Erythema multiforme and related disorders

Vol. 103 No. 5 May 2007

ORAL MEDICINE

Editor: Martin S. Greenberg

Erythema multiforme and related disorders Khalid A. Al-Johani, BDS, MSc,a Stefano Fedele, DDS, PhD,b and Stephen R. Porter, PhD, MD, FDSRCS, FDSRCSE,c London, England UNIVERSITY COLLEGE OF LONDON

Erythema multiforme (EM) and related disorders comprise a group of mucocutaneous disorders characterized by variable degrees of mucosal and cutaneous blistering and ulceration that occasionally can give rise to systemic upset and possibly compromise life. The clinical classification of these disorders has often been variable, thus making definitive diagnosis sometimes difficult. Despite being often caused by, or at least associated with, infection or drug therapy, the pathogenic mechanisms of these disorders remain unclear, and as a consequence, there are no evidencebased, reliably effective therapies. The present article reviews aspects of EM and related disorders of relevance to oral medicine clinical practice and highlights the associated potential etiologic agents, pathogenic mechanisms and therapies. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:642-54)

Erythema multiforme (EM) and related diseases give rise to mucosal erythema and ulceration with or without a variety of cutaneous rashes and pleomorphic eruptions. Classified within this group are erythema multiforme minor (EMm), erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).1 Many authors still consider EM, SJS, and TEN to be a single disease group with different degrees of clinical severity1; however, there is increasing evidence that SJS and TEN are distinct from EMm and EMM due to their contrasting clinical presentations, patient demographics, and potential causes.2-5 In this article, the classification of EMm, EMM, SJS, SJS/TEN overlap, TEN with spots with or without blisters, and TEN without spots6-8 will be used, as this generally permits appropriate interpretation of

Oral Medicine, Division of Medical, Surgical and Diagnostic Sciences, Eastman Dental Institute for Oral Health Care Sciences, University College of London. a PhD student. b Clinical lecturer. c Professor. Received for publication Mar 27, 2006; returned for revision Dec 12, 2006; accepted for publication Dec 12, 2006. 1079-2104/$ - see front matter © 2007 Mosby, Inc. All rights reserved. doi:10.1016/j.tripleo.2006.12.008

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the literature. A summary of the classification of EM and related disorders is given in Table I. CLASSIFICATION AND CLINICAL FEATURES OF ERYTHEMA MULTIFORME AND RELATED DISORDERS The current classification of EM and related disorders is based upon the presence, morphology, and extent of cutaneous and mucosal disease.6 The cutaneous lesions of erythema multiforme comprise typical targets, raised atypical targets, flat atypical targets, and macules with or without blisters.6,9 A summary of clinical features is presented in Table I. EMm Erythema multiforme minor is an acute, self-limiting disease that may be episodic or recurrent,10 sometimes showing a seasonal pattern. Erythema multiforme minor tends to arise in the third and fourth decades of life, although it can also affect children and adolescents, and rarely affects individuals under the age of 3 or older than 50.8 Erythema multiforme minor can be associated with both infectious and drug triggers, although recent studies indicate that the former are most likely.2-4 It is clinically characterized by cutaneous disease, including the aforementioned typical (Fig. 1) and/or atypical raised targets affecting less than 10% of skin surface. Mu-

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Table I. Classification and clinical features of EM and related disorders EMm

EMM

SJS

SJS/TEN

TEN

Mainly cutaneous disease; typical and/or raised atypical raised target lesions* Infectious triggers likely Less than 10% of the body surface area Often symmetric distribution, with a predilection for the extensor surfaces of the extremities Mucosal involvement uncommon; when present, only 1 site is affected, most commonly the mouth Oral lesions; mild to severe erythema, erosions, and ulcers EMm that only affects the oral mucosa may occasionally arise Cutaneous lesions, plus at least 2 different mucosal sites (oral mucosa typically affected) Infectious triggers likely Less than 10% of the body surface area but more severe than EMm Symmetrically distributed typical cutaneous targets lesions and/or atypical and raised target lesions* Oral lesions usually widespread and severe Main difference with EMM based upon the typology and location of lesions and presence of systemic symptoms Drug trigger likely Less than 10% of the body surface area but more sever than EMM Primarily atypical flat target lesions and macules rather than classic target lesions* More generally widespread rather than involving only the acral areas Multiple mucosal sites involved; scarring of mucosal lesions Prodromal flulike systemic symptoms 10%-30% of the body surface area affected; skin and mucosal involvement similar to that of SJS Drug trigger likely Prodromal flulike systemic symptoms Generally characterized by poorly defined erythematous macules and flat targets* TEN with spots is characterized by an epidermal detachment ⬎30% of the body surface; widespread purpuric macules or flat atypical targets* TEN without spots is characterized by an epidermal detachment ⬎10% of the body surface; large epidermal sheets and without any macule or target*

EM, erythema multiforme; EMm, erythema multiforme minor; EMM, erythema multiforme major; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis. *Description of skin lesions: Typical targets: individual lesions less than 3-cm diameter with a regular round shape, well-defined border, and at least 3 different zones, that is, 2 concentric rings around a central disk. One ring consists of palpable edema, paler than the center disk. Raised atypical targets: round, edematous, palpable lesions, similar to EM but with only 2 zones and/or a poorly defined border. Flat atypical targets: round lesions characteristic of EM but with only 2 zones and/or a poorly defined border and nonpalpable with the exception of a potential central blister. Macules with or without blisters: nonpalpable, erythematous, or purpuric macules with an irregular shape and size and often confluent. Blisters often occur on all or part of the macule.

cosal involvement is uncommon and generally not severe.11-13 The cutaneous target lesions follow a symmetric distribution with a predilection for the extensor surfaces of the extremities.2,6,7 Less frequently, there can be involvement of the skin of the face or trunk.14 The Nikolsky’s sign is negative, and the lesions last for 1 to 3 weeks and heal without scarring to leave areas of hyperpigmentation and/or hypopigmentation.15 Prodromal symptoms are usually absent in most instances of the EM minor, but some patients may experience mild systemic symptoms such as fever or chills.13,16 When mucosal disease is present, it is usually limited to only 1 site, most commonly the mouth.9 Similarly, EM that only affects the oral mucosa does seem to arise.15,16 The oral lesions initially manifest with edema, erythema, and erythematous macules of the lips and buccal mucosa, followed by the development of multiple vesicles and bullae that quickly rupture and result in

pseudomembrane formation. The lips tend to become swollen and show diagnostically distinctive bloody encrustations (Fig. 2). Intact vesicles are rarely observed because they rapidly break down to form ill-defined ulcers. In EMm, there is usually a mild extension of erythematous patches or superficial erosions of the oral mucosa and the lip. Target lesions may be seen on the lip17 but rarely on the intraoral mucosa. EMM Erythema multiforme major spans a wide range of clinical presentations that include mucocutaneous involvement, ranging from severe EMm to mild SJS. Some authors have suggested that EMM differs from EMm by the involvement of at least 2 different mucosal sites,8,18 which typically includes the oral mucosa. The cutaneous involvement of EMM is usually less than 10% of the body surface but is generally more severe than that of EMm. Erythema multiforme major can be

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Fig. 1. Typical targets in a patient with erythema multiforme minor. Lesions have a regular round shape, well-defined border, and show 3 different zones consisting of two 3-concentric rings around a central disk. One ring consists of palpable edema and is paler than the center disk.

