Erythema multiforme and toxic epidermal necrolysis

Erythema multiforme and toxic epidermal necrolysis
Toshiroh Iwasaki, DVM, PhD, Dip AICVD
Tokyo University of Agriculture & Technology
Fuchu, Japan
Erythema multiforme (EM) and Stevens-Johnson syndrome (SJS) are rare human and animal skin disorders
with or without mucous membrane involvement. Toxic epidermal necrolysis (TEN) has been considered as a
severe form of EM or SJS, but at the present time there are no generally accepted clinical and diagnostic
criteria for the distinction between SJS and TEN. 7 EM is further classified into two categories, EM minor or
major, depending on the existence of mucocutaneous lesions.
Classification of EM/SJS/TEN in veterinary medicine
In an article in 1998, EM/SJS/TEN in dogs was classified through the adoption of a human international
consensus clinical classification system. 3 In this article, cases of EM/SJS/TEN were sub-classified into EM
minor, EM major, SJS, SJS/TEN overlap syndrome and TEN based on the following signs: (1) flat or raised,
focal or multi-focal, target or polycyclic lesions; (2) number of mucosal surfaces involved; (3) erythematous,
pruritic, macular or patch eruption (% of body surface); and (4) epidermal detachment (% of body surface).
According to the adoption of the human international classification system, canine EM cases are usually not
associated with a history of drug exposure, while SJS, overlap syndrome and TEN are usually related to the
3, 4, 8
administration of drugs.
In human medicine, EM minor, which exhibits as indurated erythema in the extremities, is the most common
form of EM/SJS/TEN, whereas EM in dogs is recognised by dermatologists to be mainly EM major or SJS. 2
Canine EM minor usually manifests as slight cutaneous changes, like peripherally raised focal erythema,
without symptoms, that are often hidden by hair. Therefore many of these cases may have been overlooked
by owners and veterinarians. That might be one of the reasons why the occurrence of EM minor in dogs is
much less frequently diagnosed than that in humans. 8
Clinical signs of EM/SJS/TEN
There have been no reports of predilection based on gender, breed or age. 7 Cutaneous presentation of EM
presents as annular, erythematous macula, papules and plaques which become enlarged from the centre and
often form a bizarre polycystic pattern. 8 Target lesions become vesicular or bullous and then become
necrotic, before finally forming ulcers. The lesions are often distributed around the oral mucous membrane,
tongue, axilla, ventral abdomen, groin and central dorsal regions.
Histopathology of EM/SJS/TEN
The histopathology of EM/SJS/TEN in dogs includes interface dermatitis with marked apoptosis of
keratinocytes at all levels of the epithelium and hair follicles. 7,8 Mononuclear cell infiltration into the
epidermis and/or mucous membrane epithelium and dermis were more intense in the SJS/TEN group than
the EM minor and major groups. 3 A large scale study implicated that histopathological examination should
be restricted to confirmation of the diagnosis of diseases in the EM/TEN group, but not to subcategorise the
different entities. 3
Pathogenesis of EM/SJS/TEN
In the only article that examined canine EM by immunohistochemistry, the expression of the infiltrates and
keratinocytes was investigated. 1 The intra-epithelial infiltrates were CD3 + , CD8αβ + , and TCRαβ + T cells.
CD1 + and CD11c + Langerhans cells were more numerous, whereas infiltrating cells in the dermis consisted
of CD3 + , CD8αβ + and TCRαβ + T cells. 1 In dogs, it is believed that keratinocyte apoptosis is probably
induced by signals from intraepithelial CD8 + T lymphocytes. 8 Noli et al. implies that the cause of the
massive epidermal cell necrosis in TEN is not immune mediated, but toxic, and was observed by the staining
of apoptotic cells in EM and TEN cases. 6
A recent article regarding human SJS/TEN expressed that keratinocyte apoptosis was triggered by drugspecific
cytotoxic T lymphocytes using perforin/granzyme B. 2 Fas-mediated apoptosis may contribute to the
extent of keratinocyte death, but it remains controversial whether the membrane-bound or the soluble form of
Fas is responsible, and the cellular source from which it originates. 9 Cytokines produced by T lymphocytes,
macrophages, and possibly by keratinocytes themselves are thought to contribute to the pathogenesis of the
SJS/TEN spectrum. 2
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EM/SJS/TEN therapy
The most important factor in the therapy of EM/SJS/TEN is investigation and elimination of the triggering
factors. 5, 8 When this is accomplished, the symptoms are usually resolved within 1–2 weeks. 8 In idiopathic
cases of EM/SJS/TEN, a large dose of glucocorticoids with azathioprine and/or cyclosporine A may improve
clinical signs. However, in human medicine, the use of glucocorticoids for treatment of EM/SJS/TEN has
been controversial as their use may elicit systemic infection. 2, 9 The use of human immunoglobulin by
intravenous injection for the treatment of canine SJS/TEN is thought to be beneficial for the treatment of the
condition. 5
References
1. Affolter VK, Moore PF, Sandmaier BM. Immunohistochemical characterization of canine acute graft-versus-host
disease and erythema multiforme. Advances in Veterinary Dermatology 1998; 3:103-115
2. Borchers AT, Lee JL, Naguwa SM, Cheema GS, Gershwin E. Stevens-Johnson syndrome and toxic epidermal
necrolysis. Autoimmunity Reviews. 2008; 7: 598-605
3. Hinn AC, Olivry T, Luther PB, Cannon AG, Yager JA. Erythema multiforme, Stevens-Johnson syndrome, and toxic
epidermal necrolysis in the dog; Clinical presentation, drug exposure, and histopathologic correlations. Journal of
Veterinary Allergy and Clinical Immunology 1998; 6:13-
4. Mason K, Fadok V. Cutaneous drug eruption with epidermal necrosis: A discussion of pathophysiologic and
comparative aspects. Clinics in Dermatology 1994; 12: 525-528
5. Noli C, von Tscharner C, Suter M. Apoptosis in selected skin diseases. Veterinary Dermatology 1998; 9: 221-229
6. Nuttal TJ, Malham T. Successful intravenous human immunoglobulin treatment of drug-induced Stevens-Johnson
syndrome in a dog. Journal of Small Animal Dermatology 2004; 45: 357-361
7. Scott DW, Miller W, Griffin C. Erythema multiforme. In: Small Animal Dermatology 6 th ed. Philadelphia Saunders,
2001: 732-742
8. Scott DW, Miller W. Erythema multiforme in dogs and cats: literature review and case material from the Cornell
University College of Veterinary Medicine (1988-1996), Veterinary Dermatology 1999; 10: 297-309
9. Sontheimer RD. Lichenoid tissue reaction/interface dermatitis: Clinical and histological perspectives. Journal of
Investigative Dermatology 2009; 129: 1088-1099
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