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British Journal of Oral and Maxillofacial Surgery 46 (2008) 90–95

Oral mucosal diseases: Erythema multiforme

Crispian Scully a,∗ , Jose Bagan b
a University College London, Eastman Dental Institute, UK
b Service of Stomatology, University General Hospital, Valencia, Spain

Accepted 19 July 2007

Available online 4 September 2007

Abstract

Erythema multiforme (EM) is a rare acute mucocutaneous condition caused by a hypersensitivity reaction with the appearance of cytotoxic
T lymphocytes in the epithelium that induce apoptosis in keratinocytes, which leads to satellite cell necrosis. EM can be triggered by a range
of factors, but the best documented association is with preceding infection with herpes simplex virus (HSV). Most other cases are initiated
by drugs.
EM has been classified into a number of variants, mainly minor and major forms, as it may involve the mouth alone, or present as a skin
eruption with or without oral or other lesions of the mucous membrane. EM minor typically affects only one mucosa, and may be associated
with symmetrical target skin lesions on the extremities. EM major typically involves two or more mucous membranes with more variable skin
involvement. A severe variant of EM major is Stevens–Johnson syndrome, which typically extensively involves the skin. Both EM major and
Stevens–Johnson syndrome can involve internal organs and produce systemic symptoms.
Treatment of EM is controversial, as there is no reliable evidence. Precipitants should be avoided or treated and, in severe cases, corticosteroids
may be needed.
Toxic epidermal necrolysis may be similar to Stevens–Johnson syndrome, but many experts regard it as a discrete disease, and therefore it
is not discussed here.
© 2007 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Keywords: Erythema multiforme; Autoimmune; Immunosuppressants; Oral; Vesiculobullous; Skin

Introduction one mucosa, and may be associated with symmetrical target

Erythema multiforme (EM) is a rare, acute inflammatory dis-
order that affects skin, or mucous membranes, or both. It often
recurs.
EM usually affects apparently healthy young adults and
the peak age at presentation is 20–40 years although as many
as 20% of cases are children.1,2
It has been classified into several variants, mainly minor
and major forms, as it may involve the mouth alone, or may
present with a skin eruption, with or without lesions of oral or
other mucous membranes. EM minor typically affects only
∗ Corresponding author at: Eastman Dental Institute, University College
skin lesions on the extremities. EM major typically involves
two or more mucous membranes with more variable skin
involvement. A severe variant termed Stevens–Johnson syn-
drome usually involves the skin extensively.
It is not clear whether Stevens–Johnson syndrome and
toxic epidermal necrolysis are distinct aetiological and patho-
logical entities,3 so we discuss EM only: toxic epidermal
necrolysis is discussed elsewhere.4,5
Aetiology and pathogenesis

London, 256 Gray’s Inn Road, London WC1X 8LD, UK.

EM is a disorder that reacts primarily to antigens that are
Tel.: +44 20 7915 1038; fax: +44 20 7915 1039. induced by exposure to microbes or drugs,5 and has been
E-mail address: cscully@eastman.ucl.ac.uk (C. Scully). reported to be triggered by numerous microbial agents, par-

