Erythema Multiforme

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Erythema multiforme (EM)\: a type IV hypersensitivity reaction presenting with a skin rash, often triggered by infection
(commonly herpes simplex virus) or drug reactions. Typically a
Pathophysiology\: suspected immune system-triggered in
fragments on distal skin cells attracting CD4+ T helper cells. Drug-associated EM involves CD8+ cells and tumour necrosis
factor-alpha.
Common causes\: HSV-1, HSV-2, M y c o p l a s m a p n e u m o n i a e . Drugs\: anticonvulsants (barbiturates, phenytoin), NSAIDs,
antibiotics (amoxicillin, ampicillin, sulphonamides, tetracyclines).
EM major\: a
Johnson syndrome.
Risk factors\: previous EM episodes, HSV infection, M y c o p l a s m a p n e u m o n i a e infection. Others\: causative medications,
hepatitis B vaccination, syphilis, Epstein-Barr virus, cytomegalovirus, HIV, hepatitis B, lymphoma, tattoos.
Clinical features\:
EM minor\: no prodromal symptoms, starts with round erythematous macules progressing to target lesions (dark centre,
pale oedematous ring, outer darker ring). Lesions are pruritic, typically on acral and extensor surfaces, progressing
proximally.
EM major\: prodromal symptoms (weakness, joint pain, fever) 1 week before rash. A
commonly oral mucosa, with erythema and oedema.
Di
mouth disease, aphthous/herpetic stomatitis, Stevens-Johnson syndrome.
Investigations\: clinical diagnosis, skin biopsy if uncertain (apoptotic keratinocytes, spongiosis, epidermal necrosis, dermal
oedema, perivascular lymphocytic in
Management\: usually self-limiting. Treat underlying infection\: acyclovir for HSV, doxycycline for mycoplasma. Supportive
care\: oral antihistamines, topical corticosteroids, antiseptic mouthwashes, ophthalmological input if ocular involvement, oral
acyclovir for recurrent EM, hospital admission for severe oral involvement.
Complications\: EM minor resolves in 2-3 weeks, EM major up to 6 weeks. Potential mild skin discolouration, rare scarring.
Secondary infections and eye involvement can lead to scarring and reduced visual acuity.
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Introduction

Erythema multiforme (EM) is a type IV hypersensitivity reaction which presents with a skin rash.
It is typically triggered by an infection (most commonly herpes simplex virus) however it can also develop secondary drug
reactions. EM typically a
1
Erythema multiforme is characterised by target-like lesions which appear on the hands and feet and progress proximally.
It is an uncommon skin disorder, a
2Aetiology
While the pathophysiology of erythema multiforme is unclear, it is suspected that the immune system triggers an
in
2
Herpes simplex virus
Herpes simplex virus-associated erythema multiforme is caused by virus DNA fragments being deposited on distal skin
cells by monocytes, attracting CD4+ T helper cells which release interferon-gamma and trigger the in
cascade.
3
HSV-1 is the most likely causative organism, however, HSV-2 and M y c o p l a s m a p n e u m o n i a e are other possible causes.
4
HLA-DQ3 is an important marker that can be used to di
types of EM and cutaneous disorders.
3
Medications
In drug-associated erythema multiforme, the in
rather than the CD4+ cells associated with herpes simplex virus-associated EM.
3
Drugs associated with the development of erythema multiforme include\:
4
Anticonvulsants such as barbiturates and phenytoin.
Non-steroidal anti-in
Antibiotics including amoxicillin, ampicillin, sulphonamides and tetracyclines.
Erythema multiforme major
Erythema multiforme major a
1
mucosa.
The lesions in this form of erythema multiforme are more likely to blisters which can spontaneously burst.
4
It is important to note that while this form of erythema multiforme looks similar to Stevens-Johnson syndrome, they are
separate conditions which are di

Risk factors

The main risk factors for erythema multiforme include\:
5
Previous episodes of EM
Herpes simplex (1 or 2) infection
M y c o p l a s m a p n e u m o n i a e infection
Other potential risk factors include\:
Exposure to causative medications
Hepatitis B vaccination
Syphilis
Epstein-Barr virus
Cytomegalovirus
HIV infection
Hepatitis B
Lymphoma
Tattoos

