiments have demonstrated benefits in treating large wounds.53
SPECIFIC WOUND CARE There is no ‘‘gold standard’’ approach to wound care and most centers follow local trends in burn care. In general, devitalized epidermis should be
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urgently removed and covered with a non-adherent dressing. Frequent dressing changes and aggressive wound debridement should be avoided as they may interfere with re-epithelialization. Various treatments exist to cover denuded epidermis: biological, biosynthetic, silver- or antibioticimpregnated dressings.54-57 Infections in TEN are common and carry a high mortality rate. Staphylococcus aureus is frequently involved and cases of Pseudomonas infection may occur after prolonged admission.58 Active infection surveillance should occur; however, empiric prophylactic antibiotics are not recommended since no survival advantage has been established.53 In addition, unnecessary catheters and invasive devices should be avoided.10
SYSTEMIC CORTICOSTEROIDS Although historically considered a first-line treatment for TEN, steroids have been associated with increased mortality,59,60 higher rates of sepsis, and prolonged hospital admissions.59 This association is presumably due to an increased risk of infection and poorer wound healing. A recent retrospective casecontrol study in Europe, however, did not detect increased mortality from steroid treatment.61 There has been interest in brief high-dose steroid therapy early in the disease course, such as less than 48 hours’ use before significant epidermal loss.62 Follow-up in this area may be warranted; however, the use of systemic corticosteroids should be discouraged outside of trials.
INTRAVENOUS IMMUNOGLOBULIN (IVIg) To date, IVIg has been the major focus of therapeutic trials for TEN. It is thought that anti-Fas antibodies or other inhibitory antibodies within IVIg may prevent apoptosis. Numerous studies describe favorable outcomes following the use of IVIg.63-69 Brown et al70 and Bachot et al,71 in contrast, reported poorer outcomes following treatment with IVIg. Several limitations of these two studies have been put forward. In the study by Brown et al,70 the IVIg group had an average delay of 9.2 days between onset of symptoms and treatment compared with 5.6 days for the control group. Additionally, the IVIg doses used were relatively lower than many other studies. In the study by Bachot et al,71 32 of 34 patients were treated with IVIg from the same batch. High variability of anti-Fas activity between batches has been described.65,72 There is a subsequent risk in treating numerous patients from a single batch as there may be poor anti-Fas activity in a particular batch.
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In 2007, a meta-analysis of 9 IVIg trials concluded that high doses significantly improved survival.73 With each 1-g/kg increase in IVIg dose, a 4.2-fold increase in survival resulted. French, Trent, and Kerdel72 pooled the results from 8 studies and found that total doses of 2 g/kg or more had a 59% reduction in mortality between expected (SCORTEN) and observed mortality, whereas in the low-dose IVIg group (\2 g/kg total dose) only a 3% decrease in mortality was observed compared with the expected mortality using SCORTEN. They therefore concluded that doses of 3 to 4 g/kg are most likely to be effective. In summary, evidence collected thus far favors the use of high-dose IVIg for the treatment of TEN. Continued research into IVIg could involve screening batches to establish levels of anti-Fas activity.65,72 Batches with high anti-Fas activity might reveal different rates of survival compared with historical controls. Treatment with monoclonal antibodies directed at Fas could be submitted for trial once issues around availability and cost are overcome.
OTHER TREATMENTS Plasmapheresis has been used with the aim of clearing drug metabolites and cytokines. Preliminary results have shown potential survival benefits.74-78 Plasmapheresis appears safe and further prospective trials would be appropriate. Other treatments for TEN have included cyclosporine, cyclophosphamide, and anti-TNF-a antibodies.79-81 Theoretically, these treatments may provide benefit by blocking immune activation; however, currently there is not enough evidence to draw conclusions on their effects. A trial involving the anti-TNF-a agent thalidomide was ceased before the planned trial end point because of an unacceptable mortality rate in the treatment group.82 N-acetylcysteine (NAC) a precursor for glutathione (GSH) has been used in an attempt to replenish detoxification systems; however, conclusions could also not be drawn from these studies.83,84
CONCLUSION The discovery of specific genetic risks for developing TEN has been a milestone in the field of medical genetics. It has allowed the development of practical clinical guidelines based on genetic risks. The pathophysiology of TEN, however, remains incompletely understood. Current models involve an initial drug-mediated keratinocyte insult followed by up-regulation of proapoptotic systems. The early initiating events of TEN that precede the activation of proapoptotic mechanisms need to be further elucidated. By targeting early events in the disease
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process, the need for downregulation of apoptotic effector systems could be averted. Treatment of TEN over the last decade has shifted away from steroid use in preference for high-dose IVIg. IVIg should be considered the first-line adjunct to extensive supportive care in a burn intensive care unit. The development of multicenter trials will be the most effective way forward in assessing treatments for TEN. By pooling the catchment areas of numerous large referral centers, sufficient data could be collected to evaluate outcomes more efficiently. REFERENCES 1. French LE. Toxic epidermal necrolysis and Stevens Johnson syndrome: our current understanding. Allergol Int 2006;55:9-16. 2. Pereira FA, Mudgil AV, Rosmarin DM. Toxic epidermal necrolysis. J Am Acad Dermatol 2007;56:181-200. 3. Wolff K, Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Lefell DJ. Fitzpatrick’s Dermatology in general medicine. 7th ed. McGraw Hill; 2007. 4. Rzany B, Mockenhaupt M, Stocker U, Hamouda O, Schopf E. Incidence of Stevens-Johnson syndrome and toxic epidermal necrolysis in patients with the acquired immunodeficiency syndrome in Germany. Arch Dermatol 1993;129:1059. 5. Wu J, Metz C, Xu X, Abe R, Gibson AW, Edberg JC, et al. A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. J Immunol 2003;170:132-8. 6. Quinn AM, Brown K, Bonish BK, Curry J, Gordon KB, Sinacore J, et al. Uncovering histologic criteria with prognostic significance in toxic epidermal necrolysis. Arch Dermatol 2005;141: 683-7. 7. Paquet P, Pierard GE. Toxic epidermal necrolysis: revisiting the tentative link between early apoptosis and late necrosis (review). Int J Mol Med 2007;19:3-10. 8. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-85. 9. Letkko E, Papaliodis BS, Papaliodis GN, Daoud YJ, Ahmed AR, Foster CS. Stevens-Johnson syndrome and toxic epidermal necrolysis: a review of the literature. Ann Allergy Asthma Immunol 2005;94:419-36. 10. Imahara SD, Holmes JH 4th, Heimbach DM, Engrav LE, Honari S, Klein MB, et al. SCORTEN overestimates mortality in the setting of a standardized treatment protocol. J Burn Care Res 2006;27:270-5. 11. Mukasa Y, Craven N. Management of toxic epidermal necrolysis and related syndromes. Postgrad Med J 2008;84:60-5. 12. Bastuji-Garin S, Fouchard N, Bertocchi M, Roujeau JC, Revuz J, Wolkenstein P. SCORTEN: a severity-of-illness score for toxic epidermal necrolysis. J Invest Dermatol 2000;115:149-53. 13. Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR study. J Invest Dermatol 2008;128:35-44. 14. Dobrosavljevic D, Milinkovic MV, Nikolic MM. Toxic epidermal necrolysis following morbilli-parotitis vaccination. J Eur Acad Dermatol Venereol 1999;13:59-61. 15. Stevens D, Swift PG, Johnston PG, Kearney PJ, Corner BD, Burman D. Mycoplasma pneumoniae infections in children. Arch Dis Child 1978;53:38-42.
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