Erythema Multiforme

Dr Eman Alsheikh
ORAL MEDICINE
Oral Medicine Dr Eman Alsheikh

Erythema Multiforme
It is a rare immune-mediated mucocutaneous disorder that is acute in onset, recurrent
in nature & it is usually self-limiting.

Definition:
It's defined as acute, Self-limited, VB, inflammatory mucocutaneous disease that
manifests on the skin & often oral mucosa, other mucosal lesions such as genital mucosa,
or ocular mucosal may be involved.

Pathogenesis
EM represents hypersensitivity reaction to infectious agent or medications (majority of
the cases).
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Etiology
Numerous factors have linked to the development of EM.
These include:
1. Infections, (90% of cases) >> The most common infectious agent is HSV
2. Medication use, (less than 10% of cases)
3. Malignancy,
4. Autoimmune disease,
5. Radiation,
6. Immunization,
7. Menstruation.

** Foodstuffs (Benzoates, Nitrobenzene), & chemicals (Perfumes) may also act as

triggering factors

This bacterium appears to have particular importance in the

1. Infections: development of EM in children.
Infectious agents include:
i. Bacterial (Mycoplasma pneumonia, Borreliosis).
ii. Viral (Adenoviruses, Enteroviruses).
iii. Fungal infections (Coccidiodomycosis, Dermatophytes).
Oral Medicine Dr Eman Alsheikh

* Herpes associated EM:

Majority of EM patients have a history of prior herpes simplex virus (HSV) infection.
Although HSV type-1 is the most commonly associated cause, HSV type-2 can also
induce EM.

2. Drugs:
I. Antibiotics (penicillin, cephalosporins, sulphonamides)
II. Anticonvulsant drugs (Phenytoin)
III. Non-Steroidal Anti-Inflammatory Drugs (NSAIDS)
IV. Barbiturates
V. Carbamezapine

* Idiopathic:
Majority of pts have no history of recent drugs administration or infections which maybe
related to the development of EM.

Classification:
In general EM is classified as:
1) EM minor “if there is less than 10% of skin involvement & there is minimal to no
mucous membrane involvement”

2) EM major “more extensive & characteristic skin involvement with the oral mucosa &
other mucous membrane affected”

* There is a subset of EM that affects the oral mucosa only without skin involvement.
“Oral EM”
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Note:
Historically some forms of EM labeled as Steven-Johnson syndrome (SJS), & toxic
epidermal necrolysis (TEN/ Lelly’s disease). However, more recent data suggests that
EM is etiopathogenetically distinct from SJS &TEN.

⚫ Assignment >>compare between SJS and TEN {causes, symptoms & management}
Oral Medicine Dr Eman Alsheikh

Clinical Presentation

Age:
- Generally, affects those bet 20-40 years.
- 20% occurring in children.

Remission
- Remission occurred in 20% of cases.

Prodrome
- Fever - Sore throat
- Headache - Rhinorrea
- Malaise - Cough

Skin lesions:
- Onset: Appear rapidly over a few days.
- Shape & Distribution: Start as red macule that become papular, beginning primarily
in hands & moving centripetally towards trunk in a symmetric distribution.
- Site: Upper extremities, face & neck.

-The classic skin lesion consists of a central blister or necrosis with a concentric ring of
variable color around it called typical “targetoid” or “iris” lesion {that is pathognomic
of EM}; variants are called “atypical target” lesions.
-The skin may feel itchy & burnt 'burning sensation'.
-Post-inflammatory hyperpigmentation is common in dark-skinned individuals & may
worsened by sun exposure.
Oral Medicine Dr Eman Alsheikh

Oral findings:
- The oral lesions in EM range from mild erythema & erosion to large painful ulceration.
*Severe form:
a) Ulcers are large & confluent >> causing difficulty in eating, drinking & swallowing.
b) Pts may drool blood-tinged saliva
c) Extensive lip involvement with inflammation, ulceration & crusting is common.

- Oral lesions are present in 23%-70% of pts with recurrent EM.

- Intraoral lesions take the form of irregular bullae, erosions, or ulcers
surrounded by extensive erythema.

*Sites:
The most commonly affected site are:
 Lips 36%
 Buccal mucosa 31%
 Tongue 22%
 Labial mucosa 19%

Other mucosal sites:

* Genital & ocular sites are affected in 25 & 17% of cases respectively.
Oral Medicine Dr Eman Alsheikh

Differential diagnosis:
1) Primary HSV gingivostomatitis.