Fig. 2. Oral lesions in a child affected by erythema multiforme major. The lips are swollen and show bloody encrustations.

a self-limiting disease or be episodic or recurrent. Affected patients have symmetrically distributed typical cutaneous target lesions and/or atypical and raised target lesions that heal within 1 to 6 weeks.16 Infections tend to be the precipitants of EMM.2-4 Many variants of EMM have been described, including recurrent, persistent, or photosensitive EM.19-24 The oral mucosa is the most commonly involved mucosal surface but any mucosal site can be affected in the course of EMM, including the epithelium of the trachea, bronchi, or gastrointestinal tract.25-28 In EMM oral lesions are larger than that of EMm and in more than 50% of cases patients have ulceration of all oral mucosal surfaces. Multiple papules and vesicles are

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preceded by erythematous macules. The vesicles tend to rupture to leave multiple areas of superficial irregular erosions that are usually covered by a yellow fibrinous pseudomembrane.29,30,31 Eventually, multiple, large, shallow, irregular, painful ulcers surrounded by an erythematous margin and covered by whitish plaques of desquamated epithelium occur.32 They usually affect the lingual, buccal, and/or labial mucosa, and less frequently the floor of the mouth, palate, and the gingivae.29 Affected patients may have trismus, dysphonia, dysarthria, and/or dysphagia.4,33,34 The oral lesions of EMM usually heal without scarring, and in some instances there can be hyperkeratotic plaques mixed with erythematous areas.16 SJS Stevens-Johnson syndrome is a disorder characterized by sudden onset of erosions of the mucous membranes (predominantly the oral mucosa, lips, and conjunctivae) together with widespread blistering of the skin.32 Some authors still consider EMM and SJS to be the same disease1,8,35; however, the current literature describes EMM and SJS as distinct disorders. StevensJohnson syndrome comprises cutaneous disease affecting up to 10% of the body surface but gives rise to a more extensive disease than EMM because of mucosal involvement of 2 or more sites.4,6,36 Furthermore, the main difference between EMM and SJS is based upon the typology and location of lesions and the presence or absence of systemic symptoms.6,7,36 The skin lesions of SJS are primarily atypical flat target lesions and macules rather than classic target lesions, are more widespread (rather than involving only the acral areas), and can lead to significant percutaneous loss of fluid and electrolytes.37 Nikolsky’s sign is positive. Mucosal involvement is common in SJS, the oral, conjunctival, and genital mucosal surfaces being more extensively affected than in EMM.16 The oral lesions sometimes precede skin involvement by several days. The buccal mucosa, palate, and vermilion border are the most commonly affected sites. Mucosal blisters rapidly form and rupture to leave extensive irregular hemorrhagic erosions with grayish white pseudomembranes or shallow aphthous-like ulcers with hemorrhagic crusts of the lips.16 The oral lesions of SJS are extremely painful, causing dysphagia, breathing difficulties, and hypersalivation. The mucocutaneous lesions of SJS last for 2 to 6 weeks, and about one third of affected individuals have a prodromal symptom that includes fever, pharyngitis, headache, and arthralgias/myalgias, and rarely pneumonia, nephritis, or myocarditis.38 Of concern, there is a risk of scarring of mucosal lesions, which may lead to

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synechiae formation of the conjunctiva or laryngeal and/or vaginal strictures.9 A rare clinical variant of SJS includes subcorneal pustules.39 Although most cases of SJS are thought to be caused by drugs, infections may also trigger SJS. The mouth is almost always involved in SJS,40 and in severe disease the lesions extend to involve the nasal cavity, pharynx, larynx, and esophagus.41 Unlike EMm and EMM, the oral lesions of SJS usually heal with scaring.16 SJS/TEN overlap Patients with widespread macules or flat targets involving 10% to 30% of the skin surface and mucosal sites are considered to be affected by SJS/TEN overlap syndrome.6 Oral involvement resembles that of SJS. TEN Clinically, TEN is generally characterized by poorly defined erythematous macules, flat targets. In particular, TEN with spots with or without blisters is characterized by an epidermal detachment of at least 30% of the body surface, whereas TEN without spots is defined as having detachment grater than 10% of the body surface with large epidermal sheets and without any macule or target.6 Because of the extent of disease, TEN can clinically resemble second-degree superficial burns.41-43 The mucocutaneous lesions of TEN are usually preceded by fever, sore throat, skin tenderness, and anxiety.44,45 The onset of skin lesions (after the taking of the suspected causative agent) ranges from 1 to 16 days, with a mean of 4.1 days.46 Mucosal surfaces such as the oropharynx, esophagus, conjunctivae, and genitalia are commonly affected. Involvement of the colon, although unusual, may lead to necrosis and perforation.47 Toxic epidermal necrolysis usually develops suddenly and often has a poor prognosis, there being a 30% to 40% mortality rate.48,49 The oral lesions in TEN patients resemble those of SJS. EPIDEMIOLOGY Reliable epidemiological data of EM and related disorders are scarce, possibly reflecting the lack of a widely recognized classification system and the short duration of EMm and EMM not requiring hospital admission of the patient. The overall incidence of hospitalization for EMM, SJS, or TEN has been estimated to be 4.2 per 1 million person years.50 Stevens-Johnson syndrome is uncommon, perhaps occurring in 1 to 6 per 1 milllion population.50 Unlike recurrent EM, recurrence of SJS is unusual.51 The incidence of TEN has ranged from 1.3 cases per million in France,52 0.5 cases per million in the United States,35 0.89 in Germany,53 to 0.4 cases per million in Western Australia.54 The overall peak occurrences of EM and related disorders,

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apart from TEN, are in the second decade of life, with the majority of affected patients being young male adults.51 The mean age of SJS is 25 years, and 63 years for TEN,49 and in contrast to EM, there is a female to male ratio of 2:1 and 3:2 for SJS and TEN.49,54 It has been suggested that the prevalences of SJS and TEN are rising, perhaps as a consequence of continued or increased use of drug therapies.18 However, any rise in the frequency of SJS or TEN may also reflect an increase of clinical awareness and better recording of relevant data. ETIOLOGY EMm and EMM Erythema multiforme minor and EMM are often associated with preceding herpes simplex virus (HSV) infections, both HSV-1 and HSV-2 being considered to potentially give rise to EMm and EMM.55 In one study, it was reported that 71% of the EMm/EMM attacks were precipitated by a preceding HSV infection,23 particularly herpes labialis.56 Similar results were reported in a study which, using polymerase chain reaction, detected HSV-1 DNA in 66.7% of patients with EMm/ EMM and both HSV-1 and HSV-2 DNA in 5.6% of cases.57 Furthermore, HSV-DNA was found in acute recurrent EMm/EMM lesions and pigmented healed lesions of the skin several weeks after the attack.58 Overall, HSV is reported to be the single most common triggering factor of EMm/EMM56 and may account for most cases of EMm/EMM that are generally labeled as idiopathic.59 Typically, EMm/EMM lesions develop 10 to 14 days following clinical manifestations of HSV infection.60 The factors that may predispose to HSV-related EMm/EMM are unclear. HLA-DQ3 is strongly associated with herpes-associated EMm/EMM and has been proposed as a diagnostic marker in distinguishing EMm/EMM from other EM-like diseases. In addition, HLA-B15, -B35, -A33, -DR53, and -DQB1ⴱ0301 have been associated with recurrent EMm/EMM, suggesting a significant immunogenetic element in EMm/EMM pathogenesis. Aside from HSV infection, a wide range of other viral, bacterial, and fungal infections has also been implicated in triggering EMm/EMM (Table II).18 Current evidence suggests that EMm and EMM are mostly triggered by infectious agents, whereas SJS and TEN represent a separate group of disorders mainly associated with drugs as risk factors.2-4 However, food additives, chemicals, and drugs have also been reported as triggering factors18 of EMm/EMM. It is not clear if the drugs implicated in EMm/EMM differ significantly from those involved in SJS/TEN, as the different classification criteria can lead to confusion in distinguish-

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Table II. Infectious agents associated with EMm/EMM Viral agents HSV-1 HSV-2 Epstein-Barr virus Cytomegalovirus Varicella-zoster virus Adenoviruses Enteroviruses Hepatitis viruses Influenza virus Parvovirus B19 Poliovirus

Bacterial agents

Fungal agents

Parasites

Mycoplasma pneumoniae Borrelia burgdorferi Corynebacterium diphtheriae Streptococci Legionella pneumophila Salmonella Mycobacterium leprae Neisseria meningitides Mycobacterium avium complex Pneumococcus Proteus Pseudomonas Rickettsia Mycobacterium tuberculosis Vibrio parahaemolyticus Yersinia Chlamydia

Histoplasma capsulatum Coccidioides immitis

Trichomonas Toxoplasma gondii

EMm, erythema multiforme minor; EMM, erythema multiforme major.

