Vet Dermatol 2014; 25: 406–e64 DOI: 10.1111/vde.

12142

Erythema multiforme, Stevens–Johnson syndrome and

toxic epidermal necrolysis: a comparative review
Julie A. Yager
Department of Pathobiology, University of Guelph, Guelph, Ontario, Canada, N1G2W1
Correspondence: Julie A. Yager, PO Box 66, Rockwood, Ontario, Canada N0B 2K0. E-mail: julieayager@gmail.com

Background – Human erythema multiforme (EM) and Stevens–Johnson syndrome/toxic epidermal necrolysis
(SJS/TEN) are separate conditions. There is no consensus on classification criteria for the eponymous diseases in
animals.
Results – Animal EM is very different from 90% of human EM, which is herpes virus associated (HAEM). Animals
lack acrally distributed, typical raised targets. Unlike canine parvovirus ‘EM’, HAEM is not an active infection. Ani-
mal EM is often attributed to drugs, but this is rarely proved. Conversely, human and animal SJS/TEN are almost
identical, life-threatening disorders of epidermal necrosis and detachment, typically triggered by drugs (occasionally
by infectious agents). Both EM and SJS/TEN are mediated by cytotoxic lymphocyte responses against altered
keratinocytes (infectious agents or drugs). Apoptosis results from direct cytotoxicity or through soluble mediators,
namely Fas ligand, granzymes, perforin and granulysin. Diagnosis in humans is clinicopathological, with emphasis
on clinical lesions; histopathology confirms the pathological process as interface (cytotoxic) dermatitis. Human EM
is self-limiting; only recurrent and rare persistent cases require antiviral/immunosuppressive therapies. Drug-
induced EM responds to drug withdrawal. Idiopathic canine EM (>40%) is usually chronic, refractory to treatment
and may represent heterogeneous conditions. Early identification and removal of the causative drug and high-qual-
ity supportive care are critical in SJS/TEN. Mortality rate is nevertheless high.
Conclusions and clinical importance – (1) Histopathological lesions do not reliably differentiate EM, SJS and
TEN. (2) A multicentre study to develop a consensus set of clinical criteria for EM and SJS/TEN in animals is over-
due. (3) No adjunctive therapies, including intravenous immunoglobulin and ciclosporin, have met evidence-based
standards.

Abbreviations FeLV feline leukaemia virus

ACLE acute cutaneous lupus erythematosus FHV-1 feline herpes virus 1
AGEP acute generalized exanthematous pustulosis Foxp3 forkhead boxP3
ALDEN algorithm for assessment of drug causality G-CSF granulocyte colony-stimulating factor
ASAP acute syndrome of apoptotic pan-epidermolysis HAEM herpes-associated erythema multiforme
CADR cutaneous adverse drug reaction HLA human lymphocyte antigen
CCL2 chemokine (C-C motif) ligand 2 (previously HSV herpes simplex virus
MCP-1) ICAM-1 intercellular adhesion molecule 1
CCL5 chemokine (C-C motif) ligand 5 (previously IFN-c interferon-c
RANTES) iNOS inducible nitric oxidase
CLA cutaneous lymphocyte antigen La/SS-B Lupus La protein/Sjo €gren syndrome type B
CXCL9 chemokine (C-X-C motif) ligand 9 (previously antigen
MIG) MHC I
CXCL10 chemokine (C-X-C motif) ligand 10 (previously and II major histocompatibility 1 and 2
IP-10) NK cells natural killer cells
CTL cytotoxic T lymphocyte PLIMFD proliferative, lymphocytic, infundibular mural
DIEM drug-induced erythema multiforme folliculitis and dermatitis with prominent
DRESS drug rash with eosinophilia follicular apoptosis and parakeratotic casts
EM erythema multiforme PNOE proliferative and necrotizing otitis externa
hIVIG human intravenous immunoglobulin OVE overlap SJS and TEN
Fas-L Fas ligand Ro/SS-A Ro/Sjo €gren syndrome type A antigen
SCLE subacute cutaneous lupus erythematosus
SCORTEN score of toxic epidermolysis
Accepted 12 March 2014
SLE systemic lupus erythematosus
A truncated version of this review was presented at the 23rd SJS Stevens–Johnson syndrome
Annual Congress of the ESVD-ECVD, Bled, Slovenia, September SSSS staphylococcal scalded skin syndrome
2009. TEN toxic epidermal necrolysis
Sources of Funding: This study was self-funded. TCR T-cell receptor
Conflict of Interest: No conflicts of interest have been declared.

406 © 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.

 Erythema multiforme, SJS/TEN

Th-1, lesions, which he named erythema (esxudativum) multi-

Th-2, forme.19 A much more severe disease, characterized by
Th-17 T-helper cell 1, T-helper cell 2, T-helper cell 17 extensive purple macules, vesicles and erosions affecting
TLR3, skin and mucous membranes, was described by Stevens
TLR4 Toll-like receptor 3, Toll-like receptor 4 and Johnson in 1922.20 In 1950, Thomas subdivided EM
TNF-a tumour necrosis factor-a into minor and major forms.21 Erythema multiforme major
TRAIL tumour necrosis factor-related apoptosis- differed from EM minor in lesion extent, involvement of
inducing ligand mucosae and presence of systemic signs of illness. How-
TWEAK tumour necrosis factor-like weak inducer of ever, Thomas equated EM major to SJS, which marked
apoptosis the beginning of continuing confusion. In 1956, Lyell
coined the name TEN22 to describe a life-threatening dis-
order of epidermal detachment, which was probably first
Introduction reported in 1939.23 At that time, TEN was considered
unrelated to SJS.
The past 40 years have been fertile ground for the
Possibly because of a lack of agreed diagnostic crite-
description of new diseases in the developing discipline
ria for these conditions, the medical literature remained
of veterinary dermatology. It is natural that veterinary der-
very confused, especially with regard to the relationship
matologists have looked to the human literature for inspi-
between EM major and SJS, over the next 40 years. In
ration in characterizing these arising entities. Erythema
1993, a group of medical experts proposed a consen-
multiforme (EM), Stevens–Johnson syndrome (SJS) and
sus classification according to the type and extent of
toxic epidermal necrolysis (TEN) are typical examples.
the clinical lesions.14 The study by Bastuji-Garin et al.
Toxic epidermal necrolysis was the first to be described
was based on a standard atlas and an arbitrary set of
in 1979 in two dogs and a cat,1 followed by a case of
criteria (see Table S1 in Supporting information). The
canine EM in 19832 and canine SJS in 1990.3 Although
five categories proposed were bullous EM (equivalent
reported in horses,4 cattle,5,6 monkey,7 swine8 and wild-
to EM major), SJS, SJS–TEN overlap (OVE) and TEN
life species,9 this review will concentrate on comparisons
(which was subdivided into TEN with or without spots).
between human, dog and cat diseases.
The 1993 consensus determined that SJS–OVE–TEN
For many years, the position in human dermatology
were related and were distinct from bullous EM (EM
has been that EM, SJS and TEN occupy a spectrum,
major).
with EM at the milder end and TEN at the severe
It is now accepted that EM and SJS/TEN are separate
extremity. The current position is that EM is a sepa-
conditions.11,24 Erythema multiforme is divided into minor
rate disease, mostly triggered by infection with herpes
and major forms based on mucosal involvement and sys-
simplex virus (HSV).10–12 In contrast, SJS and TEN
temic signs of illness in the latter11 (Table 1). The term
(SJS/TEN) represent a spectrum of largely drug-induced
EM minor has been largely replaced by herpes-associated
disease.13–16
EM (HAEM),25 which accounts for the majority of human
In veterinary medicine, confusion abounds around EM,
cases. Drug- induced EM (DIEM) is reserved for those
SJS and TEN. Recent publications17 still represent EM as
uncommon cases with a proven drug trigger. The spec-
a milder form of SJS/TEN. There are no universally agreed
trum of SJS/TEN is subclassified into SJS, OVE and TEN
upon clinical criteria for EM for animals, making it difficult
based on the extent of epidermal detachment (<10, 10–
to differentiate EM from SJS in particular. Textbook chap-
30 and >30%, respectively).11,14 The raised nature of the
ters and review papers are forced to rely on old data (the
lesions is important in distinguishing between EM and
most recent case series of EM was published in 1999).18
SJS/TEN. Lesions of SJS/TEN are almost always flat
Thus, the current diagnosis of EM is driven largely by his-
(Table 2), whilst those of EM are almost always palpa-
topathological findings. An unfortunate tendency to
ble.11,26
equate the ‘tissue reaction pattern’ of transepidermal
cytotoxic (interface) dermatitis to the disease ‘EM’ raises
Animal
the possibility that a heterogeneous group of disorders
The relationship of EM, SJS and TEN in veterinary derma-
have been placed under the same banner. Erythema mul-
tology has also been confusing; some cases of EM in the
tiforme has become virtually synonymous with ‘drug
literature are probably SJS.3 In 1993, a multicentre study
reaction’ despite evidence to the contrary. As this review
set out to apply some aspects of the Bastuji-Garin human
will show, SJS and TEN in dogs and cats are counterparts
classification scheme to canine cases. Hinn et al.27
of the human conditions, but the situation for EM is not
proposed five categories (see Table S2 in Supporting
so clear.
information). These categories and the clinical criteria
were not identical to the human classification. In particu-
lar, target lesions were not precisely defined.
Nosology of erythema multiforme,
This paper has proved useful. It provided evidence that
Stevens–Johnson syndrome and toxic
while clinically defined canine SJS/TEN was very likely to
epidermal necrolysis
be triggered by drugs, EM was not. This paper also dem-
Human onstrated, clearly, that it is impossible for even experi-
In 1860, von Hebra described an acute-onset, mild, self- enced veterinary dermatopathologists to differentiate
limiting skin disorder, characterized by myriads of red reliably between EM and SJS/TEN; the same situation
papules that evolved into distinctive target-shaped exists in in human dermatology.14
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64. 407
Yager

