Erythema Multiforme (EM)

Dr. Rakefet Czerninski

The Department of Oral Medicine
 Erythema Multiforme (EM)
Blistering, ulcerative, mucocutaneous
condition of uncertain etiopathogenesis

Immunologically mediated process

Acute onset

Prodromal symptoms: fever, malaise, headache, cough, •

sore throat (1 week before onset).
Acute self-limited eruption-A wide spectrum of severity:
EM minor :
Self-limited -
The lesions last for1-3 weeks without scarring.

Localized eruption of the skin –

Typical and/or atypical raised target lesions.

Less than 10% of the body surface area.

Mild (only 1 site is affected ) or no mucosal
involvement

Infectious trigger - likely.

EM major & Stevens-Johnson syndrome (SJS) :
more severe mucosal and skin diseases progressive,
fulminating, severe variant
with extensive mucocutaneous epithelial necrosis.
potentially life-threatening disorders.
SJS is uncommon: 1 to 6 per 1 million populations
 Usually affects:

• healthy young adults

• males >females.
• peak age at presentation 20 -40 years
(20% of cases occur in children)
 Etiology

Reaction primarily to antigens that are induced by

exposure of usually exogenous factors
(microbes, particularly viruses, or drugs )

. with sub- and intra-epithelial vesiculation.

There may be a genetic predisposition

 Exogenous factors -Viruses
up to 70% of recurrent cases -HSV-induced
herpes-associated EM- HAEM
HSV-DNA has been detected in 36–81%.

other herpesviruses (VZV, CMV, EBV)

• adenoviruses,
• enteroviruses (Coxsackie virus B5, echoviruses),
• hepatitis viruses (A, B and C),
• influenza,
• paravaccinia, parvovirus B19, poliomyelitis, vaccinia and
variola.
 HSV association EM (HAEM)

•In single &recurrent EM 70% of

patients give a history of a
preceding herpes infection
~2 wks before onset.

•acyclovir -success in treating a

high proportion of patients with
recurrent EM (even when there
is no clear clinical association
with HSV infection)
• result of a cell mediated
immune reaction to the
precipitating agent.
• In HAEM it is most likely that
HSV–DNA fragments in the
skin or mucosa precipitate the
disease.
• HSV–DNA fragments and in
particular DNA polymerase
(PoL) have been detected in
the basal and suprabasal cell
layers of the epidermis in
lesions as well as healed
lesions for up to 3 months
HAEM
most likely that HSV—DNA fragments
in the skin or mucosa precipitate the
disease.
CD34+ cells transport fragments of HSV to
the epithelium
and T cells accumulate in response to
HSV antigens and damage cells.
 Exogenous factors- other infectious
agents
Bacteria :Mycoplasma pneumoniae, borreliosis, cat
scratch disease, diphtheria, haemolytic streptococci,
legionellosis, leprosy, Neisseria meningitidis,
Mycobacterium avium complex, pneumococcus,
Proteus, Pseudomonas, Rickettsia, Salmonella,
Staphylococcus, syphilis, tuberculosis, tularemia,
typhoid, Vibrio parahaemolyticus, Yersinia, Chlamydia,
lymphogranuloma venereum and psittacosis
Fungal infections :coccidiodomycosis,
dermatophytes or histoplasmosis

Parasites :Trichomonas and Toxoplasma gondii.

Vaccines:
Diphtheria-tetanus
Hepatitis B
Small-pox
 Exogenous factors- Food additives or
chemicals

benzoates
nitrobenzene
perfumes or
terpenes
Drugs
T-cell-mediated immune reaction to the precipitating agent

Cytotoxic immunological attack on keratinocytes that

express non-self antigens,

subsequent sub-epithelial and intra-epithelial

vesiculation;

widespread blistering and erosions

Drug-induced EM: it is thought that
reactive drug metabolites induce the
disease,
keratinocyte apoptosis is induced by tumour
necrosis factor alpha (TNF-) that is
released from keratinocytes,
macrophages,and monocytes causes the
tissue damage.
• viral infections -trigger EM minor /major
• drug ingestion -trigger more severe SJS
• However this is not absolute

The etiology of EM is unclear in most patients

 Oral presentation

oral lesions in 70% of EM (minor /major)

precede other lesions or may arise in
isolation.
lips-
swollen
cracked,
bleeding
crusted
 Oral presentation
lesions progress to blisters
& ulceration

intraoral lesions on non-

keratinised mucosae
most pronounced - anterior
parts of the mouth.

some cases may be very

severe, particularly if
accompanied by
widespread oral ulceration
• Recurrences ~25% in wks -ys
usually attacks last for
10–20 days
once or twice a year