Table III. Drugs reported to give rise to EM and related disorders* Associated drugs

Highly suspected drugs

Antibacterial Sulfonamides (trimethoprin-sulfamethoxazole), aminopenicillins, cephalosporins, quinolones, tetracyclines Anticonvulsants Phenobarbital, phenytoin, carbamazepine, valproic acid Nonsteroidal anti-inflammatory drugs Oxicam (piroxicam, tenoxicam) Antifungals Imidazole Other categories Allopurinol, chlormezanone, acetaminophen,† systemic cortico steroids

Antibacterial Sulfonamides (trimethoprin-sulfamethoxazole) Anticonvulsants Phenobarbital, phenytoin, carbamazepine, valproic acid Nonsteroidal anti-inflammatory drugs Oxicam (piroxicam, tenoxicam)

Other categories Allopurinol, chlormezanone

EM, erythema multiforme. *The window for relevant exposure restricted to 1 week before the index date except for drugs with long elimination half-life, for which 2 or 3 weeks were used. †In countries other than France.

ing between EMM, SJS, and TEN. A recent 6-year European prospective study identified 2 groups of drugs as the main potential triggers of EM and related disorders, these being defined as associated drugs or highly suspected drugs, on the basis of the relative risk associated with the use of specific drugs (Table III).2,61 SJS and TEN Current evidence suggests that drugs account at least for 50% of episodes of SJS62 and 95% of all TEN in adults.40,63-65 Infection may account for the remainder of instances of SJS and TEN, mainly in children, where the differentiation between infection-induced EMm/ EMM and drug-induced SJS/TEN is not as clear as that in adults.66 More than 120 different drugs have been reported as causal agents,67,68 and those with a higher

relative risk are listed in Table III. Geographic variations have been reported; in France, for example, antibiotics and analgesics are the most common drugs implicated,68 whereas in Malaysia anticonvulsants are the most frequent precipitants of SJS/TEN.62 There are also temporal variations in the drugs associated with SJS/TEN. For example, in India in the late 1980s antitubercular medication was the most common cause of TEN,69 whereas nowadays anticonvulsants are reported to be the most common causative group of drugs.70 The high prevalence of SJS and TEN among those receiving antibiotics may simply reflect their frequent use compared with other drugs.48,50 Indeed, in one study, 82% of cases of SJS and TEN could be attributed to a single drug, ␤-lactam antibiotics being the predominant group.71 Immunogenetic factors may influence suscep-

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Table IV. Nonpharmacological causative agents of SJS/TEN Agent Bacteria Viruses Fungus Systemic diseases

Yersinia, Streptococcus, typhoid fever, pneumococcus, enterobacteriaceae, Mycobacterium tuberculosis, brucellosis, tularaemia, Treponema pallidum, and Mycoplasma pneumoniae HSV-1 and HSV-2, herpes zoster, enterovirus, adenovirus, measles, mumps, HIV, HIV-2 influenza, Epstein-Barr virus, hepatitis A, B, and C Coccidioidomycosis, dermatophytosis, and histoplasmosis Lymphoma, leukemia, systemic lupus erythematosus, cholestatic liver disease, and graft-versus-host disease

SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; HSV, herpes simplex virus; HIV, human immunodeficiency virus.

tibility to drug-induced disease, for example, an association between the HLA-Bⴱ1502 allele and carbamazepine-induced SJS may reflect the incidence of SJS in persons of Han Chinese origin.72 However, there seems to be a subgroup of patients in whom a mild form of SJS is mainly related to infections, generally Mycoplasma pneumoniae but also HSV (Table IV). These patients are usually children and typically have a better prognosis than those affected by druginduced SJS.47,64-66,73-76 There have been rare reports of SJS/TEN associated with lymphoma,77 leukemia,78 systemic lupus erythematosus,79 cholestatic liver disease,80 and graft-versus-host disease81 (Table IV). It is unclear, however, whether TEN resulted from the allied disease or its treatment. An increased number of instances of TEN in human immunodeficiency virus (HIV)-related disease have been reported,18,82,83 this probably reflecting a deficiency of glutathione and a reduced capacity to detoxify drug metabolites such as the hydroxylamine derivatives of sulphamethoxazole.84 Indeed, sulfonamides commonly used for the treatment and prophylaxis of Pneumocystis carinii infection may underlie 30% of episodes of SJS/TEN in HIV-infected persons,85 and, more recently, both nucleoside reversetranscriptase and protease inhibitors of HIV have been reported to give rise to SJS/TEN.82 However, the clinical features of TEN are similar regardless of the presence or absence of HIV-related disease.86 PATHOGENESIS EMm and EMM The exact pathogenesis of EMm/EMM is unknown. It has been suggested that an immunologically mediated (i.e., lymphocytic) reaction to an infectious agent or drug leads to skin and mucosal lesions concentrated at the dermal-epithelial junction. Recent studies have provided a better understanding of the molecular and immunologic events underlying HSV-associated EMm/ EMM and their main differences with respect to druginduced EMm/EMM.87-89 Briefly, it is suggested that disease development begins with HSV infection of epithelial skin cells, and subsequently circulating mononuclear CD34⫹ cells (Langerhans cell precursors). The

latter transport the HSV-DNA fragments to distant skin sites, where an immunomediated epidermal damage through the production of interferon-␥ (IFN-␥) is initiated.88-90 In contrast to HSV-associated EMm/EMM, drug-associated EMm/EMM seems to involve CD8⫹ T-cell attack, and expression of tumor necrosis factor ␣ (TNF-␣) in lesional skin, in the absence of HSV DNA.88-89 In addition to a cellular immune response, humoral immune mechanisms may be involved in the pathogenesis of EM-like disease91,92 as a subpopulation of EM patients has been reported to have autoantibodies against desmoplakins I and II91 and antiepidermal autoantibodies.93 SJS and TEN Stevens-Johnson syndrome and TEN are characterized by apoptosis and necrosis of keratinocytes in the epidermis94 with separation of the epidermis from the underlying dermis, resulting in bullae. It remains controversial as to whether the apoptotic process is mediated by soluble mediators such as TNF-␣ nitric oxide, or cellular immune cells such as cytotoxic T cells.95 Several pathogenic mechanisms have been suggested to explain the extensive tissue necrosis of SJS and TEN, including altered drug metabolism96 or drug hypersensitivity reactions. It may be that hepatic cytochrome P450-dependent enzymes play a critical role in the formation of a drug-related antigen, which is then recognized as foreign by antigen-specific T cells.97 Certainly TEN may have an immunologically mediated basis as disease due to the fact that sulfonamide has been associated with HLA- A29, B12, and DR7, whereas oxicam-related TEN is associated with A2 and B12.98 Blisters within the necrotic epidermis of TEN contain large amounts of lymphocytes, which are predominantly activated T and NK cytotoxic cells.99101 The T lymphocytes present within the lesions of TEN exhibit, without any restimulation, a drug-specific cytotoxicity against autologous cells,102 and this, together with the serum cytokine profile of TEN patients,101 supports the notion that SJS and TEN may be immunologically mediated. Although the tar-

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Table V. Histopathological features of EM and related disorders EMm and EMM