Table 1. Comparison of erythema multiforme (EM) in humans, dogs and cats (adapted from French and Prins)11
Mucosal Systemic
Species EM type Types of skin lesions Distribution involvement signs Precipitating factors
Humans EM minor Typical targets Extremities, face Absent or mild Absent Herpes simplex (DNA
 papular atypical targets fragments) 90%
All lesions are raised Other infectious
agents
Rarely, drugs
Bullous EM Typical targets Extremities, face Present Present Herpes simplex (DNA
(EM major)  papular atypical targets fragments)
+ occasional bullous lesions Mycoplasma
with <10% pneumoniae
detachment* Other infectious
All lesions are raised agents
Rarely, drugs
Dogs EM minor Wide range of lesions Trunkal, often axillary and none or 1 mucosa‡ Absent Idiopathic
and cats described, with no consensus† inguinal, mucocutaneous, Drugs, dietary
Erythematous macules or head, generalized substances, vaccine
papules, often crusted; raised or Possibly feline
flat targetoid lesions, typical herpes virus§
targets rare; polycyclic, arciform,
erythematous or purpuric lesions
(<50%); vesicles, bullae, ulcers;
urticaria; scaly  erythematous
macules, papules, plaques
(hyperkeratotic ‘EM’); alopecia
(follicular ‘EM’); generalized
scaling (some feline EM)
EM major Flat or raised, focal or multifocal As above >1‡ Present Drugs¶
polycyclic, targetoid (rarely typical) Some infections
lesions; erythematous or purpuric
macular or patchy eruptions; <10%
detachment‡
*Bastuji-Garin et al.14 †Some of the conditions in dogs and cats identified as EM by biopsy results may represent other diseases showing a similar
cytotoxic tissue reaction pattern. ‡Hinn et al.27 §Canine parvovirus ‘EM’ is an active infection differing from herpes-associated erythema multi-
forme. ¶Some cases described in the veterinary literature as EM may be Stevens–Johnson syndrome.

the virus.25,30 The major capsid protein, virion protein 5,

Precipitating factors
Erythema multiforme
Human
Erythema multiforme is usually associated with previous
HSV-1 (less commonly HSV-2) infection. Viral fragments,
largely DNA polymerase (Pol),25,28 are present in lesions
of EM,29 but it is rare to find whole virions or to culture
is not expressed in HAEM lesions, indicating the absence
of viral replication. Fragments of HSV are disseminated to
the skin by CD34+ Langerhans cell precursors.31 Interest-
ingly, transplanted stem cells may also carry Pol and trig-
ger an erythematous eruption.32 An intriguing and still
unanswered question is why the vast majority of people
with HSV infections do not develop HAEM. Numerous
other viruses, including Epstein–Barr,33 parvovirus B19

Table 2. Comparison of Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in humans, dogs and cats (adapted from French
and Prins)11
Mucosal Systemic
Disease Species Types of skin lesions Distribution involvement signs Precipitating factors
SJS Humans Dusky macules, bullous Trunk, face Severe Present Drugs
lesions, atypical targets Mycoplasma
 epidermal detachment <10%* pneumoniae
Dogs and Erythematous or purpuric, Trunk, often axillary Severe Present Drugs
cats macular or patchy eruption and inguinal, (more than Bacterial infections
Epidermal detachment <10% mucocutaneous one mucosa)
junctions, generalized
TEN‡ Humans Dusky macules Trunk, face Severe Present Drugs
Atypical targets
Poorly delineated
erythematous plaques
Epidermal detachment >30%
Dogs and Erythematous or purpuric, Trunk, often axillary and Severe (more Present Drugs in the broad
cats macular or patchy eruption inguinal, mucocutaneous than one mucosa) sense
Epidermal detachment >30%† junctions, generalized Flea dip (D-limonene)
*Bastuji-Garin et al.14 †Hinn et al.27 ‡Overlap syndrome (between SJS and TEN) is distinguished by degree of epidermal detachment (10–30%).

408 © 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.