• usually resolve after about six

episodes (range: 2–24)
within a mean period of
10 years (range: 2–36 years).
 Clinical Features

Wide spectrum of severity,

from mild limited disease to a
severe, widespread and life-
threatening illness
 EM minor
• the mildest form
• typically 'target' lesions
/bullae on extremities.
• lesions may be itchy
• systemic symptoms
fever and malaise
• By definition, mucous
membrane involvement -
limited to one site
(usually oral). skin lesions, usually
symmetrically distributed
on the extensor surfaces
of the arms and legs
.
‫גב בכף היד‬ ‫בכף היד‬

‫ברגל‬ ‫זרוע‬
 Skin lesions-sub classification

“ Typical targets” - EM minor &

milder EM major

symmetrical distribution on the

extensor surfaces of the extremities
• individual lesions
• less than 3 cm diameter
• regular round shape,
• a well-defined border,
• 2 concentric palpable,
oedematous rings
• paler than the centre disc.
 EM major
• severe form of the disease
• involvement of multiple mucous membranes
(genital, ocular, laryngeal and esophagus)
• skin lesions like EM minor or atypical :
bullae & a greater area. 'Raised atypical targets' –
EM major or in SJS.

The value of distinguishing clinically-questionable

The minor and major forms are closely linked.

 Other mucosae

Eye involvement
Lacrimation and photophobia.

Genital lesions
painful - urinary retention
 Diagnosis

Difficult, need to differentiate from:

• Viral infections
• pemphigus,
• pemphigoid
• TEN
No specific diagnostic tests for EM
Diagnosis is mainly clinical
 Diagnosis
Diagnosis is mainly clinical
• supported if necessary by biopsy
of perilesional tissue,

with histological and immunostaining examination

However, pathology can be variable and
immunostaining is not specific for EM.
 Histopathology

epithelium -oedematous
intra- and sub-epithelial vesicles.
infiltration of lymphocytes and macrophages in the lamina
propria and within the epithelium
necrosis both of basal and supra-basal epithelial cells
 Diagnosis

EM major :
• complete blood count (CBC)
• urea and electrolytes,
• erythrocyte sedimentation rate (ESR),
• liver function tests,
• cultures from blood, sputum and erosive areas.
To identify an aetiological agent serology for
HSV/ M. pneumoniae,
or other micro-organisms.
 Treatment
Spontaneous healing of EM
up to 2–3 weeks in minor
up to 6 weeks in major EM.
Considered a benign self-limiting disease
Treatment -indicated but controversial
• Identification of the cause -if possible.
• drug -must be withdrawn.
• Infections -appropriately treated
(after cultures and/or serologic tests )
 Treatment

• acyclovir in HAEM
• tetracycline in EM related to M.
pneumoniae.

• A 5-day course of acyclovir at the first sign of lesions,

• prophylaxis in HAEM :400 mg qds for 6 months
• Continuous therapy of valacyclovir, 500 mg twice a day
 Treatment
• No specific treatment

• Supportive care is important;

liquid diet and IV fluid therapy may be
necessary.
Electrolytes and nutritional support.

• Symptomatic treatment:
oral antihistamines, analgesics, local skin care,
and soothing mouthwashes,
 Corticosteroids
Controversial.
Minor EM -

topical corticosteroids- may respond

systemic corticosteroids- may be required

Systemic corticosteroid: prednisone 40-80

mg per day for one to two weeks (rare)
(Al-Johani et. al. OOOOE 2007; 103:642-54)
moreux MR et. al. Am Fam Physician 2006;74: 1883-8)
 Corticosteroids
Major EM /SJS –
may need systemic corticosteroids

Prednisone 60 mg daily until lesions recede, then

decrease by 10 mg on each successive day
(Clinican’s Guide to Treatment of Common Oral
Conditions Fifth Edition, AAOM 2001).

Prednisolone 0.5–1.0 mg kg1 day1 tapered over 7–

10 days and/or azathioprine or other immunomodulatory
drugs.
• Beneficial effects of hemodialysis, plasmapheresis, cyclosporin,
immunoglobulin, levamisole, thalidomide, dapsone, and cyclophosphamide
have been documented in case reports.
 Medical Care

Early ophthalmological & dermatological consultation

(diagnosis and management)
The use of liquid antiseptics
(0.05% chlorhexidine),
during bathing is preferable.

Topical treatment, including that for genital involvement

& for eye involvement
Oral Diseases

Volume 11 Page 261 - September 2005

MUCOSAL DISEASES SERIES Number IV Erythema multiforme

P Farthing, J-V Bagan, C Scully