SJS

TEN

Moderate to dense perivascular inflammatory infiltrate (CD4⫹ lymphocytes and histocytes) within the papillary dermis and along the dermoepidermal junction Dermal edema Intraepithelial/subepithelial vesicles and/or bullae Hydropic degeneration of basal keratinocytes Apoptotic keratinocytes Epithelial necrosis with and intercellular edema Eosinophilic infiltrate (might correlate with drug-associated forms, but also with age and duration of disease) Deposition of C3 and fibrin along the basement membrane and IgM, C3, and fibrin around blood vessels Full-thickness epithelial necrosis of the epidermis and mucous membranes Less perivascular dermal inflammation (CD4⫹ lymphocytes) than in EMm and EMM Orthohyperkeratosis and spongiosis Subepidermal blister Deposition of C3 and IgG along the basement membrane and around blood vessels Intercellular and/or intracellular edema Histopathology similar to SJS (keratinocyte necrosis with epidermal detachment from the underlying dermis) Subepidermal blisters Less perivascular dermal inflammation (CD4⫹ lymphocytes) than in EMm and EMM

EM, erythema multiforme; EMm, erythema multiforme minor; EMM, erythema multiforme major; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

get of any immunologically mediated attack is probably the epithelial keratinocyte, it may be that blood vessels are also affected.51 Of perhaps greatest relevance, it has been demonstrated that the cutaneous changes of SJS and TEN reflect keratinocyte apoptosis caused by interactions between cell death receptors and their ligand.44 In particular, activation of the cell receptors Fas (via FasL) and CD95R (via CD95RL) are important steps in causing diffuse apoptotic cell death of epidermal cells in SJS and TEN.44,94,103,104 Intracellular nitric oxide may be the ultimate mediator of the epidermal apoptosis and necrosis of SJS and TEN.105,106

role.113,117 The detection of intralesional HSV-DNA via polymerase chain reaction, as well as immunohistochemistry for IFN-␥ and TNF-␣, may be useful tests to differentiate herpes-associated EMm/EMM from drug-associated EMm/EMM and SJS.88 M pneumonia infection may be confirmed by a rising antibody titre between the acute and convalescent phases of EMM/ SJS; other less commonly employed tests are the MycoIgM test and radiolabeled DNA probe, the latter of which detects M pneumoniae ribosomal RNA.51 Lastly, it has been suggested that serum FasL levels may be a good indicator for the early diagnosis in TEN and SJS, but this assay is not available routinely.95

DIAGNOSIS There is no reliable laboratory-based mean of definitively diagnosing EM and related disorders. Diagnosis usually entails excluding other similar diseases by careful review of the clinical history and detailed clinical examination. Histopathological examination of lesional and perilesional tissue may reveal relevant features (summarized in Table V),3,9,16,53,99,107-113 but direct and indirect immunofluorescence is generally unhelpful other than to exclude other vesiculobullous disorders. A full blood count is usually not helpful, although in severe EM, SJS and TEN there is usually a rise in the erythrocyte sedimentation rate. Cutaneous patch testing may aid identification of causative agents114,115 as may rechallenge testing, although there is a risk of further disease.37,116 In vitro release of IFN-␥ and macrophage migration inhibition factor from peripheral blood lymphocytes may indicate a drug-specific immune response and possibly have some diagnostic

TREATMENT The treatment of EM, SJS, and TEN can be difficult. There are no available systematic reviews, and randomized controlled trials are scarce. A further difficulty is that diagnostic and classification criteria used in previous studies are often either different or unclear. Since the management of EMm is quite different from that of EMM, SJS and TEN, EMm therapy will be discussed separately. EMm In patients with cutaneous EMm, symptomatic treatment with antihistamines and topical corticosteroids may be sufficient. If the oral mucosa is affected, mouthwashes containing local anesthetic and mild antiseptic compounds may help in relieving painful oral symptoms. However, there are no detailed studies confirming that such a management protocol is reliably effective, and high-potency topical corticosteroids and short

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Table VI. Summary of management of EMM, SJS, and TEN Procedure

Comment

Withdrawal of causative drugs

Withdrawal of likely causative drug therapy can lessen morbidity and possibly mortality of SJS and TEN45 The identification of causative drugs in patients can be difficult Following the “length of exposure” rule can be helpful (i.e., drugs commenced in the last 7-21 days are likely culprits)61

Supportive care

Similar means to those used for cutaneous burns (i.e., environmental temperature control, careful and aseptic handling, sterile field creation, avoidance of any adhesive material, initiation of oral nutrition by nasogastric tube, and anticoagulation)6,130 Broad-spectrum antibiotics are generally required because 15%-45% of patients with SJS and TEN can die as a consequence of septicaemia6,130

Systemic corticosteroid therapy

Remains controversial (may not improve prognosis131 and may adversely affect the outcome by increasing the risk of infectious complications and delay healing)129,132-139

Noncorticosteroid immunosuppressive/ modulating regimens Azathioprine23 Cyclophosphamide140-142 Ciclosporin143-144 Mycophenolate mofetil24 Dapsone23,145 Interferon-alpha146,147 Anti-TNF-alpha agents Intravenous Immunoglobulins Plasmapheresis

Clinical benefit is variable Thalidomide has been associated with unexplained significant excess of mortality,148 but infliximab therapy may lessen disease progression and hasten resolution of skin lesions149,150 Intravenous immunoglobulin (⫾ plasmapheresis) may be of potential benefit but more detailed studies are warranted44,103,151-165 Effect of N-acetylcysteine166 and ulinastatin (a trypsin inhibitor) are unclear167

EM, erythema multiforme; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis.

courses of systemic prednisone have been reported to be very effective in controlling lesions of oral EMm.15 In patients with HSV-associated EMm, antiviral therapies have been reported to be of clinical benefit, particularly in preventing recurrences.60,118-121 A 5-day course of acyclovir (200 mg 5 times daily) at the onset of HSV infection was found to be useful as a preventive therapy in patients with recurrent HSV-related EMm.23 Furthermore, continuous low-dose systemic acyclovir therapy may completely suppress attacks of recurrent EMm, and in some cases may induce disease remission.12,122,123 In patients with postherpetic EMm resistant to acyclovir, valacyclovir has been reported to be effective.124 Nevertheless, HSV-associated EMm is known to recur after cessation of antiviral therapy. Sunscreens and zinc sulphate solution applied to the site of cutaneous HSV infection may also help in preventing relapses.21,125,126 EMM, SJS, and TEN Treatment of widespread cutaneous and mucosal lesions of EMM, SJS, and TEN often necessitates a multidisciplinary systemic management. Therapy has historically included systemic corticosteroids, corticosteroid-sparing immunosuppressive drugs, and hospital-based supportive and/or intensive care. In addition,

adequate topical therapy of necrotic skin and involved mucosal surfaces is important.9 However, detailed analysis of available therapeutic regimens is difficult due to the different diagnostic/classification criteria used in previous studies and the lack of well-performed clinical trials. As a consequence, the management of these conditions is often based upon the experience of a single center, as well as nonexperimental observational studies. It has been recommended that the optimal management of patients with significant skin loss should be in a burns unit23,46,126,127 with the treatment of the skin loss being similar to that of patients with burn injuries. The treatment of TEN differs markedly between burn units and general hospitals in their use of enteral nutrition, prophylactic antibiotics, corticosteroids, and wound management,126 all of which can influence the mortality rate.128 However, unlike fullthickness burns, the underlying dermis in SJS and TEN is intact and epidermal regrowth usually commences within 3 to 4 days with no need of epidermal grafts.129 Overall, the following aspects should be considered in management of EMM, SJS, and TEN patients: withdrawal of causative drugs,45,61 supportive care and antibiotics,6,130 systemic corticosteroids,129,131-139 and other immunosuppressants and immunomodulating agents23,140-167 (Table VI).