and cytomegalovirus, are rarely implicated.11 Myco-
plasma pneumoniae may elicit EM major, but is more
commonly associated with SJS in children.34 Unusual
triggers for EM (typically recurrent or persistent clinical
types) include fungal infections (candidiasis), benzoic acid
ingestion, progesterone (either in contraceptives or
endogenous) and poison ivy exposure.12 Erythema multi-
forme-like lesions also occur in systemic diseases (e.g.
subset of lupus erythematosus,35 originally Rowell
syndrome, Behcet’s disease and inflammatory bowel
disease).11,36
A small proportion of cases of human EM (<10%) are
drug triggered.11 The most common culprits are similar to
those responsible for SJS/TEN, including sulfonamides,
anti-epileptics, nonsteroidal anti-inflammatory drugs and
antibiotics.11
Animal
There has been a tacit acceptance that EM in animals is
equivalent to an adverse drug reaction (CADR), although
recent textbooks have made an attempt to redress this
misconception.37 The evidence is very much to the con-
trary. In a multicentre retrospective study, only 19% of
canine EM cases were drug related.27 In another retro-
spective study, which included previously reported cases,
a drug trigger was identified in 59%.18
Triggers for classical drug-induced EM in dogs include
sulphonamides, antibiotics38,39 and levamisole.40 Other
triggers, which may be considered ‘drugs’ in the broad
sense, include beef/soy diet,18 commercial dog food,41
neutraceutical product,42 infections (pyoderma, anal
furunculosis and Pseudomonas otitis)2,18 and neopla-
sia.37 One report implicates intranasal Bordetella bron-
chiseptica vaccine, given subcutaneously in error.43 Of
these published cases, only those triggered by beef/soy,
commercial dog food and a neutraceutical product have
been proved through (unintentional) rechallenge. In the
absence of provocation testing, the majority of the pub-
lished cases of drug-induced EM must be considered
anecdotal.18
Canine parvovirus-associated EM is a rare example of
systemic viral infection, albeit with atypical skin involve-
ment. It is not analogous to HAEM. Parvovirus inclu-
sions in lesional keratinocytes indicated viral
replication.44,45 Feline herpes virus (FHV-1)-associated
EM is alluded to in textbooks and has been the subject
of conference presentations.46,47 Unlike HAEM patients,
the cats responded to antiviral medication.48 Viral DNA
has been identified by PCR, but FHV-1 PCR is not
highly specific, particularly in vaccinated cats.49 Interest-
ingly, pol and thymidine kinase were identified in one
cat, similar to HAEM50 (T. Olivry 2013, personal com-
munication). It is possible that necrotizing and prolifera-
tive otitis externa of cats (PNOE)51 is equivalent to the
rare persistent form of human EM. To date, however,
all attempts to demonstrate viral involvement have
been unfruitful.
Drug-associated feline EM has been attributed to anti-
bacterial drugs, including antibiotics18,38,52 and aurothio-
glucose.53 Erythema multiforme-like histological lesions
occur in association with feline thymoma in cats,54 lead-
ing to an exfoliative dermatosis rather than targetoid clini-
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
Erythema multiforme, SJS/TEN
cal lesions. It is probable that these cases have a different
pathogenesis. Rather than an alteration of epidermal anti-
genicity causing cytotoxic T cells (CTLs) to target and
destroy these altered cells, changes in maintenance of
active tolerance in the abnormal thymic environment
could allow normal keratinocytes to be identified errone-
ously as ‘foreign’. There are insufficient data to confirm a
putative case of canine thymoma-associated EM.17
Stevens–Johnson syndrome and toxic epidermal
necrolysis
Human and animal
Drugs are the main precipitating factors of SJS/TEN in
humans and animals. The high-risk drugs in people are an-
timicrobials, particularly sulphonamides, nonsteroidal
anti-inflammatory drugs (particularly oxicams), nevirapine
in acquired immunodeficiency syndrome (AIDS) patients,
allopurinol and anticonvulsants (lamotrigine, carbamaze-
pine, phenytoin and phenobarbital).55–59 Sulphonamides
and antibiotics, particularly cephalosporins and penicillins,
levamisole, diethylcarbamazine and phenobarbital are rec-
ognized triggers in animals.37,40 Flea dips containing D-lim-
onene have been implicated in severe necrotizing
dermatitis resembling TEN in cats and dogs.60–62 The
main infectious cause of SJS in people is M. pneumo-
niae.11 Interestingly, Mycoplasma bovis has been associ-
ated with TEN lesions in calves.6 Other rare triggers
include vaccination, dengue virus infection and radiologi-
cal contrast agents (human),15 FeLV antiserum (cat) and
neoplasia (dog).1 A low number of SJS/TEN cases are idi-
opathic.63
Pathogenesis
The keratinocyte is the target of a misdirected immune
response, whether this is precipitated by a drug or by an
infectious agent. This leads to apoptotic cell death that is
typically patchy in EM and extensive to confluent in SJS/
TEN. The pathomechanisms are different in EM and SJS/
TEN. Lymphocyte-mediated direct cytotoxicity of target
keratinocytes occurs in EM, but in SJS/TEN there is little
evidence of cell–cell contact in fully developed lesions.
While a role for soluble Fas ligand (FasL) has been pro-
posed,64 granulysin released from cytotoxic T lympho-
cytes and natural killer (NK) cells appears to be the major
mediator of the widespread cell death in SJS/TEN.65
Erythema multiforme
Human and animal
Mechanisms of HAEM differ from those of the much
rarer drug-induced form of human EM.66 Both are
T-helper 1 (Th-1) responses, but in HAEM, interferon-c
(IFN-c) is the dominant cytokine.66 Interestingly, the
dominant cytokine in DIEM in people is tumour necrosis
factor-a (TNF-a), as in TEN.67,68
The presence of viral proteins or DNA fragments on the
surface of keratinocytes elicits an a/b CD4+ Th-1
response.68 The activated T cells produce IFN-c,66 setting
off a cytokine cascade. The chemokines CCL-2, CCL-5,
CXCL-9 and CXCL-10 are expressed at the interface in le-
409
Yager
sional skin, with negligible expression of neutrophil
chemoattractants.69 The majority of cells in the epidermis
are a/b CD8+ T cells, whereas CD4+ cells are mostly
found in the dermis, along with dendritic cells and macro-
phages.69,70 Many dermal CD4+ T lymphocytes express
Foxp3+, indicating that they are regulatory T cells
(Treg).71 Interferon-c also activates NK cells and
upregulates MHC-I and MHC-II expression, potentially
promoting antigen presentation, thus amplifying the HSV-
specific immune response. Effector CD8+ cytotoxic
T cells attach to HSV antigen-expressing keratinocytes, a
process facilitated by upregulation of intercellular adhe-
sion molecule 1 (ICAM-1), also amplified by IFN-c. Inter-
estingly, the pattern of ICAM-1 expression differs in EM,
lichen planus and systemic lupus erythematosus (SLE),
reflecting the distribution of the targeted keratinocytes in
each disease.72 Apoptosis is mediated by exocytosis of
the protease contents of the cytolytic granules from
CD8+ T lymphocytes, NK cells and other innate
T cells.73,74 Granzymes enter the target cell through tran-
sient pores induced by perforin75 and trigger intrinsic
apoptosis by both caspase-dependent and -independent
mechanisms. Granulysin is a highly potent cationic serine
protease, which disrupts the transmembrane potential of
mitochondrial membranes and triggers intrinsic apopto-
sis.71
Little is known of the pathogenesis of EM in animals. A
study of EM and graft-versus-host disease in dogs76
revealed a similar population of a/b CD4+ Th-1 cells and
CD8+ cytotoxic effector cells, but their antigenic specific-
ity is unknown, as is the cytokine milieu. Whether NK
cells contribute, as in people, has not been evaluated in
dogs and cats.
Stevens–Johnson syndrome and toxic epidermal
necrolysis
Human and animal
The pathogenesis of SJS/TEN in humans has been an
area of active investigation, but little is known about the
mechanisms in affected animals. In people, one question
seminal to the pathogenesis of SJS/TEN (and to other
CADRs) is: how do drugs cause sensitization? The hapten
model proposes that small moieties of drug form covalent
bonds with host peptides, rendering these immunogenic.
The p-i concept posits that drug moieties interact directly
with the T-cell receptor (TCR) and the peptide-loaded
human lymphocyte antigen (HLA) molecule in a noncova-
lent manner. Experimental data support both models.15 In
veterinary cases, antidrug antibodies, in levels that corre-
lated with the presence of drug protein adducts, were
demonstrated in sulphonamide-sensitive dogs.77 A third
mechanism describes alterations in the shape and, con-
sequently, the chemistry, of the antigen-binding clefts of
susceptible HLA allotypes following noncovalent binding
of the triggering drugs. This affects the repertoire of
endogenous peptides that can bind to that re-engineered
HLA cleft. The altered ‘self’ then activates drug-specific
T cells.78
A second question is: why do CADRs occur in only
some individuals, when the triggering drugs are widely
used?15 It has been known for some time that certain
410
HLA allotypes confer susceptibility to particular drugs in
people.79 It is now evident that these are not simply
genetic markers but they have a functional role (reviewed
by Lee and Chung80). Two requirements must be met for
sensitization to occur, i.e. a particular HLA subtype and
the presence of a particular TCR clonotype.81 The innate
immune system may also play a role in susceptibility, for
example through alterations in Toll-like receptor 3 (TLR3)
activity.82
Keratinocyte cytotoxicity is mediated largely by CD8+
and NK CTLs demonstrable in skin and blister fluids of
TEN patients.83,84 Enhancement of T-cell activation,
through decreased activity of regulatory T cells, may be a
contributory factor.85 Lesions also contain activated CD4+
T lymphocytes that express CD40 ligand86 (also demon-
strated in ‘EM’ dogs).76 This is an important costimulator
of macrophages, keratinocytes and dendritic cells, leading
to upregulation of adhesion molecules, release of inflam-
matory mediators and apoptosis. The mostly dermal
CD4+ T cells show no Th-1–Th-2 polarity, according to
cytokine profiles.87 Skin-seeking CLA+ CD4+ Th-17
lymphocytes have been identified recently in blood and
blister fluid of TEN patients in numbers that correlate with
the degree of epidermal detachment.88 Whilst SJS/TEN
are not thought of as neutrophilic diseases, myeloperoxi-
dase-positive granulocytes occur in TEN lesions.86 Mono-
cyte lineage CD14+ and CD16+ cells are numerous in very
early TEN lesions, suggesting an active, rather than
‘clean-up’, role.89 Macrophages and dendritic cells may
contribute by secreting apoptosis-triggering molecules,
such TNF-related apoptosis-inducing ligand (TRAIL; extrin-
sic pathway) and TNF-like weak inducer of apoptosis
(TWEAK; intrinsic pathway).90,91 Involvement of the
innate immune system is suggested by demonstration of
b-defensins in SJS/TEN blister fluid.92 Furthermore, TEN
lesional keratinocytes have been shown to express the
nonclassical MHC class 1 protein HLA-E, thus sensitizing
them to killing through the CD94/NKG2C killer lectin-like
receptor expressed by NK CTLs93 as well as by a subset
of CD8+ T cells.94
The third question revolves around the mechanism of
cell death. In SJS/TEN, cell death is often confluent; a fact
that cannot readily be explained by direct cytotoxicity. A
role for soluble cytotoxic proteins that trigger death
receptors, such as TNF-a and Fas-L, has been sug-
gested.95 Blister fluid is rich in soluble Fas-L, but the lack
of in vivo activity cast doubt on its primary role. Recently,
a facilitatory role has been suggested for inducible nitric
oxide (iNOS). Keratinocyte iNOS, stimulated by TNF-a
and IFN-c, upregulates Fas-L production.96 As keratino-
cytes already express Fas, a wave of keratinocyte-to-
keratinocyte apoptosis would follow activation of the
extrinsic pathway. Oxidative stress and cytokines such as
TNF-a may also contribute to epidermal cell death.97 It
should be noted that TNF-a also sets in motion the
nuclear factor-jB apoptotic pathway, and a controversial
proposal has been made that it may be protective against
CTLs.98 This is one possible explanation for the paradoxi-
cal increased death rate seen in SJS/TEN patients treated
with the anti-TNF-a drug, thalidomide.99
More recently, attention has focused on the serine pro-
tease, granulysin,80 already described for its role in direct
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
 Erythema multiforme, SJS/TEN

cellular cytotoxicity in EM. Significantly, rising levels of
granulysin are detectable in the serum of TEN patients,
before skin detachment is advanced.100 High-expressing
granulysin-positive CTLs can be demonstrated in lesions
of TEN/SJS by indirect immunohistochemistry. Blister
fluid contains orders of magnitude more granulysin than
soluble Fas-L, granzyme B or perforin.65 Depletion of gra-
nulysin reduces the cytotoxic effect, and lesions mimick-
ing SJS/TEN are induced when granulysin is injected into
normal mouse skin. Interestingly, granulysin may also
amplify the inflammatory/immune response by activating
antigen-presenting cells through Toll-like receptor 4 (TLR-
4), thus bridging specific and innate immunity.65,101
Clinical lesions
Erythema multiforme
Human and animal
Gross changes. The clinical lesions of canine EM have
been likened to those in people. Whilst red and irregular
in shape, they are seldom exact counterparts of the typi-
cal target in human EM (Table 1). Typical targets are very
precisely defined.14 They are round, sharply demarcated,
<3 cm in diameter, with at least three different zones of
colour. A dark-red central disc is surrounded by concentric
rings of palpable oedematous tissue and peripheral ery-
thema (Figure 1a). The central disc becomes crusted,
sometimes developing a bulla before ulcerating. While an
excellent example of a canine typical target is illustrated
in Small Animal Dermatology,37 the majority of animal
lesions do not comply (Figure 1b,c). Canine and feline EM
lesions are described as erythematous macules, papules
and plaques with indurated borders that clear centrally,
sometimes becoming cyanotic or purpuric.18 The defini-
tion of targetoid lesions in the retrospective study of EM,
SJS and TEN by Hinn et al.27 did not differentiate
between typical and atypical targets, describing the EM
minor lesions as ‘flat or raised, focal or multifocal, target
or polycyclic’. Only very rarely are human EM targets flat.
Animal lesions (Figure 1b) are more akin to human atypi-
cal targets,14 which have only two colour zones and an
irregular border. These are more frequent in bullous EM
(major) (Figure 1d). Many cases described as canine EM
have haemorrhagic, macular, vesiculobullous and ulcera-
tive lesions more suggestive of EM major or SJS (Fig-
ure 2a).18 While central crusting of targetoid lesions is
common to human and animal lesions (Figure 1c), some
cases of canine EM have very heavily crusted and/or scaly
plaques (Figure 3).37,42 Lesions in cats have been

Figure 1. Comparison of typical targets in human erythema multiforme (EM) with targetoid lesions in dogs. (a) Human. Typical targets of herpes-
associated erythema multiforme (HAEM). These are round, raised lesions with three zones of colour change. (b) Dog. Atypical targets from early
stages of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). These coalescing lesions have two zones of colour change, with
central necrosis and an erythematous raised border. (c) Dog. Cutaneous adverse drug reaction triggered by cephalosporin. Crusted targetoid
lesions. (d) Human. Coalescing, targetoid lesions in bullous EM. Photographs (a) and (d) courtesy of Steven Kossard. Photographs (b) and (c)
courtesy of Jan Declercq.

© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64. 411

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described as maculopapular, vesiculobullous and ulcera-
tive18,102 or exfoliative.47 Urticaria-type lesions have
been described in people, dogs and, particularly, in
horses.37,103 It is important to ensure that lesions are
fixed, and not evanescent, as occurs in true urticaria.11,37
In both people and animals, postinflammatory hyperpig-
mentation may result (Figure 2b).11,12
Lesion distribution. The distribution of the lesions is
markedly different in human and animal EM. In people,
EM is predominantly acral and facial.11 In dogs, lesions
typically involve the trunk, particularly the glabrous skin of
the groin and axilla (Figure 2a,b), but also the inner pinna,
footpads and the mucocutaneous junctions.37 In both
people and animals, the clinical lesions are usually bilat-
eral. Mucosal involvement is not uncommon in animals.
In people, mucosal involvement occurs in EM major, but
to a minor extent, if at all, in HAEM.11 A recent paper
describing EM limited to the oral cavity in seven dogs
may be an example of the tendency to equate the histo-
logical lesion of transepidermal cytotoxic (interface) der-
matitis with the disease entity EM.104 Oral EM is very
rarely reported in humans, and most cases appear in the
dental, rather than the dermatology, literature.105,106
These cases are typically chronic or recurrent rather than
self-limiting, which tends to suggest an immune
response to a chronic viral infection rather than the postvi-
ral immune events that typify HAEM. Favourable
Figure 2. Dog. Clinical lesions of idiopathic ‘EM’. (a) Serpiginous
ulcerative lesions that are flat and lack typical targets. Photograph
courtesy of Francesca Abramo. (b) Dog. Healed lesions from a similar
case. Classical inguinal and axillary distribution and reticulate hyper-
pigmentation. Photograph courtesy of Wendy Parker.
412
Figure 3. Dog. Thick, crusted plaques are another manifestation of
persistent ‘EM’. Photograph courtesy of Keith Linder.
response to periodontal treatment, with or without antibi-
otics, suggests a lichenoid tissue reaction to oral patho-
gens, rather than a canine homologue to human oral
EM.104
Nature of the clinical course. Herpes-associated
erythema multiforme is typically short term and self-limit-
ing. Recurrent cases of EM in people are usually linked to
episodes of HSV infection, although a disputed number
are idiopathic.11,12,107 Persistent EM in people, as
opposed to recurrent EM, is extremely rare; in 2007,
there were only 23 known cases.108 Chronic viral
infections, neoplasia and systemic diseases have been
implicated in these human cases.12,108,109 In a lupus
subset, previously known as Rowell’s syndrome,35 wide-
spread atypical targetoid lesions, often papulonecrotic or
bullous and, occasionally, urticarial, resemble the spec-
trum of lesions in canine EM. These patients have a par-
ticular pattern of immunological abnormalities.110,111 It
may be worthwhile testing dogs with persistent ‘EM’ for
antibodies to Ro/Sjo€gren syndrome type A antigen (Ro/
SS-A) and Lupus La protein/Sjo €gren syndrome type B
antigen (La/SS-B).
According to Miller, Griffin and Campbell, EM in dogs
and cats may run a mild course, with spontaneous regres-
sion.37 Removal of the likely trigger brought about clinical
improvement in 10 dogs, within 2 weeks.18 What differs
markedly from human EM is the relatively large propor-
tion of chronic or relapsing cases in dogs. These lesions
may last months to years. In one review, seven of 16
(43%) dogs were in this category. In these dogs, there
was no known trigger.18 Given that many persistent
cases occur in aged dogs, the anecdotal term ‘old-dog
EM’ has emerged, but has not been validated by a pub-
lished case series. Exudative and proliferative lesions
affecting the face and ears (Figure 8a), not targetoid
lesions, are usual manifestations.112 Old-dog EM is unli-
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.

kely to be a counterpart to human HAEM, sharing only a
common tissue reaction pattern.
Systemic signs. Systemic signs of illness occur in EM
major, but not HAEM.11 Many reports of EM in animals
describe systemic signs,18 suggesting that at the very
least these are equivalent to EM major but may be more
akin to SJS.37
Stevens–Johnson syndrome/toxic epidermal
necrolysis
Human and animal
Clinical signs of SJS/TEN are very similar in humans and
animals (Figures 4 and 5). Disease onset is sudden, with
severe systemic signs (anorexia, lethargy and depression)
and widespread, usually painful, skin and mucosal
lesions. Initial lesions range from dusky to purpuric irregu-
lar macules and patches, which may or may not develop
blisters, to flat typical and atypical targets (Table 2).
Lesions often coalesce into arciform or serpiginous
shapes. Epidermal detachment is a hallmark and leads to
widespread ulceration (Figures 4a and 5a,b,e). A positive
pseudo-Nikolskiy sign (where pressure causes separation
of erythematous as apposed to normal skin) is demon-
strable in animal and human SJS/TEN.
Erosions and ulcers are the main presenting signs in
dogs and cats, often affecting mucocutaneous junctions
(Figures 4a,b and 5b,e,f). Large areas of detachment
result from minor pressure (Figure 5b,e). Early lesions
include erythematous to haemorrhagic macules or
patches and coalescing erythematous atypical targetoid
lesions (Figure 1b). Distribution is trunkal, becoming gen-
eralized. The footpads of animals (and the soles of the
feet) are often involved (Figure 5f).11 Mucosal ulcerations
chiefly affect the oral cavity (Figure 5c,d), but the tracheo-
bronchial, urogenital and oesophageal mucosae are sus-
ceptible. Corneal involvement occurs in people and
animals.3,11
Stevens–Johnson syndrome and TEN are clinical emer-
gencies, with a high mortality rate in all species, largely
Figure 4. Stevens–Johnson Syndrome. (a) Dog. Vesiculobullous lesion on the inner pinna following administration of trimethoprim-sulphadiazine.
Photograph courtesy of Thierry Olivry. (b) Dog. Mucocutaneous junctions are typically involved in SJS. Photograph courtesy of Jan Declercq.
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
Erythema multiforme, SJS/TEN
due to sepsis. The mortality rate in people is 1–5% in SJS
and 25–35% in TEN.11 A scoring system for human
patients (SCORTEN; see Table S3 in Supporting informa-
tion) predicts the chance of mortality based on seven
prognostic factors.113 This could be adopted readily for
animal cases. Accurate mortality data for animal SJS (and
bullous EM) are not available. However, the mortality rate
for TEN in animals, based on relatively few case reports,
is very high. This is almost certainly because ancillary sup-
port cannot be delivered at the same high level as human
critical care.114
Histological lesions
The histological lesions in both EM and SJS/TEN
reflect the pathogenesis, namely lymphocyte-mediated
epidermal cell death. In terms of tissue reaction pat-
tern, as defined by Weedon,115 EM is an example of
lichenoid tissue reaction. In terms of pattern analysis,
EM is considered a classic vacuolar/cell-poor interface
dermatitis, despite the fact that apoptotic cells are not
restricted to the interface and lymphocytic inflamma-
tion may be significant. In TEN, the entire epidermis is
dead. The inadequacy of the current classification sys-
tem of interface/lichenoid dermatitis is well illustrated
by these diseases. In the author’s opinion, they
are better considered to be disorders of epidermal
cytotoxicity.116
Erythema multiforme
Human
Cytotoxic (interface) dermatitis, in which keratinocyte
apoptosis is not limited to the basal and suprabasal lay-
ers, with basilar hydropic degeneration (vacuolar change)
and mild lymphocytic infiltration at the interface are typi-
cal findings (Figure 6a).115,117,118 A mononuclear ‘liche-
noid’ band is not a feature of human EM. Satellitosis
(apposition of lymphoid cells and dying keratinocytes) is
usually present. Apoptotic fragments (Civatte or colloid
bodies) may be found in the epidermis and dermis. Pres-
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Figure 5. The clinical appearance of TEN/SJS is similar in humans and animals. Extensive epidermal detachment in human (a) and dog (b). Oral
involvement is common in TEN but also occurs in SJS in dog (c) and human (d). (e) Dog. Flat, erosive lesions in the inguinal area. (f) Dog. Footpad
involvement in SJS/TEN can mimic autoimmune blistering diseases. Photographs courtesy of Steven Kossard (a,d), Keith Linder (c), Jan Declercq
(b,e) and Alessandra Fondati (f).
ervation of the normal basket-weave stratum corneum is
characteristic (Figure 6a).115,119 However, in older
lesions of HAEM or in bullous EM (Figure 7a), full-thick-
ness epidermal necrosis may mimic SJS/TEN (Fig-
ure 7b). The lesions illustrated in some cases of
recurrent and persistent EM have superficially located
apoptotic keratinocytes (‘dyskeratotic’ cells), with overly-
ing parakeratosis and lesser involvement of the basal
layer.120,121 Lymphocytic perivascular dermatitis affects
superficial and mid-level plexii (Figure 6a) (in contrast to
fixed drug eruptions, in which deep plexii are involved).
Eosinophils are rarely present.122 Vasculitis is not consid-
ered a lesion of human EM despite some reports to the
contrary.115 Whilst superficial dermal oedema is often
present (Figure 6a), an earlier classification of lesions as
‘dermal’ EM has been abandoned.115
Erythema multiforme may be difficult to differentiate
histologically from other cytotoxic dermatitides, particu-
larly acute graft-versus-host disease and some cases of
acute cutaneous lupus erythematosus. Erythema multi-
forme-like lesions occur in conjunction with suprabasilar
acantholysis in paraneoplastic pemphigus, but both
lesions may not be present in a single biopsy.123,124
Animal
The microscopic lesions of canine EM are similar to those
described above, not surprisingly as the chief resem-
blance to human EM is histological, rather than clinical.
Like human EM, the pattern is cytotoxic (interface) der-
matitis, with cell death occurring in suprabasilar as well as
basal layers. In the author’s opinion, however, a higher
proportion of apoptotic keratinocytes are found in outer
levels of the stratum spinosum in some cases of canine
414
EM than in classic human lesions. In addition, hydropic
degeneration of the basal layer may not be such a promi-
nent feature (compare Figure 6a,b). Whether these fea-
tures simply reflect a longer lesion duration or whether
they represent a subset of canine cases, perhaps of dif-
ferent aetiology, remains unknown. It would be interest-
ing to compare the histological lesions of drug-associated
human EM with canine EM. Intraepidermal mononuclear
cell infiltrates are predominantly lymphoid (CD8+
T cells).76 Intraepidermal mononuclear cells with abun-
dant lightly eosinophilic cytoplasm and indented nuclei
are Langerhans cells, as has been shown by cell marker
studies (CD1a+, CD11c+).76 Clusters of Langerhans cells
may be confused with early epitheliotropic lymphoma.
Confluent epidermal necrosis is common in canine
lesions, as in human lesions. Neutrophils infiltrate eroded
lesions and eosinophils may be present; whether these
are more common in drug-associated EM, as has been
suggested in people,115 is unknown.
A major difference between canine and human EM is
the tendency for the follicular infundibular epithelium to
be affected in the dog, not least because EM in people
typically affects glabrous skin. Lesions that appear to
target the follicular isthmus (and sebaceous gland), and
sparing the interfollicular dermis, have been termed ‘fol-
licular EM’.112 In the author’s experience, such lesions
are associated with progressive scarring alopecia, rather
than targetoid or ulcerative lesions normally associated
with EM. Lymphocytic mural cytotoxic (interface) folliculi-
tis is a reaction pattern that is well recognized as a cause
of scarring alopecia in people.125 The conditions under
this banner include lichen planopilaris (so far only diag-
nosed in people), pseudopelade (a controversial term in
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.