0266-4356/$ – see front matter © 2007 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.bjoms.2007.07.202
 C. Scully, J. Bagan / British Journal of Oral and Maxillofacial Surgery 46 (2008) 90–95
ticularly viruses, mainly herpes simplex virus (HSV), which
is implicated in up to 70% of recurrent cases.6 Many patients
with EM give a history of a preceding HSV infection within
two weeks of the onset of the condition, and 7–10 HSV-
DNA has been detected in 36–81%.11–16 A more recent study
using nested PCR (polymerase chain reaction) found HSV-
1 in 66%, HSV-2 in 28%, and both HSV1 and 2 in 6% of
patients.17 HSV-induced EM is called herpes-associated EM,
or HAEM.
A range of drugs may also precipitate EM.5,18–21 (Table 1).
Previous use of medication has been identified in 59% of
cases, and there has been a striking increase in the number of
cases caused by cephalosporins.22
Other precipitants are diverse: for example, one type of
EM has been associated with phenytoin and cranial radiation
therapy (hence the term EMPACT).23
EM seems to result from a T-cell-mediated immune reac-
tion to the precipitating agent, which leads to a cytotoxic
immunological attack on keratinocytes that express non-self-
antigens, with subsequent sub-epithelial and intra-epithelial
vesiculation; this leads to widespread blistering and erosions
(Fig. 1).
In HAEM it is most likely that HSV—DNA fragments
in the skin or mucosa precipitate the disease.15 CD34+
cells transport fragments of HSV to the epithelium,24 and
T cells accumulate in response to HSV antigens and dam-
age cells.25,26 However, in drug-induced EM, it is thought
that reactive drug metabolites induce the disease,27 and
keratinocyte apoptosis is induced by tumour necrosis fac-
tor alpha (TNF-␣) that is released from keratinocytes,
macrophages, and monocytes causes the tissue damage.28
Fig. 1. Pathogenesis of erythema multiforme.
91
There may be a genetic predisposition to EM, with various
HLA associations, but none are diagnostic.
In the Stevens–Johnson syndrome/toxic epidermal
necrolysis disease spectrum, activated T lymphocytes,
macrophages, and neutrophils, seem to be implicated in the
tissue damage by the Fas/FasL apoptotic pathway, and the
CD40/CD40L system may be an important pathway of induc-
tion of the lesions.29
Clinical features
The presentation of EM ranges from a self-limited,
mild, exanthematous variant with minimal oral involve-
ment (EM minor) to a progressive, fulminating, severe
variant with extensive mucocutaneous epithelial necrosis
(Stevens–Johnson syndrome), with EM major intermediate in
severity. In general there seems to be an association between
the type of aetiological agent and the severity of the disease,
so viral infections seem to trigger EM minor or major, but
drug ingestion tends to trigger more severe Stevens–Johnson
syndrome.30
Oral lesions
Oral involvement is seen in some 70% of patients with EM
with:
• lips that become swollen and cracked, bleeding, and
crusted (Figs. 2 and 3);
 92
Table 1
Most common associations with erythema multiforme
Micro-organisms Drugs Food additives or Immune and other

C. Scully, J. Bagan / British Journal of Oral and Maxillofacial Surgery 46 (2008) 90–95
chemicals conditions

Viruses Bacteria Fungi and parasites

Herpes viruses: Mycoplasma pneumoniae Coccidiodomycosis, Allopurinol Benzoates Graft versus host disease
(Herpes simplex viruses, Varicella-zoster virus, Borreliosis, Dermatophytes, Barbiturates Nitrobenzene Immunisation: (BCG,
Cytomegalovirus, Epstein-Barr virus) Cat scratch disease Histoplasmosis, Cancer chemotherapeutic agents Perfumes hepatitis B, smallpox)
Adenoviruses Chlamydia Sporotrichosis Carbamazepine Terpenes Inflammatory bowel
disease
Enteroviruses: Corynebacterium diphtheriae Trichomonas Cephalosporins Polyarteritis nodosa
(Coxsackie virus B5, echoviruses), Haemolytic streptococci Toxoplasma gondii Herbal remedies Pregnancy
Hepatitis viruses (A, B, and C), Legionellosis Lamotrigine Sarcoidosis
Human immunodeficiency viruses: Lymphogranuloma venereum Non-steroidal anti-inflammatory drugs Systemic lupus
erythematosus
Influenza, Neisseria meningitidis
Paravaccinia, Mycobacterium avium complex Penicillins
Parvovirus B19 Mycobacterium leprae Phenytoin
Poliomyelitis Mycobacterium tuberculosis Progesterone
Vaccinia Proteus Protease inhibitors
Pseudomonas Sulphonamides
Psittacosis
Rickettsia
Salmonella
Staphylococcus
Streptococcus pneumoniae
Treponema pallidum
Tularemia
Typhoid
Vibrio parahaemolyticus
Yersinia
 C. Scully, J. Bagan / British Journal of Oral and Maxillofacial Surgery 46 (2008) 90–95 93

Fig. 2. Labial lesions of erythema multiforme showing blood-stained crusted

lips.

Fig. 4. (a) and (b) Intraoral erosive lesions of erythema multiforme.

Fig. 3. Labial lesions of erythema multiforme showing diffuse erosions.