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LONG-TERM OUTCOME AND COMPLICATIONS EMm EM minor usually runs a mild clinical course, each episode lasting 2 to 3 weeks. Recurrence rates are highly variable, ranging from a few episodes of disease to rare long-term persistent EMm.24 The duration of recurrent EMm ranges between 2 and 36 years, with a mean of 9.5 years.19,32 EMM and SJS/TEN Severe EMM and SJS/TEN are less likely to recur than EMm but have much higher rates of associated morbidity and mortality.37,168 The mortality rate of severe EMM, SJS/TEN may be up to 15%,28 whereas that of TEN varies from 10% to 70%,48,49 with a mean rate of about 29%. At least half of all deaths in TEN are due to infection.33 Patients who survive after an episode of severe EMM, SJS and TEN often develop long-term complications that can significantly and permanently affect quality of life. Common complications include severe cutaneous and mucosal scarring, nail dystrophies, and esophageal stenosis leading to dysphagia and malnutrition. Ocular complications, including symblepharon, ectropion, keratoconjunctivitis sicca, and corneal opacification can arise and may warrant further medical and/or surgical treatments.37,43,45,52,169-175 The recently suggested SCORTEN system for the evaluation of TEN176 may prove to be a useful clinical tool in the assessment of patients prior to determining appropriate therapy, and hopefully, in the improvement of patient prognosis.151,176

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CONCLUSION Erythema multiforme minor, EMM, SJS, and TEN represent a spectrum of immunologically mediated disorders that are often precipitated by infection or drug therapy. The exact pathogenic mechanisms of each disorder remain unclear. Patients can sometimes have resolution of the disease with various immunosuppressive, antimicrobial, and supportive strategies. Severe disease, however, can still lead to significant long-term morbidity and mortality. As there remains no specific diagnostic test, early clinical recognition of disease remains essential to promptly initiate appropriate treatment.125 REFERENCES 1. Katz J, Livneh A, Shemer J, Danon YL, Peretz B. Herpes simplex-associated erythema multiforme (HAEM): a clinical therapeutic dilemma. Pediatr Dent 1999;21:359-62. 2. Auquier-Dunant A, Mockenhaupt M, Naldi L, Correia O, Schroder W, Roujeau JC, et al. Severe cutaneous adverse reactions. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens-Johnson syndrome, and

18. 19.

20.

21.

22. 23.

24.

25.

toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 2002;138:1019-24. Cote B, Wechsler J, Bastuji-Garin S, Assier H, Revuz J, Roujeau JC. Clinicopathologic correlation in erythema multiforme and Stevens-Johnson syndrome. Arch Dermatol 1995;131:1268-72. Assier H, Bastuji-Garin S, Revuz J, Roujeau JC. Erythema multiforme with mucous membrane involvement and StevensJohnson syndrome are clinically different disorders with distinct causes. Arch Dermatol 1995;131:539-43. Williams PM, Conklin RJ. Erythema multiforme: a review and contrast from Stevens-Johnson syndrome/toxic epidermal necrolysis. Dent Clin North Am 2005;49:67-76. Bastuji-Garin, Rzany B, Stern RS, Shear NH, Naldi L, Roujeau JC. Clincal classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993;129:92-6. Huff JC. Erythema multiforme. Dermatol Clin 1985;3:141-52. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8:763-5. Rappersberger K, Foedinger D. Treatment of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Dermatol Ther 2002;15:397-407. Sakurai M. Erythema multiforme in children: unusual clinical features with seasonal occurrence. J Dermatol 1989;16:361-8. Ginsburg CM. Stevens-Johnson syndrome in children. Pediatr Infect Dis 1982;1:155-8. Brice SL, Huff JC, Weston WL. Erythema multiforme. Curr Probl Dermatol 1990;2:3-12. Hurwitz S. Erythema multiforme: a review of its characteristics, diagnostic criteria, and management. Pediatr Rev 1990;11: 217-22. Micalizzi C, Farris A. Erythema multiforme along Blaschko’s lines. J Eur Acad Dermatol Venereol 2000;14:203-4. Lozada-Nur F, Gorsky M, Silverman S Jr. Oral erythema multiforme clinical observations and treatment of 95 patients. Oral Surg Oral Med Oral Pathol 1989;67:36-40. Ayangco L, Rogers RS 3rd. Oral manifestations of erythema multiforme. Dermatol Clin 2003;21:195-205. Weston WL, Morelli JG, Rogers M. Target lesions on the lips: childhood herpes simplex associated with erythema multiforme mimics Stevens-Johnson syndrome. J Am Acad Dermatol 1997;37:848-50. Farthing P, Bagan JV, Scully C. Mucosal disease series. Number IV. Erythema multiforme. Oral Dis 2005;11:261-7. Leigh IM, Mowbray JF, Levene GM, Sutherland S. Recurrent and continuous erythema multiforme–a clinical and immunological study. Clin Exp Dermatol 1985;10:58-67. Drago F, Parodi A, Rebora A. Persistent erythema multiforme: report of two new cases and review of literature. J Am Acad Dermatol 1995;33:366-9. Calzavara Pinton PG, Venturini M, Capezzera R, Zane C, Facchetti F. Photosensitive erythema multiforme and erythema multiforme-like polymorphous light eruption. Photodermatol Photoimmunol Photomed 2003;19:157-9. Huff JC, Weston WL. Recurrent erythema multiforme. Medicine (Baltimore) 1989;68:133-40. Schofield JK, Tatnall FM, Leigh IM. Recurrent erythema multiforme: clinical features and treatment in a large series of patients. Br J Dermatol 1993;128:542-5. Davis MD, Rogers RS 3rd, Pittelkow MR. Recurrent erythema multiforme/Stevens-Johnson syndrome response to mycophenolate mofetil. Arch Dermatol 2002;138:1547-50. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331:1272-85.

OOOOE Volume 103, Number 5 26. Sheridan RL, Schulz JT, Ryan CM, Schnitzer JJ, Lawlor D, Driscoll DN, et al. Long-term consequences of toxic epidermal necrolysis in children. Pediatrics 2002;109:74-8. 27. Al-Ubaidy SS, Nally FF. Erythema multiforme. Review of twenty-six cases. Oral Surg Oral Med Oral Pathol 1976;41: 601-6. 28. Kennett S. Erythema multiforme affecting the oral cavity. Oral Surg Oral Med Oral Pathol 1968;25:366-73. 29. Farthing PM, Maragou P, Coates M, Tatnall F, Leigh IM, Williams DM. Characteristics of the oral lesions in patients with cutaneous recurrent erythema multiforme. J Oral Pathol Med 1995;24:9-13. 30. Bean SF, Quezada RK. Recurrent oral erythema multiforme. Clinical experience with 11 patients. JAMA 1983;249:2810-2. 31. Gebel K, Hornestein OP. Drug-induced oral erythema multiforme. Results of a long-term retrospective study. Dermatologica 1984;168:35-40. 32. Zweiban B, Cohen H, Chandrasoma P. Gastrointestinal involvement complicating Stevens-Johnson syndrome. Gastroenterology 1986;91:469-74. 33. Edmond BJ, Hu JC, Weston WL. Erythema multiforme. Pediatr Clin N Am 1983;30:631-40. 34. Nethercott JR, Choi BCK. Erythema multiforme (Stevens-Johnson syndrome)-charts of 123 hospitalized patients. Dermatologica 1985;171:383-96. 35. Chan HL. Observations on drug-induced toxic epidermal necrolysis in Singapore. J Am Acad Dermatol 1984;10:973-8. 36. Roujeau JC. Stevens-Johnson syndrome and toxic epidermal necrolysis are severity variants of the same disease, which differs from: erythema multiforme. J Dermatol 1997;24:726-9. 37. Fritsch PO, Sidoroff A. Drug-induced Stevens-Johnson syndrome/toxic epidermal necrolysis. Am J Clin Dermatol 2000;1: 349-60. 38. Kasper M. Stevens-Johnson syndrome. Clin J Oncol Nurs 2001;5:25-6. 39. Sneddon IB. Subcorneal pustules in erythema multiforme. Br J Dermatol 1973;88:605-7. 40. Tay Y-K, Huff JC, Weston WL. Mycoplasma pneumoniae infection is associated with Stevens-Johnson syndrome, not erythema multiforme (Von Hebra). J Am Acad Dermatol 1996;35:757-60. 41. 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;25:1307-10. 42. Bachot N, Revuz J, Roujeau JC. Intravenous immunoglobulin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis: a prospective non-comparative study showing no benefit on mortality or progression. Arch Dermatol 2003; 139:33-6. 43. Ghislain PD, Roujeau JC. Treatment of severe drug reactions: Stevens-Johnson syndrome, toxic epidermal necrolysis and hypersensitivity syndrome. Dermatol Online J 2002;81:5. 44. 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. 45. 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. 46. Khoo AK, Foo CL. Toxic epidermal necrolysis in a burns centre: a 6-year review. Burns 1996;22:275-8. 47. Carter FM, Mitchell CK. Toxic epidermal necrolysis–an un-

Al-Johani et al. 651

48.