Figure 6. Histopathology of EM. (a) Human. Classic microscopic
lesions of HAEM. Apoptosis is basal and suprabasal in this exam-
ple (arrows). Hydropic change in basal layer (arrowheads) and mild
lymphocytic interface infiltration is typical. The stratum corneum is
normal. Photograph courtesy of Steven Kossard. (b) Dog. Photomi-
crograph of EM lesion. Note the transepidermal apoptotic cells
(arrowheads) and satellitosis (arrows). The stratum corneum is
partly parakeratotic. Haematoxylin and eosin stain. (c) Dog. Photo-
micrograph of subacute EM lesion. Apoptotic cells are transepider-
mal. The stratum corneum is parakeratotic. Round, lightly
eosinophilic cells in the stratum corneum (white arrowheads)
represent apoptotic cells; not to be confused with acantholytic
cells. Haematoxylin and eosin stain.
human and animal dermatology)115 and some types of
cutaneous lupus erythematosus.125
The histological lesions of feline EM resemble those in
the dog and human. Again, this is to be expected because
the diagnosis is driven by the histological findings of cyto-
toxic (interface) dermatitis.47 The microscopic lesions of
thymoma-associated paraneoplastic exfoliative dermato-
sis in cats are EM like, in that they represent an epidermal
cytotoxicity reaction pattern. They have been described
both as cell rich and as cell poor, possibly reflecting the
duration of the lesions.54,126 In addition to marked
hyperkeratosis, sebaceous glands are targeted and may
be absent in some cases. Similar lesions of exfoliative
dermatitis, with no accompanying thymoma, have been
characterized as a form of feline EM.112
Surface changes of hyperkeratosis and parakeratosis
are much more common in canine EM than in human
EM, in which the stratum corneum is usually normal
(compare Figures 6a–c and 8b). In the persistent form of
canine EM, hyperkeratosis and parakeratosis may be very
marked. (Figure 8b). These microscopic lesions may cor-
relate with clinical scaling and are anecdotally referred to
as ‘hyperkeratotic EM’ (Figure 8a). This term has not
been validated in the literature, although it is in common
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
Erythema multiforme, SJS/TEN
usage.112 In these cases, dead cells are more numerous
superficially. Remnant apoptotic cells in the stratum cor-
neum (‘pink ghosts’) can be misinterpreted as ageing
acantholytic cells histologically and on cytological smears
(Figures 6c and 8b). There is less evidence of apoptosis
and vacuolar change at the interface (Figure 8b). Hair folli-
cle infundibula may be affected, sometimes with marked
follicular parakeratosis and cast formation. Hyperkeratotic
EM is very similar to so-called ‘old-dog’ EM.
In veterinary dermatology, there are other clinical scal-
ing disorders that may be confused with EM if the histo-
logical lesions alone are taken into account. These are
characterized by a transepidermal cytotoxic dermatitis,
but differ from ‘classic’ EM in that there is less basilar
apoptosis and hydropic degeneration, significant hyper-
and parakeratosis, a greater degree of superficial apopto-
sis (previously known as ‘dyskeratosis’) and more intense
granulocytic inflammation that cannot be explained by
ulceration or erosion. Neutrophils sometimes cluster
around apoptotic cells along with mononuclear cells.
Additionally, lesions have a distinctly follicular bias. These
conditions include the ciclosporin-responsive ‘prolifera-
tive, lymphocytic, infundibular mural folliculitis and derma-
titis with prominent follicular apoptosis and parakeratotic
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Figure 7. (a) Human. Vesicular EM lesion. (b) Human. Photomicrograph from vesicular EM lesion showing full-thickness epidermal necrosis that
should not be confused with SJS or TEN. Haematoxylin and eosin stain. Courtesy Steven Kossard.
casts’ (PLIMFD), typically in young Labrador retrievers.127
(Figure 9a,c,e). A very similar case, also in a Labrador
retriever puppy, was reported in 1983 (Figure 9b,d,f).128
This dog is of interest because of the rapid clinical
response to oral vitamin A (40,000 IU twice daily); this
treatment was required for life.128 Whether vitamin A
acted to suppress lymphocytic inflammation or to ‘nor-
malize’ a putative underlying cornification defect remains
unknown. A significantly large subset of canine superficial
necrolytic dermatitis cases show prominent single cell
death in the outer stratum spinosum. (Figure 10). Similar
lesions are recognized rarely in human necrolytic migra-
tory erythema.115 The feline condition initially discussed
anecdotally as feline aural or pinnal ‘hyperkeratotic EM’
and now known as proliferative and necrotizing otitis ex-
terna (PNOE;51 Figure 11a,b) also has significant outer
epidermal apoptosis, which can be confused with lesions
of EM (Figure 11c).
The pathogenesis of these unusual scaling disorders
with histological lesions of epidermal cytotoxicity, hyper-
keratosis and parakeratosis, remains unknown. Such
lesions may simply reflect chronicity or a low-grade per-
sistent CTL attack on the epidermis, with sufficient time
elapsing to alter significantly the terminal differentiation
patterns of the epidermis in response to injury lower in
the epidermis. They could also reflect alteration of super-
ficial keratinocytes (by persistent viral or bacterial anti-
gens) as has been proposed for cases of recurrent and
persistent EM in humans12 and for PNOE in cats
(although no virus has been identified yet).51 Finally, one
could postulate that physiological abnormalities in
keratinocyte function, including underlying cornification
disorders of genetic or epigenetic origin, may be the initia-
416
tors of CTL-mediated immune responses, due to actions
of the ‘epimmunome’.129
Stevens–Johnson syndrome/toxic epidermal
necrolysis
Human and animal
In SJS/TEN, in both people and animals, keratinocyte
cell death is typically more extensive than in EM.130
The lesions progress from single cell necrosis to clus-
ters of dying cells to full-thickness confluent necrosis
(Figure 12a,b). There may be significant keratinocyte
cell swelling in outer spinous and granulosum layers.131
In dogs and cats, the follicular infundibular epithelium
is usually affected concurrently. While the composition
of the inflammatory infiltrate (lymphoid cells, macro-
phages and dendritic cells) is similar to that of EM, the
infiltration is usually, but not always, sparser.67 The
lack of inflammation is most pronounced in TEN,
where there is virtually no cellular infiltration in fully
developed lesions (Figure 13). Full-thickness epidermal
necrosis may induce separation from the underlying
dermis (hence the name epidermal necrolysis; Fig-
ure 13a). The necrosis in TEN appears coagulative his-
tologically (Figure 13a). In peracute cases, the lesions
may be subtle, with only pyknosis of nuclei and
hypereosinophilia of the cytoplasm to indicate the cata-
strophic epidermal cell death (Figure 13b). Inexperi-
enced pathologists may mistake the lesions of TEN for
a burn. Toxic epidermal necrolysis is distinguished from
a burn by the lack of dermal necrosis. Some cases
described in the literature as TEN may be questionable,
because significant dermal necrosis was reported.132
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.