• intraoral lesions typically on the non-keratinised mucosa
and most pronounced in the anterior parts of the mouth.
Diffuse and widespread macules blister and ulcerate, pro-
ducing a clinical picture that is difficult to differentiate
from other vesiculobullous disorders (Fig. 4a and b).
Other mucosa
Involvement of the eye may cause lacrimation and photo-
phobia. Genital lesions are painful and may cause urinary
retention.
EM minor
In EM minor, involvement of the mucous membrane is
limited to one site only - usually the oral mucosa.31 EM
minor is often also characterised by rashes, which are usu-
ally symmetrically distributed on the extensor surfaces of
the arms and legs. Rashes are various but typically they are
“iris” or “target” lesions or bullae on extremities, which may
itch.5

Skin lesions

Skin lesions in EM minor (Fig. 5) are usually macules or

erythematous papules that develop into classic target or iris
lesions in a symmetrical distribution. Occasionally bullae
may develop. “Typical targets” are defined as individual
lesions less than 3 cm diameter with a regular round shape, a
well-defined border, and two concentric palpable oedematous
rings, paler than the centre disc.
“Raised atypical targets” are most common in severe EM
major and Stevens–Johnson syndrome. They are similar in
appearance to target lesions, but are palpable. Fig. 5. Cutaneous lesions of erythema multiforme.
94 C. Scully, J. Bagan / British Journal of Oral and Maxillofacial Surgery 46 (2008) 90–95
EM major
EM major is more severe, and is characterised by involve-
ment of multiple mucous membranes31 —the oral cavity, and
others including the genital, ocular, laryngeal, or oesophageal
mucosae, or a combination. The skin lesions usually resem-
ble those of EM minor but may also be atypical, raised and
can include bullae.
Stevens–Johnson syndrome
Stevens–Johnson syndrome is more severe than EM major,
and causes widespread lesions that affect the skin; there are
lesions in the mouth, eyes, pharynx, larynx, oesophagus, and
genitals (balanitis, urethritis or vulval ulcers, or both), and
sometimes flu-like symptoms, fever, sore throat, headache,
arthralgias, myalgias, pneumonia, nephritis, or myocarditis.
Ocular changes that resemble those of mucous membrane
pemphigoid – dry eyes and symblepharon – may result, and
Stevens–Johnson syndrome may be followed by sicca syn-
drome, or even Sjögren’s syndrome.32
Diagnosis of EM
The clinical appearance of diffuse and widespread oral
ulceration can be difficult to differentiate from other vesicu-
lobullous disorders such as pemphigus or pemphigoid. EM
should also be differentiated from viral stomatitides, and
toxic epidermal necrolysis.5 Features more suggestive of EM
are
• the acute onset (or recurrent nature),
• oral erosions typically located on the lip and anteriorly in
the mouth, and
• pleomorphic skin and other lesions.
There are no specific diagnostic tests for EM, and so the
diagnosis is usually supported by perilesional tissue biopsy
and exclusion of other causes. Histological examination
and immunostaining often show intraepithelial oedema and
spongiosis early on, with satellite cell necrosis (individual
eosinophilic necrotic keratinocytes surrounded by lympho-
cytes), vacuolar degeneration of the basement membrane
zone, and severe papillary oedema with sub-epithelial or
intra-epithelial vesiculation. There is intense lymphocytic
infiltration at the basement membrane zone and perivascu-
larly, and non-specific immune deposits of IgM, C3, and fibrin
at these sites. However, signs can be variable and immunos-
taining is not specific for EM.
A complete blood count; measurement of urea and elec-
trolytes, erythrocyte sedimentation rate (ESR), and liver
function tests; together with HSV and mycoplasma serol-
ogy; and microbial cultures from blood, sputum, and erosive
areas should be taken in severe cases.
Management of EM
Any precipitants should be removed or treated. Causal drugs
should be stopped and relevant infections treated. Antiviral
agents may be indicated in HAEM, and a 5-day course of
aciclovir 200 mg five times daily at the first sign of lesions,
or 400 mg four times daily for 6 months, or continuous treat-
ment using valacyclovir, 500 mg twice a day, is useful for
prophylaxis. Tetracycline 250 mg four times a day for at least
one week may be indicated in EM related to Mycoplasma
pneumoniae.
No specific treatment is available for EM itself, but anal-
gesics and a liquid diet may be necessary. In severe forms of
EM, hospital and supportive care are often important: intra-
venous fluids may be required, as may early ophthalmological
and dermatological consultations.
Corticosteroids are the most commonly used drugs in the
management of EM, despite the lack of evidence. EM minor
may respond to topical corticosteroids. Patients with EM
major or Stevens–Johnson syndrome should be treated with
systemic corticosteroids (prednisolone 0.5–1.0 mg/kg/day
tapered over 7–10 days) or azathioprine, or both, or other
immunomodulatory drugs22 such as cyclophosphamide, dap-
sone, cyclosporin, levamisole, thalidomide,33,34 or interferon
␣.35,36
Ciclosporin given intermittently may control recurrent
EM.36
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