2) Autoimmune diseases such as emphigus/ pemphigoid

3) SJS (with major EM)

4) Recurrent aphthous ulcer (with recurrent oral EM)

Primary HSV gingivostomatitis:

Similar in: viral prodrome / erosion / & ulcerations

Diff by: oral ulcers of HSV are smaller & well circumscribed, whereas EM lesions are
larger & irregular.

Autoimmune diseases such as emphigus/ pemphigoid

Similar in: oral + skin lesions

diff by: shape of the lesion / EM is acute heals within weeks whereas Autoimmune
diseases are chronic & slowly progressive diseases that usually persists for months.

SJS
Similarity: crusts on lips, skin lesions

diff by:
- Macular atypical targetoid lesions, widespread dusky erythema with blisters.
- Usually begins on trunk and spreads distally
- Painful, tender skin
- Severe mucosal involvement (mucosal erosions present in at least one site in >90% of
patients) & Presence of constitutional symptoms

-Pathology: Extensive epidermal necrosis with paucity of inflammatory cells

Oral Medicine Dr Eman Alsheikh

RAU:
*with oral EM

- Similarity: oral ulcerations without skin lesions

- diff by: RAU ovoid or round ulcers whereas the ulcers of EM more diffuse & irrigular
with marked erythema.

Diagnosis
1. Clinical history

2. Clinical examination

3. Skin biopsy

4. Laboratory studies

➢ Clinical history
- Acute, episodic, self-limiting
- Symptoms of HSV, Mycoplasma pneumoniae and other infections
- Thorough medication history

➢ Clinical examination
- Acral extremities
- Typical targets
- Raised atypical targets
- Mucosal involvement

➢ Skin biopsy
- Hematoxylin & eosin stain
- Direct immunofluorescence
- Tzanck smear and/or skin, oral or genital swab sent for HSV PCR
Oral Medicine Dr Eman Alsheikh

➢ Laboratory studies
a) Testing for ESR, white blood cell count, liver function enzymes, electrolytes
b) When respiratory symptoms, then M. pneumoniae serologic testing, chest
radiograph, throat swab PCR for M. pneumoniae
c) Indirect immunofluorescence to rule out autoimmune blistering disorder

* Histopathology:
Early:
Cutanous lesions show lymphocytes & histiocytes in the superficial dermal vessels.

later:
- Hydropic degeneration of basal cells
- Keratinocyte apoptosis & necrosis
- Superficial bulla formation
- Lymphocyte infiltration
*Leukocyte exocytosis is also usually noted.

*Similar changes are seen in the biopsies of pts with oral EM.

Management:
- Mild:
Pain >> systemic / topical analgesics.
SLD “resolve within weeks” >> supportive
care.

- More severe:
Systemic Cs
Topical Cs “help resolve lesions”

* HIV cases:
- Antiviral medications (acyclovir: at the first sign of disease in recurrent EM >> control
the disease)
Oral Medicine Dr Eman Alsheikh

- Other drugs:
i. Dapsone “100-150 mg/d”
ii. Hydroxycoroquin “antimalarials”
iii. Colchicine
iv. Intravenous immunoglobulin

NOTE
- Continuous acyclovir at 400 mg/day prevent development of EM in most pts with
HSV associated disease
- EM not related to HSV respond well to azathioprine “100-150 mg/d”

*Ophthalmology consultation is imperative for pts with ocular involvement in order to

evaluate & manage involvement & to prevent long-term sequelae.

ttt of oral EM:

Patients with minimal involvement such as painful erosions, can be treated with:
- High-potency topical Corticosteroids gel
- Oral antiseptic washes
- Oral anesthetic solutions.

Some patients have extensive mucosal involvement & debilitating pain that prevents
sufficient oral intake.
These patients may require systemic Cs (such as Prednisone [40–60 mg/d with dosage
tapered over 2–4 weeks] to decrease severity & disease duration.

Question:
An 8-year-old boy presents with targetoid lesions on his hands and face. He has
recently received a 5-day course of azithromycin for treatment of a febrile illness with
upper respiratory symptoms. He has no prior history of herpes simplex virus infection.
What is the most likely inciting agent of his condition?
a. Epstein–Barr virus.
b. Mycoplasma pneumoniae infection.
c. Azithromycin therapy.
d. Parvovirus B19 infection.
e. Adenovirus infection.