49. 50.

51.

52.

53.

54. 55.

56.

57.

58.

59.

60.

61.

62.

63.

64. 65.

66.

usual cause of colonic perforation. Report of a case. Dis Colon Rectum 1993;36:773-7. Chan HL, Stern RS, Arndt KA, Langlois J, Jick SS, Jick H, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. A population-based study with particular reference to reactions caused by drugs among outpatients. Arch Dermatol 1990;126:43-7. Schwartz RA. Toxic epidermal necrolysis. Cutis 1997;59: 123-8. Schopf E, Stuhmer A, Rzany B, Victor N, Zentgraf R, Kapp JF. Toxic epidermal necrolysis and Stevens-Johnson syndrome. An epidemiologic study from West Germany. Arch Dermatol 1991;127:839-42. Vanfleteren I, Van Gysel D, De Brandt C. Stevens-Johnson syndrome: a diagnostic challenge in the absence of skin lesions. Paediatric Dermatol 2003;20:52-6. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990;23:1039-58. Rzany B, Mockenhaupt M, Baur S, Schroder W, Stocker U, Mueller J, et al. Epidemiology of erythema exudativum multiforme majus, Stevens-Johnson syndrome, and toxic epidermal necrolysis in Germany (1990-1992): structure and results of a population-based registry. J Clin Epidemiol 1996;149:769-73. Brand R, Rohr JB. Toxic epidermal necrolysis in Western Australia. Australas J Dermatol 2000;41:31-3. Goldberg LH, Sperber J. Erythema multiforme due to herpes simplex: treatment with oral acyclovir. South Med J 1986; 79:757-9. Kokuba H, Imafuku S, Huang S, Aurelian L, Burnett JW. Erythema multiforme lesions are associated with expression of a herpes simplex virus (HSV) gene and qualitative alterations in the HSV-specific T-cell response. Br J Dermatol 1998; 138:952-64. Sun Y, Chan RK, Tan SH, Ng PP. Detection and genotyping of human herpes simplex viruses in cutaneous lesions of erythema multiforme by nested PCR. J Med Virol 2003;71:423-8. Imafuku S, Kokuba H, Aurelian L, Burnett J. Expression of herpes simplex virus DNA fragments located in epidermal keratinocytes and germinative cells is associated with the development of erythema multiforme lesions. J Invest Dermatol 1997;109:550-6. Brice SL, Krzemien D, Weston WL, Huff JC. Detection of herpes simplex virus DNA in cutaneous lesions of erythema multiforme. J Invest Dermatol 1989;74:372-4. Lemak MA, Duvic M, Bean SF. Oral acyclovir for the prevention of herpes-associated erythema multiforme. J Am Acad Dermatol 1986;15:50-4. Roujeau JC, Kelly JP, Naldi L, Rzany B, Stern RS, Anderson T, et al. Medication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333:1600-7. Kamaliah MD, Zainal D, Mokhtar N, Nazmi N. Erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis in northeastern Malaysia. Int J Dermatol 1998; 37:520-3. Leaute-Labreze, T Lamireau, D Chawki, J Maleville, A Taïeb. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnsonn syndrome. Arch Dis Child 2000; 83:347-52. Yung A, Agnew K, Snow J, Oliver F. Two unusual cases of toxic epidermal necrolysis. Australas J Dermatol 2002;43:35-8. Hockett KC. Stevens-Johnson syndrome and toxic epidermal necrolysis: oncologic considerations. Clin J Oncol Nurs 2003; 8:27-30. Leaute-Labreze C, Lamireau T, Chawki D, Maleville J, Taieb

652

67.

68.

69. 70.

71.

72.

73.

74.

75.

76.

77. 78.

79.

80. 81.

82.

83.

84.

85.

86.

87.

OOOOE May 2007

Al-Johani et al. A. Diagnosis, classification, and management of erythema multiforme and Stevens-Johnson syndrome. Arch Dis Child 2000; 83:347-52. 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;123:1166-70. Roujeau JC, Chosidow O, Saiag P, Guillaume JC. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990;23:1039-58. Nanda A, Kaur S. Drug-induced toxic epidermal necrolysis in developing countries. Arch Dermatol 1990;126:125. Kanwar AJ, Dogra S, Kumar B. Changing pattern of druginduced toxic epidermal necrolysis in developing countries. Clin Exp Dermatol 2004;29:425-6. Wong KC, Kennedy PJ, Lee S. Clinical manifestations and outcomes in 17 cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Australas J Dermatol 1999;40:131-4. Chung WH, Hung SI, Hong HS, Hsih MS, Yang LC, Ho HC, et al. Medical genetics: a marker for Stevens-Johnson syndrome. Nature 2000;1:428-86. Larregue M, Pouvreau A, Prigent F, Lorette G, Canuel C. Stevens-Johnson syndrome and pulmonary infection by Mycoplasma pneumonia. Sem Hop 1982;58:478-84. Kalb RE, Grossman ME, Neu HC. Stevens-Johnson syndrome due to Mycoplasma pneumoniae in an adult. Am J Med 1985;79:541-4. Salmon P, Rademaker M. Erythema multiforme associated with an outbreak of Mycoplasma pneumoniae function. N Z Med J 1993;106:449-50. Levy M, Shear NH. Mycoplasma pneumoniae infections and Stevens-Johnson syndrome. Report of eight cases and review of the literature. Clin Pediatr (Phila) 1991;30:42-9. Stawiski MA, Ross LR. Toxic epidermal necrolysis and mixed histiolymphocytic lymphoma. Cutis 1981;28:286-9. Hsiao LT, Chung HM, Lin JT, Chiou TJ, Liu JH, Fan FS, et al. Stevens-Johnson syndrome after treatment with STI571: a case report. Br J Haematol 2002;117:620-2. Samimi SS, Siegfried E. Stevens-Johnson syndrome developing in a girl with systemic lupus erythematosus on high-dose corticosteroid therapy. Pediatr Dermatol 2002;19:52-5. Morelli MS, O Brien FX. Stevens-Johnson Syndrome and cholestatic hepatitis. Dig Dis Sci 2001;46:2385-8. Takeda H, Mitsuhashi Y, Kondo S, Kato Y, Tajima K. Toxic epidermal necrolysis possibly linked to hyperacute graft-versushost disease after allogeneic bone marrow transplantation. J Dermatol 1997;24:635-41. Rotunda A, Hirsch RJ, Scheinfeld N, Weinberg JM. Severe cutaneous reactions associated with the use of human immunodeficiency virus medications. Acta Derm Venereol 2003;83:1-9. Cattelan AM, Trevenzoli M, Sasset L, Sgarabotto D, Lanzafame M, Meneghetti F. Toxic epidermal necrolysis induced by nevirapine therapy: description of two cases and review of the literature. J Infect 2001;43:246-9. Van der Ven AJ, Koopmans PP, Vree TB, van der Meer JW. Adverse reactions to co-trimoxazole in HIV infection. Lancet 1991;338:431-3. Saiag P, Caumes E, Chosidow O, Revuz J, Roujeau JC. Druginduced toxic epidermal necrolysis (Lyell syndrome) in patients infected with the human immunodeficiency virus. J Am Acad Dermatol 1992;26:567-74. Pacheco H, Araujo T, Kerdel F. Toxic epidermal necrolysis in a pregnant, HIV-infected woman. Int J Dermatol 2002;41: 600-1. Ono F, Sharma BK, Smith CC, Burnett JW, Aurelian L.