Figure 8. Old-dog EM. (a) Chronic (>12 month) scaling and alopecic
lesions on the face of an 8-year-old Labrador retriever. Lesions were
nonresponsive to antibiotics. Photograph courtesy of Karen Beningo.
(b) Photomicrograph from this lesion showing ‘lichenoid dermatitis
reaction’, otherwise known as lichenoid-interface dermatitis, with
transepidermal apoptosis and satellitosis (arrows) of interfollicular
epidermis. Pigmentary incontinence is prominent (white asterisk).
Inset shows apoptotic cells and lymphocytic satellitosis (arrow). Hae-
matoxylin and eosin stain.
Distinguishing TEN histologically from acute graft-
versus-host disease can be a major problem in trans-
plantation patients.115,133
Differential diagnosis
Erythema multiforme
Humans and animals
In humans, there are few clinical differential diagnoses
for EM; the acute onset of bilateral, acral, typical
targets is virtually pathognomonic.11 In contrast, the
lesions of canine EM are very heterogeneous, leading
to a long list of differential diagnoses. Thus, diseases
as various as urticaria, dermatophytosis, demodicosis,
bacterial folliculitis, superficial spreading pyoderma and
bullous autoimmune skin disease are alternative clinical
diagnoses for canine EM.37,112 If scaling–crusting
lesions are included, and it is debatable that they should
be, superficial necrolytic dermatitis, zinc-responsive
dermatoses and other cornification disorders should be
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
Erythema multiforme, SJS/TEN
considered as differential diagnoses for canine EM.
Cornification diseases would not be considered differen-
tial diagnoses for human EM. Likewise, in cats, with
clinical lesions ranging from mucocutaneous ulcerations
to generalized exfoliative dermatoses, differential diag-
noses are numerous.
It is emphasized in human texts that nondermatolo-
gists are prone to misdiagnose giant urticaria as EM.11
Urticarial lesions (unless associated with vasculitis)
show no evidence of epidermal damage and last <12 h.
Oedema of hands, face and feet is also a feature of
urticaria that is not seen in EM. It is very important to
rule out urticaria in cases of suspected canine and
equine EM. Interestingly, peripheral oedema has been
noted in some published cases of canine EM.18 As an
indicator of vascular damage, rather than of an epider-
mal cytotoxic reaction, oedema suggests urticaria and/
or vasculopathy.
In people, targetoid lesions also occur in vasculitis,
some forms of SLE, fixed drug eruptions and polymor-
phous light eruption in children.11,12 These conditions are
distinguished by established clinical criteria in most
instances, except fixed drug eruption. Only rarely is histo-
logical examination necessary to differentiate EM from
other targetoid conditions.11
Stevens–Johnson syndrome/toxic epidermal
necrolysis
Human
The main clinical differential diagnoses in humans are
staphylococcal scalded skin syndrome (SSSS; Lyell’s
original paper on TEN included, inadvertently, a case of
SSSS), acute generalized exanthematous pustulosis
(AGEP), severe cases of EM major and, in particular,
generalized fixed drug eruptions, which closely mimic
SJS/TEN (Steven Kossard, 2013, personal communica-
tion).11 Drug rash with eosinophilia and systemic symp-
toms (DRESS) is not a disease of epidermal
detachment but may be confused with the early rash
stages of TEN.134 Acute graft-versus-host disease in its
most severe form is virtually identical to SJS/TEN.134
Widespread blistering eruptions with some resem-
blance clinically (and histologically) to SJS/TEN were
recently described in association with a new variant of
coxsackievirus A6.135 Burns are usually distinguished by
the history and distribution of lesions. Vesiculobullous
autoimmune disorders, such as bullous pemphigoid,
pemphigus vulgaris, paraneoplastic pemphigus and
drug-induced linear IgA bullous dermatosis, are distin-
guished by clinical context and histological findings.11
Rare cases of both systemic and acute/subacute lupus
erythematosus (ACLE/SCLE) may present as a TEN-like
bullous disease. Given that the apoptosis is pan-epider-
mal, the acronym ASAP (acute syndrome of apoptotic
pan-epidermolysis) has been proposed.136
Animal
The list of differential diagnoses for SJS/TEN is more
limited than in humans. Owing to the lack of agreed-upon
criteria, it is difficult to distinguish bullous EM from SJS/
TEN. It is felt that some cases in the literature that have
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Figure 9. Disorders with microscopic EM-like cytotoxicity lesions: scaling disorders in Labrador retrievers. Dog 1: ciclosporin responsive (a,c,e).
Dog 2: vitamin A responsive (b,d,f). Photomicrographs (a) and (b) show almost identical histological lesions of transepidermal lymphocytic cytotox-
icity in follicular infundibular epithelia from each dog. Haematoxylin and eosin stain. Photomicrograph (a) courtesy of Sherry Myers. Clinical presen-
tation of generalized scale and crust. (c) Generalized plaques in dog 1. Photograph courtesy of Kinga Gortel. (d) Diffuse generalized scaling and
crusting (secondary pyoderma) lesions in dog 2. (inset shows lesions before bathing). (e) Dog 1. Clinical response after 3 months of ciclosporin
treatment, having failed vitamin A treatment. Photograh courtesy of Kinga Gortel. (f) Dog 2. Clinical response after 6 weeks of oral vitamin A treat-
ment. Dog 1 was also illustrated in the report by Hargis et al.127 Dog 2 was also illustrated in a report by Parker et al.128

418 © 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.

 Erythema multiforme, SJS/TEN

Figure 10. Diseases with microscopic EM-like epidermal cytotoxic-

ity lesions: superficial necrolytic dermatitis subset. Dog. Photomicro-
graph showing cytotoxic dermatitis with satellitosis, lymphocytic and
neutrophilic exocytosis. Haematoxylin and eosin stain.

been diagnosed as EM are more likely to be SJS.37 Burns,

bullous autoimmune diseases, SLE, superficial suppura-
tive dermatitis of miniature schnauzers and vasculitis
should be considered. One major differential diagnosis in
dogs is epitheliotropic lymphoma. Not only are the clinical
lesions similar, but it is not always possible for patholo-
gists to differentiate mucosal SJS lesions from early
cases of epitheliotropic lymphoma, as evidenced in a
recent retrospective review.104

Diagnosis
The diagnosis of EM, SJS and TEN is clinicopathologi-
cal.12,37,134 In people, the diagnosis relies largely on clini-
cal findings (Tables 1 and 2). A practical algorithm
suggested by Bastiji-Garin et al.14 is to ask what is the
nature of the discrete lesions and what is the percentage
of epidermal detachment, rather than concentrate on the
number of mucosae involved. The diagnosis of SJS/TEN
no longer requires mucosal involvement, although it is
present in the majority of cases. Histopathology is
reserved for purposes of differential diagnosis and dis-
ease confirmation.11,12,134 In veterinary medicine, the
absence of clear clinical criteria places major emphasis,
sometimes misplaced, on skin biopsy results.37
Erythema multiforme
Human
The diagnostic investigation for people with EM gener-
ally does not rely on laboratory testing when the clinical
presentation is classical and the history suggests a link
to HSV infection.11 In the low percentage of cases
(~10%) that are not HSV associated, a drug trigger may
be investigated. In recurrent cases, PCR to identify
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
Figure 11. Diseases with microscopic EM-like cytotoxicity lesions:
proliferative and necrotizing otitis externa of cats (PNOE). (a) Kitten.
Massive scale-crusts accumulate on inner pinna and external ear
canal. Photograph courtesy of Caroline deJaham. (b) Low-power pho-
tomicrograph of biopsy from cat in (a), showing proliferative lesion,
with marked follicular plugging with columns of parakeratotic
squames (arrows). Haematoxylin and eosin stain. (c) Higher magnifi-
cation of affected follicular infundibulum showing lymphocytic mural
cytotoxic (interface) folliculitis with numerous single dead cells
(arrowheads) and evidence of satellitosis (arrows) in the hyperplastic
infundibular wall. Haematoxylin and eosin stain.
involvement of HSV or other viruses is indicated.12 If
respiratory symptoms are present, radiographs, PCR
and serological testing for M. pneumoniae are per-
formed.12 The rare cases of persistent EM require
extensive laboratory testing to rule out infectious,
inflammatory, autoimmune or even neoplastic underly-
ing disorders.12
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Figure 12. Stevens–Johnson syndrome/toxic epidermal necrolysis.
(a) Human. Photomicrograph showing partial to full-thickness epider-
mal necrosis that could be confused histologically with TEN. Note
paucity of inflammatory cell infiltrates. Haematoxylin and eosin stain.
Courtesy of Steven Kossard. (b) Dog. Photomicrograph of lesions
adjacent to an ulcer. The cytotoxic lesions vary from individual apop-
totic cells (arrowheads) to groups of dead cells (arrows) to areas of
confluent necrosis (asterisk). Lymphocytes and neutrophils are
migrating into the epidermis. Haematoxylin and eosin stain.
Animal
As a wide range of clinical lesions is currently acceptable
for EM in animals, the diagnosis is very often based on
the biopsy findings. The heavy reliance on histological
lesions for the diagnosis of EM in veterinary medicine37
raises two problems. Firstly, a variety of diseases demon-
strating a transepidermal pattern of epidermal cytotoxicity
may be classified as EM, irrespective of the clinical pre-
sentation. Secondly, it is not possible to differentiate
accurately between EM, particularly EM major, SJS and
TEN using histological criteria alone.14,27 Full-thickness
epidermal necrosis is not uncommon in EM lesions; indi-
vidual apoptotic cells with satellitosis are seen in TEN,
depending on timing of the biopsy and selection of the
biopsy site.
Stevens–Johnson syndrome/toxic epidermal
necrolysis
Human and animal
The diagnosis of SJS/TEN relies on history (sudden
onset, systemic signs of illness, drug history) and clinical
presentation, as summarized in Table 2.11,134 In human
420
Figure 13. Toxic epidermal necrolysis. (a) Cat. Photomicrograph
showing detachment of necrotic epidermis from the unremarkable
dermis (in distinction to burn lesions). Inset shows the complete kary-
olysis of detached epidermis. (b) Dog. Photomicrograph of peracute
lesions following levamisole treatment. Note pyknotic nuclei in the
detaching necrotic epidermis. Courtesy of Ken Mason. Haematoxylin
and eosin stain.
medicine, the number of mucosae is considered less
important that the nature of the clinical lesions (flat not
raised) and the extent of the epidermal detachment. It
may be worthwhile reconsidering the criteria reported
for canine SJS/TEN in light of this.27 Histopathology
plays a role in confirmation of the pathological process
and in differential diagnosis. In people, the early clinical
presentation may be indistinguishable from ‘ordinary’
drug rashes. In dogs, early lesions may resemble the
polycyclic lesions of ‘EM’ (Figure 1b). Thus, serum mark-
ers to distinguish such lesions from early TEN are of
great interest diagnostically. Soluble Fas-L, perforin/gran-
zyme B, soluble CD40 ligand, serum mobility group pro-
tein B1 (HMGB1), a-defensins and granulysin are
potential candidates.134,137,138 Fas ligand and granulysin
levels are of particular interest, because both increase
before development of skin detachment or mucosal
lesions.137,138 A rapid immunochromatographic strip
test100 for granulysin has been developed for humans
and should be investigated for use in animals.
The chief value of immunofluorescence/immunohisto-
chemical testing lies in ruling out autoimmune bullous
dermatoses.134 However, in a research setting, sensitive
assays were able to differentiate early lesions of EM
major from SJS/TEN by demonstrating significantly more
granulysin- and perforin-positive cells and significantly
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
 Erythema multiforme, SJS/TEN

