Clinical case
A 25-year-old women presents to the oral medicine department with a two week history of painful oral ulcers, bloody crusting on the lips, and difficulty eating due to severe oral pain. One week ago she experiences a cold sore on her upper lip.
On examination she has widespread irregular erosions affecting both buccal and labial mucosa, tongue, and blood-stained crusting of both lips. Multiple target lesions are present across the back of her hands and forearms.
Pathophysiology
Erythema multiforme is an acute immune-mediated mucocutaneous disorder characterised by epithelial cell injury resulting from a delayed type IV hypersensitivity reaction. Most cases are triggered by infection, particularly herpes simplex virus (HSV) or mycoplasma bacteria, however erythema multiforme can also be triggered by medications.
Erythema multiforme exists on a spectrum ranging from mild disease affecting the skin alone to severe mucosal involvement. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are now generally regarded as distinct conditions, although they share some clinical and pathological features.
Key mechanisms include:
Cell-mediated immune response directed against keratinocytes expressing foreign antigens.
Cytotoxic CD8+ T lymphocyte-mediated destruction of epithelial cells.
HSV infection is the most common precipitating factor, accounting for the majority of recurrent cases.
Drug-induced cases may occur following exposure to antibiotics, non-steroidal anti-inflammatory drugs (NSAIDs) and anticonvulsants.
Inflammatory damage results in epithelial necrosis and ulceration of the oral mucosa and skin.
Epidemiology and Risk Factors
Erythema multiforme most commonly affects adolescents and young adults but can occur at any age.
Clinical Features
Symptoms
Acute onset of painful oral ulceration.
Difficulty eating, drinking and speaking.
Burning sensation of the oral mucosa.
Lip pain and crusting.
Skin rash, particularly affecting the extremities.
History of preceding herpes simplex infection in many cases.
Constitutional symptoms such as malaise, fever and headache may occur.
Signs
Oral manifestations
Widespread irregular ulcers and erosions affecting the oral mucosa.
Haemorrhagic crusting of the lips (a characteristic finding).
Buccal mucosa, labial mucosa, tongue and soft palate are commonly affected.
Oral lesions are often more extensive and painful than recurrent aphthous ulceration.
Gingival involvement may occur.
Cutaneous manifestations
Classic target (iris) lesions consisting of:
Central dusky or necrotic zone.
Surrounding pale oedematous ring.
Outer erythematous halo.
Typically distributed symmetrically on the hands, forearms, feet and lower limbs.
Lesions may be papular, macular or bullous.
Other mucosal involvement
Conjunctival inflammation.
Genital ulceration or erosions.
Nasal or pharyngeal mucosal involvement.
Investigations
Diagnosis for erythema multiforme is usually made clinically, as there is no single gold standard investigation, however work up for cases of erythema multiforme can be used to identify precipitating factors and exclude alternative diagnosis'. These can include:
Full medication history for potential drug triggers
Blood tests (FBC, CRP, ESR, U+E)
Viral investigations for HSV (e.g. PCR swabs)
Mycoplasma testing if clinically indicated - e.g. chest XR, sputum sample
Incisional biopsy with histopathological assessment
Direct immunofluorescence to exclude vesiculobullous disorders
In recurrent or persistent erythema multiforme without a clear precipitant, there should be consideration for solid organ/haematological malignancies
Differential diagnosis
Recurrent aphthous stomatitis → localised recurrent oral ulcers without skin lesions or haemorrhagic lip crusting.