Clinical features

Erythema multiforme minorErythema multiforme minor typically features no prodromal symptoms and classically starts with round erythematous
macules. 1
These macules then develop into papules which then progress to the target lesions characteristic of erythema
multiforme.
6
The target lesions have a dark centre with a blister or a crust, surrounded by a pale oedematous ring, which is then
surrounded by an outermost darker ring. Atypical lesions can also occur which have only two zones.
1
EM minor has a polymorphous pattern due to the di
1
be necessary to identify the target lesions. EM minor lesions may also be pruritic, so excoriation marks may be noted.
The distribution of lesions typically involves the acral and extensor surfaces of the extremities. These lesions then progress
proximally towards the trunk (however the trunk is usually less a
6
Figure 1. Erythema multiforme classical target lesions.
7
Erythema multiforme major
Erythema multiforme major typically involves prodromal symptoms including weakness, painful joints and fevers that
present around one week prior to the cutaneous manifestations of the disease.
1,6
EM major also a
oedema. 6
The oral mucosa is most often a
gastrointestinal, ocular and respiratory sites.
1,6

Di

Di
9
Urticaria
Dermatitis herpetiformis
Vasculitis
Pemphigus
For those with mucosal involvement, the di
Hand, foot and mouth disease
Aphthous stomatitis
Herpetic stomatitis
Steven-Johnson syndromeInvestigations
In most cases, the diagnosis of erythema multiforme is made based on clinical examination
2
If there is diagnostic uncertainty, a skin biopsy can be performed. Histology typically reveals the following\:⁸
Apoptotic and degenerative keratinocytes at the base of the epidermis
Spongiosis and blisters in the epidermis
Small areas of epidermal necrosis (large sheets of epidermal necrosis are often seen in toxic epidermal necrolysis and
Stevens-Johnson syndrome)
Super
Perivascular lymphocytic in
Further investigations can be performed to determine whether herpes simplex or mycoplasma is the cause of erythema
multiforme (e.g. swabs, sputum sample, chest X-ray).
2

Management

Most cases of erythema multiforme require no treatment as the condition is self-limiting. However, if erythema multiforme
develops secondary to an infective cause, this should be treated.
Acyclovir is used to treat herpes simplex infections and doxycycline is used to treat mycoplasma infections.
Other supportive management options include\:
1
Oral antihistamines and topical corticosteroids\: to reduce pruritis.
Mouthwashes which have antiseptic and local anaesthetic components\: to help with oral pain.
Ophthalmological input\: if there is ocular involvement.
Oral acyclovir (taken for 6 months)\: for recurrent erythema multiforme (even if herpes simplex is not an obvious trigger).
Hospital admission\: if there is severe oral involvement. Hospitalisation is to aid with nutrition and
preventing secondary infection of the lesions.

Complications

Erythema multiforme minor will usually resolve spontaneously over two to three weeks while erythema multiforme major
can take up to six weeks to completely resolve. There may be mild skin discolouration following this condition, but
scarring is rare.
1
Secondary infection may develop at sites of EM.
Eye involvement in erythema multiforme major can result in scarring and reduced visual acuity.
1

References

DermNet NZ. E r y t h e m a M u l t i f o r m e . Published in 2015. Available from\: [LINK]
Plaza, J. E r y t h e m a M u l t i f o r m e . Published in 2020. Available from\: [LINK]
Lamoreux M, Sternbach M, Hsu T. E r y t h e m a M u l t i f o r m e . Published in 2006. Available from\: [LINK]
Stinson A. W h a t T o K n o w A b o u t E r y t h e m a M u l t i f o r m e . Published in 2018. Available from\: [LINK]
BMJ Best Practice. E r y t h e m a M u l t i f o r m e . Published in 2018. Available from\: [LINK]
Sokumbi O, Wetter D. C l i n i c a l f e a t u r e s , d i a g n o s i s , a n d t r e a t m e n t o f e r y t h e m a m u l t i f o r m e \: a r e v i e w f o r t h e p r a c t i c i n g
d e r m a t o l o g i s t . Published in 2012. Available from\: [LINK]
Figure 1. Grook Da Oger. E r y t h e m a M u l t i f o r m e E M . Licence\: [CC-BY-SA]. Available from\: [LINK]
Figure 2. Dermatology Atlas. E r y t h e m a m u l t i f o r m e . Available from\: [LINK]Benedetti J. E r y t h e m a M u l t i f o r m e . Published i2020. Available from\: [LINK]
DermNet NZ. E r y t h e m a m u l t i f o r m e \: h i s t o l o g i c a l f e a t u r e s a n d m e c h a n i s m s . Published in 2009. Available from\: [LINK]

Reviewer

Dr Leah Mapara
Clinical fellow in dermatology

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Contents

Introduction
Aetiology
Risk factors
Clinical features
Di
I ti ti
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