88.

89.

90.

91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

CD34⫹ cells in the peripheral blood transport herpes simplex virus DNA fragments to the skin of patients with erythema multiforme (HAEM). J Invest Dermatol 2005;124:1215-24. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J 2003;9:1. Kokuba H, Aurelian L, Burnett J. Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions. J Invest Dermatol 1999;113:808-15. Spandau U, Brocker EB, Kampgen E, Gillitzer R. CC and CXC chemokines are differentially expressed in erythema multiforme in vivo. Arch Dermatol 2002;138:1027-33. Foedinger D, Anhalt G, Boecskoer B, Elbe A, Wolff K, Rappersberger K. Autoantibodies to desmoplakin I and II in patients with erythema multiforme. J Exp Med 1995;181: 169-79. Foedinger D, Elbe-Burger A, Sterniczky B, Lackner M, Horvat R, Wolff K, et al. Erythema multiforme associated human autoantibodies against desmoplakin II and I: biochemical characterization and passive transfer studies into newborn mice. J Invest Dermatol 1998;111:503-10. Matsuoka LY, Wortsman J, Stanley JR. Epidermal autoantibodies in erythema multiforme. J Am Acad Dermatol 1989;21: 677-80. Paul C, Wolkenstein P, Adle H, Wechsler J, Garchon JH, Revuz J, et al. Apoptosis as a mechanism of keratinocyte death in toxic epidermal necrolysis. Br J Dermatol 1996;134:710-4. 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. Friedmann PS, Strickland I, Pirmohamed M, Park BK. Investigation of mechanisms in toxic epidermal necrolysis induced by carbamazepine. Arch Dermatol 1994;130:598-604. Hertl M, Jugert F, Merk HF. CD8⫹ dermal T-cells from a sulfamethoxazole-induced bullous exanthem proliferate in response to drug-modified liver microsomes. Br J Dermatol 1995;132:215-20. Roujeau JC, Huynh TN, Bracq C, Guillaume JC, Revuz J, Touraine R. Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol 1987;123:1171-3. Correia O, Delgado L, Ramos JP, Resende C, Flemming Torrinha JA. Cutaneous T-cell recruitment in toxic epidermal necrolysis. Further evidence of CD8⫹ lymphocyte involvement. Arch Dermatol 1993;129:466-8. Le Cleach L, Delaire S, Boumsell L, Bagot M, BougaultVillada I, Bensussan A, et al. Blister fluid T lymphocytes during toxic epidermal necrolysis are functional cytotoxic cells, which express human natural killer (NK) inhibitory receptors. Clin Exp Immunol 2000;119:225-30. Correia O, Delgado L, Barbosa IL, Campilho F, FlemingTorrinha J. Increased interleukin 10, tumor necrosis factor alpha, and interleukin 6 levels in blister fluid of toxic epidermal necrolysis. J Am Acad Dermatol 2002;47:58-62. Nassif A, Bensussan A, Dorothee G, Mami-Chouaib F, Bachot N, Bagot M, et al. Drug specific cytotoxic T-cells in the skin lesions of a patient with toxic epidermal necrolysis. J Invest Dermatol 2002;118:728-33. 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.

OOOOE Volume 103, Number 5 104. Wehrli P, Viard I, Bullani R, Tschopp J, French LE. Death receptors in cutaneous biology and disease. J Invest Dermatol 2000;115:141-8. 105. Snyder SH, Bredt DS. Biological roles of nitric oxide. Sci Am 1992;266:68-77. 106. Chlichlia K, Peter ME, Rocha M, Scaffidi C, Bucur M, Krammer PH, et al. Caspase activation is required for nitric oxide-mediated, CD95 (APO-1/Fas)-dependent and independent apoptosis in human neoplastic lymphoid cells. Blood 1998; 91:4311-20. 107. Paquet P, Pierard GE. Erythema multiforme and toxic epidermal necrolysis: a comparative study. Am J Dermatopathol 1997;19:127-32. 108. Bedi TR, Pinkus H. Histopathological spectrum of erythema multiforme. Br J Dermatol 1976;95:243-50. 109. Larcher C, Gasser A, Hattmannstorfer R, Obexer P, Furhapter C, Fritsch P, et al. Interaction of HSV-1 infected peripheral blood mononuclear cells with cultured dermal microvascular endothelial cells: a potential model for the pathogenesis of HSV-1 induced erythema multiforme. J Invest Dermatol 2001; 116:150-6. 110. Patterson JW, Parsons JM, Blaylock WK, Mills AS. Eosinophils in skin lesions of erythema multiforme. Arch Pathol Lab Med 1989;113:36-9. 111. Howland WW, Golitz LE, Weston WL, Huff JC. Erythema multiforme: clinical, histopathologic, and immunologic study. J Am Acad Dermatol 1984;10:438-46. 112. Nishida K, Yamanishi K, Yamada K, Dota A, Kawasaki S, Quantock AJ, et al. Epithelial hyperproliferation and transglutaminase 1 gene expression in Stevens-Johnson syndrome conjunctiva. Am J Pathol 1999;154:331-6. 113. Halevy S, Cohen AD, Livni E. The diagnostic role of the in vitro drug-induced interferon-gamma release test in StevensJohnson syndrome. Int J Dermatol 1999;38:835-40. 114. Wolkenstein P, Chosidow O, Flechet ML, Robbiola O, Paul M, Dume L, et al. Patch testing in severe cutaneous adverse drug reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Contact Dermatitis 1996;35:234-6. 115. Shimizu S, Chen KR, Pratchyapruit WO, Shimizu H. Tropicalwood-induced bullous erythema multiforme. Dermatology 2000; 200:59-62. 116. Halevi A, Ben-Amitai D, Garty BZ. Toxic epidermal necrolysis associated with acetaminophen ingestion. Ann Pharmacother 2000;34:32-4. 117. Livni E, Lapidoth M, Halevy S. In vitro release of interferongamma and macrophage migration inhibition factor in druginduced urticaria and angioedema. Acta Derm Venereol 1999; 79:18-22. 118. Green JA, Spruance SL, Wenerstrom G, Piepkorn MW. Postherpetic erythema multiforme prevented with prophylactic oral acyclovir. Ann Intern Med 1985;102:632-3. 119. Lynn WA, Davidson RN, Wansbrough-Jones MH. Successful use of oral acyclovir to prevent herpes simplex-associated erythema multiforme. J Infect 1987;15:192-3. 120. Choy AC, Yarnold PR, Brown JE, Kayaloglou GT, Greenberger PA, Patterson R. Virus induced erythema multiforme and StevensJohnson syndrome. Allergy Proc 1995;16:157-61. 121. Cheriyan S, Patterson R. Recurrent Stevens-Johnson syndrome secondary to herpes simplex: a follow up on a successful management program. Allergy Asthma Proc 1996;17:71-3. 122. Tatnall FM, Schofield JK, Leigh IM. A double-blind, placebocontrolled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 1995;132:267-70. 123. Molnar I, Matulis M. Arthritis associated with recurrent ery-

Al-Johani et al. 653

124.

125.

126.

127.