fewer CD4+ and Foxp3 +(Treg) cells in the SJS/TEN mandatory. Persistent cases of canine EM may respond
group.71 to corticosteroids and azothiaprine (Table 3).18 However,
Frozen sections are used to facilitate rapid diagnosis when therapy is tapered, recurrences are common, par-
of SJS/TEN in people. While finding full-thickness epi- ticularly in idiopathic cases.18 Immunosuppressive drugs
dermal necrosis is highly sensitive, it is unfortunately of have been used successfully in treating hyperkeratotic
low specificity.134 Depending on the clinical stage, full- disorders with underlying lesions of epidermal cytotoxic-
thickness necrosis may be the dominant lesion in an ity. Ciclosporin was efficacious in PLIMFD;127 however,
EM biopsy (Figure 7b); conversely, mild cytotoxic (inter- the dosage required and the duration of therapy varied
face) dermatitis may be all that is present in some from dog to dog. Topical tacrolimus (0.1%) is effective in
lesions of SJS/TEN.14,139 Although dermal inflammation feline PNOE.51
is generally more intense in EM and epidermal cell
death is more prominent in SJS/TEN, pathologists can-
Stevens–Johnson syndrome/toxic epidermal
not accurately predict the clinical disease (or likehood of
necrolysis
mortality) from the histopathological findings.14,27,117 It
is the combination of histopathological findings in con- Human and animal
cert with the clinical presentation that renders the final Identifying the candidate drug through careful evaluation
diagnosis. of the history is crucial in the successful management of
patients with SJS/TEN, whether in human or veterinary
medicine.134,141 When multiple drugs have been used,
Treatment
discontinuing all candidate drugs is recommended.11 The
prompt withdrawal of the causative drug will reduce the
Erythema multiforme
chance of death in human TEN patients by ~30% per
Human day.142
Herpes-associated erythema multiforme is a self-limiting Unfortunately, there is no specific laboratory test to
disease, and treatment, if given at all, is usually symptom- confirm a particular drug involvement, and the gold stan-
atic.11,12 Administration of anti-HSV drugs has no effect dard (provocation testing) is obviously contraindicated.11
on the clinical course.140 Cessation of drug therapy is In vitro lymphocyte transformation tests, which measure
essential in those uncommon cases where EM is drug patients’ lymphocyte proliferative responses to specific
induced. Recurrent EM requires prolonged courses of an- drugs, have proven unreliable in SJS/TEN.143 Nor is patch
tiviral drugs.12 Idiopathic recurrent EM and persistent EM testing of recovered patients useful in identifying causal
may necessitate immunomodulatory treatment, in drugs retrospectively.144 However, ALDEN, which is an
addition to antiviral therapy. Drugs include azathioprine, algorithm of drug causality specific for human TEN, could
dapsone, mycophenolate, ciclosporin, prednisolone, anti- be adapted for animals.63
malarial drugs and intravenous immunoglobulin.12 There Aggressive patient monitoring and fluid and electrolyte
are no clinical trials to validate these treatments, and all therapy, pain therapy, antibiotic and symptomatic treat-
have significant adverse effects. ment for mucosal and cutaneous ulcerations are of para-
mount importance (reviewed by Schwartz et al.134). Early
Animal referral to a burns unit has been shown to improve sur-
In animals, given that there is no proven counterpart (as vival significantly.145,146
yet) to HAEM, spontaneous resolution without treatment A wide range of adjunctive immunomodulatory thera-
is unlikely. If a drug history can be elicited, withdrawal is pies are used in SJS/TEN (Table 3), but to date no spe-
Table 3. Treatment for erythema multiforme (EM) and Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in humans and animals
Disease Species Treatment
Erythema multiforme Human Symptomatic only for herpes-associated EM (HAEM)
Drug withdrawal for drug-induced EM (DIEM)
Antiviral therapy for recurrent EM
Adjunctive immunosuppressive/anti-inflammatory therapy including azathiaprine, mycophenolate,
dapsone, intravenous immunoglobulin, ciclosporin etc for recurrent and persistent EM
Dog and cat Drug withdrawal in appropriate cases
Supportive therapy
Immunosuppressive therapy in refractory, persistent cases (azathioprine, glucocorticoids,
pentoxyphylline, ciclosporin)*
SJS/TEN Human Drug withdrawal
Advanced supportive therapy (burn unit)
Adjunctive immunosuppressive therapy:* corticosteroids (early, high dosage, short duration),
ciclosporin, intravenous immunoglobulin, granulocyte colony-stimulating factor may promote
healing, tumour necrosis factor-a inhibitors such as infliximab and pentoxyphylline, plasmapheresis
(may remove pro-inflammatory cytokines), antioxidant and antiapoptotic (N-acetylcysteine)
Dog and cat Drug withdrawal
Advanced supportive therapy
Adjunctive immunosuppressive therapy:* glucocorticoids, azathioprine, ciclosporin,
intravenous immunoglobulin
*None of these treatments has been validated by evidence-based methodology.

© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64. 421

Yager

Table 4. Key points

• In humans, erythema multiforme (EM) is separate from SJS and TEN, but SJS and TEN are related conditions (SJS/TEN). There is currently no
consensus classification for animals.
• The chief underlying pathomechanism is a cytotoxic response by CD8+ T lymphocytes and natural killer cells directed against keratinocytes,
whose antigenicity is altered by infectious agents or drugs. Apoptosis results largely from direct cellular cytotoxicity (EM) or by actions of soluble
mediators of cell death (SJS/TEN). The soluble mediators include Fas ligand, granzymes, perforin and, most importantly, granulysin.
• The role of the pathologist is to confirm the presence of cytotoxic (interface) dermatitis and to rule out clinical differential diagnoses. Although
there are histological differences between EM and SJS/TEN, these conditions cannot reliably be distinguished by histological criteria alone.
• The diagnosis of EM and SJS/TEN is based on clinicopathological findings.
SJS/TEN is clinically similar in people and animals and is mostly triggered by drugs; occasionally by infectious agents.
• It is doubtful that a true counterpart to the most common manifestation of human EM (herpes associated) has been identified in animals, with
the possible exception of feline herpes-associated EM.
• A significant number of EM cases in animals are idiopathic. Drug reactions account for between 19 and 59% of canine cases based on two case
series. The vast majority of putative drug-related cases of EM in animals are not proven.
• A central veterinary database to collect and analyse EM and SJS/TEN cases, with the aim of developing a consensus classification system,
would be useful.

cific therapy has achieved the standards of evidence-
based medicine.11 The introduction of human intrave-
nous immunoglobulin (hIVIG) was heralded as a
breakthrough in the treatment of TEN.147 It is based on
the premise that cell death can be counteracted by high
concentrations of anti-Fas antibodies in the immunoglob-
ulin fraction.148 The results of numerous, often heteroge-
neous studies, into hIVIG efficacy are contradictory.134 It
is likely that institutions contributing to the early studies
offered a higher standard of supportive care, thus
confounding the results. Some studies have shown that
higher dosages of IVIG (>2 g/kg) were associated with
better outcomes.149 A recent meta-analysis indicated
that when data are adjusted for age, total body surface
area affected and delay in treatment, the hIVIG dose no
longer correlates with mortality. It may not be surprising
that many studies showed no significant effect on mor-
tality,150 given that granulysin is more likely than Fas-L to
be the main effector molecule. One review134 concluded
that further multicentre, randomized controlled trials,
employing a sufficiently large patient cohort for statistical
significance, are necessary to resolve the question.
Human IVIG is extremely expensive and is rarely
employed in animal cases. It has been used successfully
in treating a cat with postvaccinal ‘EM’ and two dogs
with probable drug reactions.102,132 A 2011 review of
indications for hIVIG therapy suggested great promise
for treatment of animal skin disease.151 Given the lack of
convincing evidence for efficacy in humans, as well as
the expense, hIVIG may not be justified for pets. The
possibility of serum sickness is another potential contra-
vention to its use in animals.
Corticosteroids have been a mainstay, albeit controver-
sial, in the treatment of human SJS/TEN.11 Concerns
about potential negative effects (increasing chance of
infection, interference with wound healing and higher
mortality rates) have not been borne out in larger stud-
ies.150 In humans, corticosteroids appear to have a role if
given early, in high doses and for a short period.134 There
are individual reports of apparently successful use of
immunosuppressive glucocorticoids or azathioprine in
dogs and cats with SJS/TEN or severe ‘EM’.1,18,37 There
is an insufficient body of data to determine optimal drug
dosages for animals, but the human experience suggests
that rapid effective immunosuppression with early taper-
ing may be the best route to follow.
422
Ciclosporin may prove to be an effective treatment for
SJS/TEN.37,134 As a calcineurin inhibitor, ciclosporin limits
lymphocyte proliferation, thus precluding release of cyto-
toxic products from activated CTLs, and also inhibits
intrinsic apoptosis. In a recent open study, 29 people with
SJS, SJS/TEN overlap or TEN received ciclosporin for at
least 10 days. There was rapid clinical improvement, and
the mortality rare was zero.152
Other treatments include plasmapheresis, N-acetyl-
cysteine and inhibitors of TNF-a (infliximab in humans
and pentoxiphylline in humans and animals).37,134,153
Granulocyte-stimulating colony factor (G-CSF), used for
TEN patients with granulocytopenia, promoted such
rapid re-epithelialization that it was suggested its use
should be considered in the absence of neutropenia.154
Cost (and availability) would probably be prohibitive for
animals.
Conclusions
The key points of this review are summarized in
Table 4. The contention that TEN in animals has been
correctly identified with the human disease is sup-
ported. It is also highly likely that SJS in animals is a
counterpart to the human disease. It would appear rea-
sonable, therefore, to ‘borrow’ from recent human
research to improve diagnosis (e.g. determine whether
serum granulysin levels are important as a predictor of
SJS/TEN in animals) and treatment (e.g. initial results
suggesting efficacy of ciclosporin). It is equally clear that
most cases of canine EM are not equivalent to HAEM,
the main form of human EM. Feline EM may represent
an analogous condition, but this remains to be proved.
Whilst some cases of canine EM are drug induced, a
significant proportion are idiopathic. These are likely to
represent a heterogeneous group of conditions, sharing
mechanisms but not aetiology. We do not know where
other diseases of epidermal cytotoxicity, such as feline
PNOE, some scaling dermatoses in Labrador retrievers
(and other breeds), so-called ‘old-dog’ EM, ‘hyperkera-
totic’ EM and exfoliative dermatoses of cats (whether
thymoma associated or not), should be classified. What
is needed is an international study group, charged with
the mandate to collect and analyse data and to develop
a standardized set of diagnostic criteria for EM and SJS/
TEN in animals.
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.

Acknowledgements
The author is very grateful to Steven Kossard for gener-
ous provision of illustrative material for human EM and
SJS/TEN and for helpful discussion of the review’s con-
tents. Veterinary colleagues Thierry Olivry, Jan Declercq,
Keith Linder, Ken Mason, Ann Hargis, Sherry Myers,
Kinga Gortel, Caroline de Jaham, Francesca Abramo,
Karen Beningo and Alessandra Fondati are likewise
acknowledged for their generous provision of clinical and
histological images and for discussions of this topic over
the years.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article.
Table S1. Bastuji-Garin et al.14 proposed clinical classifi-
cation of cases of toxic epidermal necrolysis, Stevens–
Johnson syndrome and erythema multiforme.
Table S2. Hinn et al.27 criteria for clinical classification of
canine erythema multiforme, Stevens–Johnson syn-
drome and toxic epidermal necrolysis.
Table S3. Prognostic scoring system for patients with
toxic epidermal necrolysis (SCORTEN).
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.
 Erythema multiforme, SJS/TEN

Resume 
Contexte – L’e rythe
me multiforme humain (EM) et le syndrome de Stevens–Johnson/ne crolyse epidermi-
que toxique (SJS/TEN) sont des atteintes distinctes. Il n’existe pas de consensus sur les crite res de classifi-
cation pour les maladies e ponymes de l’animal.
Resultats – L’EM chez l’animal est tre s diffe
rent des 90% des formes humaines associe es 
a l’herpes virus
(HAEM). Les animaux ne pre sentent pas d’atteintes des extre mite s par des le
sions en cible typiques. A la
rence de l’EM lie
diffe  au parvovirus canin, l’HAEM n’est pas une infection active. L’EM animal est souvent
 aux me
attribue dicaments mais est rarement prouve . A l’inverse, les SJS/TEN animal et humain sont pre-
sque identiques, typiquement de clenche par des me dicaments (parfois par des agents infectieux), entrai-
nant un de tachement et une ne crose epidermique. L’EM et SJS/TEN sont me die
s par une re ponse
lymphocytaire cytotoxique dirige e contre les keratinocytes alte re
s (agents infectieux ou drogues). L’apop-
tose resulte de la cytotoxicite directe (EM) ou des me diateurs solubles, appele s Fas ligand, granzymes,
perforine et granulysine (SJS/TEN). Le diagnostic chez l’homme est clinicopathologique avec une emphase
sions cliniques; l’histopathologie confirme le processus pathologique de dermatite d’interface (cy-
sur les le
totoxique). L’EM de l’homme est autolimitant; seuls les cas persistants ou re cidivants ne cessitent des
traitements antiviraux/immunosuppresseurs. L’EM me dicamento-induit re pond  ^t du traitement. Les
a l’arre
EM idiopathiques canins (>40%) sont habituellement chroniques, re fractaires aux traitements et peuvent
representer des conditions he  te
rogenes. Une identification pre coce, l’arre
^t du traitement  a l’origine des
sions et un traitement de soutien de haute qualite
le  sont indispensables pour les SJS/TEN. Le taux de
mortalite reste e
leve quoiqu’il en soit.
Conclusions et importance clinique – Les le sions histopathologiques ne permettent pas une distinction
fiable entre EM, SJS et TEN. Une e tude multicentrique est ne cessaire pour de velopper un consensus des
res cliniques de l’EM et SJS/TEN chez l’animal. Aucun traitement, y compris l’immunoglobuline intra-
crite
veineuse, n’ont permis de re unir des faisceaux de preuves suffisants mais la ciclosporine est prometteuse.

Resumen
Introduccio  n – El eritema multiforme humano (EM) y el sındrome de Stevens-Johnson/necrolisis epider-
mal toxica (SJS/TEN) son dos condiciones separadas. No existe un consenso en los criterios de clasificac-
n de las enfermedades epo
io nimas en animales.
Resultados – La EM animal es muy diferente de un 90% de las formas humanas de EM, que est a asociada
n por herpes virus (HAEM). Los animales no presentan distribucio
a la infeccio n en las extremidades dis-
tales de las tıpicas lesiones en diana. Al contrario que la EM producida por parvovirus canino, la HAEM no
es una infeccio n activa. La EM en animales a menudo se atribuye a f armacos, pero raramente se prueba.
Por el contrario, las formas animal y humana de SJS/TEN son casi ide nticas, con enfermedades de alto ries-
go para la vida produciendo necrosis epide rmica y separacio n, tıpicamente ocasionadas por f armacos (oca-
sionalmente agentes infecciosos). Tanto EM como SJS/TEN est an mediados por respuesta de linfocitos T
xicos frente a queratinocitos alterados (agentes infecciosos o f
to armacos). La apoptosis resulta de citotox-
icidad directa (EM) o a trave s de mediadores solubles, por ejemplo el ligando de Fas, grazimas, perforina, y
granulisina (SJS/TEN). El diagno stico en humanos es clınicopatolo gico, con e
nfasis en la lesiones clınicas;
la histopatologıa confirma el proceso patolo gico como una dermatitis de interfase (citoto xica). La EM en
humanos es autolimitante, solamente recidivante, y so lo en algunos casos raros persistentes se requieren
terapias antivirales/inmunosupresoras. La EM inducida por f armacos responde a la interrupcio n del tratami-
ento. La EM canina idiopatica (>40%) es habitualmente cro nica, resistente al tratamiento, y puede repres-
entar un grupo heteroge neo de condiciones. La identificacio n temprana y la retirada del farmaco causante,
ası como un cuidado me dico de alta calidad son crıticos en SJS/TEN. Sin embargo la mortalidad es au n ası
elevada.
Conclusiones e importancia clınica – Las lesiones histopatolo gicas no diferencian de forma definitiva
EM, SJS y TEN. Se necesita un estudio multice ntrico para desarrollar unos criterios clınicos consensuados
que permitan el diagno stico diferencial de EM y SJS/TEN en animales. No hay terapias adyuvantes, incluida
el tratamiento intravenoso con inmunoglobulina, que hayan presentado buenos resultados basados en evi-
dencia, aunque la ciclosporina es prometedora.

Zusammenfassung
Hintergrund – Erythema multiforme (EM) des Menschen und das Stevens-Johnson Syndrom/toxische
epidermale Nekrolyse (SJS/TEN) sind separate Krankheitsbilder. Es gibt keinen Konsens in Bezug auf die
€r diese namensgebenden Krankheiten bei Tieren.
Klassifikationskriterien fu
Ergebnisse – EM des Tieres ist sehr verschieden von 90% des EM des Menschen, welches mit Herpesvi-
rus im Zusammenhang steht (HAEM). Bei den Tieren fehlt die akrale Verteilung von typisch erhabenen Tar-
gets. Im Gegensatz zum „EM” durch canines Parvovirus ist HAEM keine aktive Infektion. EM beim Tier
wird oft auf Medikamente zuru €ckgefu
€hrt, obwohl das selten bewiesen werden kann. Auf der anderen Seite
sind SJS/TEN von Mensch und Tier fast identische, lebensbedrohliche Erkrankungen mit epidermaler Nek-
© 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64. e63
Yager

rose und Ablo €sung, welche typischerweise durch Medikamente (gelegentlich durch Infektionen) ausgelo €st
werden. Sowohl EM wie auch SJS/TEN werden durch zytotoxische Lymphozytenreaktionen gegenu €ber
ver€anderten Keratinozyten (infektio€sen Agentien oder Medikamenten) vermittelt. Die Apoptose resultiert
aus direkter Zytotoxizit€at (EM) oder durch lo
€sliche Mediatoren, n€ amlich Fas Ligand, Granzyme, Perforin
und Granulysin (SJS/TEN). Die Diagnose beim Menschen ist eine klinisch pathologische, mit Betonung auf
klinischen Ver€anderungen; die Histopathologie best€atigt den pathologischen Prozess als Interface (zytotox-
ische) Dermatitis. EM des Menschen ist selbst-limitierend; nur wiederkehrende und seltene persistierende
F€alle beno
€tigen antivirale/immunsuppressive Therapien. Medikamenten-induziertes EM reagiert auf Abset-
zen der Behandlung. Das idiopathische EM (>40%) des Hundes ist u €blicherweise chronisch, be-
handlungsresistent und ko €nnte heterogene Erkrankungen repr€ asentieren. Ein fru €hes Erkennen und ein
Absetzen des verursachenden Wirkstoffes und eine hochqualitative Intensivbehandlung sind bei SJS/TEN
essentiell. Die Sterberate ist dennoch hoch.
Schlussfolgerungen und klinische Bedeutung – Die histopathologischen Ver€ anderungen unterscheiden
nicht verl€asslich zwischen EM, SJS und TEN. Eine Multizenterstudie, um einen Konsensus fu €r ein Set an
klinischen Kriterien fu€r EM und SJS/TEN bei Tieren zu entwickeln, ist u €berf€
allig. Keine unterstu €tzenden
Therapien, wie intraveno €ses Immunglobulin, haben evidenz-basierte Standards erfu €llt, aber Ciclosporin ist
vielversprechend.

e64 © 2014 ESVD and ACVD, Veterinary Dermatology, 25, 406–e64.