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

thema multiforme responding to oral acyclovir. Clin Rheumatol 2002;21:415-7. Kerob D, Assier-Bonnet H, Esnault-Gelly P, Blanc F, Saiag P. Recurrent erythema multiforme unresponsive to acyclovir prophylaxis and responsive to valacyclovir continuous therapy. Arch Dermatol 1998;134:876-7. Brody I. Topical treatment of recurrent herpes simplex and post-herpetic erythema multiforme with low concentrations of zinc sulphate solution. Br J Dermatol 1981;104:191-4. 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. Jackel R, Fuchs M, Raff T, Wiedemann B. Drug-induced toxic epidermal necrolysis with involvement of the intestinal and respiratory tract. A case report. Anaesthesist 2002;51:815-9. 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. Kelemen JJ 3rd, Cioffi WG, McManus WF, Mason AD, Pruitt BA. Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995;180:273-8. Ruiz-Maldonado R. Acute disseminated epidermal necrolysis types 1, 2, and 3. Study of sixty cases. J Am Acad Dermatol 1985;13:623-5. Rzany B, Schmitt H, Schopf E. Toxic epidermal necrolysis in patients receiving glucocorticosteroids. Acta Derm Venereol 1991;71:171-2. Revuz J, Roujeau J-C, Guillaume J-C, Penso D, Touraine R. Treatment of toxic epidermal necrolysis. Creteil’s experience. Arch Dermatol 1987;123:1156-8. 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. Patterson R, Dykewicz MS, Gonzalzles A, Grammer LC, Green D, Greenberger PA, et al. Erythema multiforme and StevensJohnson syndrome. Descriptive and therapeutic controversy. Chest 1990;98:331-6. Spies M, Sanford AP, Aili Low JF, Wolf SE, Herndon DN. Treatment of extensive toxic epidermal necrolysis in children. Pediatrics 2001;108:1162-8. Prendiville JS, Hebert AA, Greenwald MJ, Esterly NB. Management of Stevens-Johnson syndrome and toxic epidermal necrolysis in children. J Pediatr 1989;115:881-7. Avakian R, Flowers F, Araujo OE, Ramos-Caro FA. Toxic epidermal necrolysis: a review. J Am Acad Dermatol 1991; 25:69-79. 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. Guibal G, 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;131:669-72. Heng MC, Allen SG. Efficacy of cyclophoshamide in toxic epidermal necrolysis: clinical and pathophysiologic aspects. J Am Acad Dermatol 1991;25:778-86. 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. Trautmann A, Klein CE, Kampgen E, Brocker EB. Severe bullous drug reactions treated successfully with cyclophosphamide. Br J Dermatol 1998;139:1127-8.

654

OOOOE May 2007

Al-Johani et al.

143. Arevalo JM, Lorente JA, Gonzales-Herrada C, Jimenez-Reyes J. Treatment of toxic epidermal necrolysis with cyclosporin A. J Trauma 2000;48:473-8. 144. Robak E, Robak T, Gora-Tybor J, Chojnowski K, Strzelecka B, Waszczykowska E, et al. Toxic epidermal necrolysis in a patient with severe aplastic anemia treated with cyclosporin A and G-CSF. J Med 2001;32:31-9. 145. Mahendran R, Grant JW, Norris PG. Dapsone-responsive persistent erythema multiforme. Dermatology 2000;200:281-2. 146. Berard F, Pincemaille B, Charhon A, Perrot H. Persistent erythema multiforme associated with chronic hepatitis C virus infection. Efficacy of interferon alpha. Ann Dermatol Venereol 1997;124:329-31. 147. Dumas V, Thieulent N, Souillet Al, Jullien D, Faure M, Claudy A. Recurrent erythema multiforme and chronic hepatitis C: efficacy of interferon alpha. Br J Dermatol 2000;142:1248-9. 148. 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. 149. 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. 150. Hunger RE, Hunziker T, Buettiker U, Braathen LR, Yawalkar N. Rapid resolution of toxic epidermal necrolysis with antiTNF-alpha treatment. J Allergy Clin Immunol 2005;116:923-4. 151. Prins C, Kerdel FA, Padilla RS, Hunziker T, Chimenti S, Viard I, et al. Treatment of toxic epidermal necrolysis with high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 2003;139:26-32. 152. Hebert AA, Bogle MA. Intravenous immunoglobulin prophylaxis for recurrent Stevens-Johnson syndrome. J Am Acad Dermatol 2004;50:286-8. 153. 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. 154. Claes P, Wintzen M, Allard S, Simons P, De Coninck A, Lacor P. Nevirapine-induced toxic epidermal necrolysis and toxic hepatitis treated successfully with a combination of intravenous immunoglobulins and N-acetylcysteine. Eur J Intern Med 2004;15:255-8. 155. Stella M, Cassano P, Bollero D, Clemente A. Toxic epidermal necrolysis treated with intravenous high-dose immunoglobulins: our experience. Dermatology 2001;203:45-9. 156. Paquet P, Jacob E, Damas P, Pierard GE. Treatment of druginduced toxic epidermal necrolysis (Lyell’s syndrome) with intravenous human immunoglobulins. Burns 2001;27:652-5. 157. 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. 158. Bachot N, Roujeau JC. Intravenous immunoglobulins in the treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol 2003;3:269-74. 159. Schifferli J, Leski M, Favre H, Imbach P, Nydegger U, Davies K. High-dose intravenous IgG treatment and renal function. Lancet 1991;337:457-8. 160. Stahl M, Schifferli JA. The renal risks of high-dose intravenous immunoglobulin treatment. Nephrol Dial Transplant 1998; 13:2182-5. 161. Matsumoto Y, Naniwa D, Banno S, Sugiura Y. The efficacy of therapeutic plasmapheresis for the treatment of fatal hemophagocytic syndrome: two case reports. Ther Apher 1998;2:300-4.

162. 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. 163. 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. 164. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmapheresis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol 1985;121:1548-9. 165. Lissia M, Figus A, Rubino C. Intravenous immunoglobulins and plasmapheresis combined treatment in patients with severe toxic epidermal necrolysis: preliminary report. Br J Plast Surg 2005;58:504-10. 166. Velez A, Moreno JC. Toxic epidermal necrolysis treated with N-acetylcysteine. J Am Acad Dermatol 2002;46:469-70. 167. Inamo Y, Okubo T, Wada M, Fuchigami S, Hashimoto K, Fuchigami T, et al. Intravenous ulinastatin therapy for StevensJohnson syndrome and toxic epidermal necrolysis in pediatric patients. Three case reports. Int Arch Allergy Immunol 2002; 127:89-94. 168. Ringheanu M, Laude TA. Toxic epidermal necrolysis in children-an update. Clin Pediatr (Phila) 2000;39:687-94. 169. Rottermann EM, Julia MV, Rovira J, Pari FJ, Morales L. Esophageal stenosis following Stevens-Johnson syndrome. Treatment with balloon dilation. Clin Pediatr (Phila) 1990; 29:336-8. 170. Power WJ, Ghoraishi M, Merayo-Lloves J, Neves RA, Foster CS. Analysis of the acute ophthalmic manifestations of the erythema multiforme/ Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum. Ophthalmology 1995;102: 1669-76. 171. Lebargy F, Wolkenstein P, Gisselbrecht M, Lange F, FleuryFeith J, Delclaux C, et al. Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study. Intensive Care Med 1997;23:1237-1244. 172. Forman R, Koren G, Shear NH. Erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis in children: a review of 10 years’ experience. Drug Saf 2002;25:965-72. 173. Dawe S, Bentley R, Creamer D. Toxic epidermal necrolysis complicated by delayed mucosal healing and haemorrhagic mucositis. Clin Exp Dermatol 2003;28:454-5. 174. Magina S, Lisboa C, Leal V, Palmares J, Mesquita-Guimaraes J. Dermatological and ophthalmological sequels in toxic epidermal necrolysis. Dermatology 2003;207:33-6. 175. Agrawal A, Bramble MG, Shehade S, Dean J. Oesophageal stricturing secondary to adult Stevens-Johnson syndrome: similarities in presentation and management to corrosive injury. Endoscopy 2003;35:454-6. 176. 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: 149-153.

Reprint requests: Stephen Porter, PhD, MD, FDSRCS, FDSRCSE Oral Medicine Unit UCL Eastman Dental Institute for Oral Health Care Sciences 256 Gray’s Inn Road London WC1X 8LD, UK [email protected]