Erythema multiforme (EM) is an immune-mediated mucocutaneous syndrome usually triggered by a viral or bacterial infection, most commonly by Herpes simplex or Mycoplasma pneumoniae. A COVID-19 infection or vaccine can trigger EM. A drug, such as an NSAID, antiepileptic or antimicrobial, can rarely act as a trigger (in less than 10% of the cases). However, the aetiology frequently remains unknown.
Drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN) are two forms of a separate syndrome that includes EM-like mucosal changes but the skin symptoms are different.
Patients with Stevens-Johnson syndrome or TEN must be referred immediately to specialist care.
Symptoms
Erythema multiforme
EM minor: symmetrical lesions predominantly on the limbs with a characteristic cockade pattern (target lesions) of 1-2 cm in diameter, which may have a small central vesicle (pictures F1F2F3F4F5F6). The rash can spread to the face and body, but covers no more than 10% of the skin. There are no or few mucosal symptoms.
EM major: the rash is more severe and extensive, the vesicles are large and mucosal involvement, most often in the mouth, is present (pictures F7F8F9F10F11).
Patients are usually young adults.
Patients' ethnic background does not affect the incidence of the syndrome.
Lesions develop over a few days and do not change their location.
Mild disease forms heal spontaneously within 1-3 weeks, but skin hyperpigmentation may persist for months.
Symptoms may recur.
EM will not progress into toxic epidermal necrolysis.
The patient usually has mild fever as a general symptom and feels generally ill.
Mycoplasma and Chlamydia pneumoniae infections may cause, especially in children, a clinical picture where breaks in the oral mucosa are the primary symptom and there are only few or no findings on the skin. This is considered a distinct syndrome, different in pathophysiology from other mucocutaneous diseases.
Stevens-Johnson syndrome and toxic epidermal necrolysis (TEN)
Different degrees of the same drug reaction
Stevens-Johnson syndrome (pictureF12) is a drug reaction with purpuric lesions involving less than 10% of total body surface area. Eroding vesicles are present on the skin and mucous membranes.
Toxic epidermal necrolysis (Lyell's syndrome) (picture F13) is a serious drug reaction with epidermal detachment involving over 30% of total body surface area and mucosal erosions. The patient will have systemic symptoms and need aggressive treatment.
The most common triggering agents are non-steroidal anti-inflammatory drugs, antimicrobial drugs, antiepileptics and allopurinol.
Diagnosis
Diagnosis is based on patient history and the clinical picture.
Histopathological findings are non-specific.
Treatment
EM minor
Mild forms of EM resolve without treatment.
If the bacterial infection that triggered the reaction is known, it should be treated.
If the reaction was triggered by a drug, the drug is discontinued.
EM major
Systemic glucocorticoids for 2-4 weeks are generally prescribed, even though no clear evidence is available on their efficacy. The starting dose of prednisone or prednisolone is 30-60 mg/day.
A dermatologist should be consulted for appropriate topical treatment of the skin and mucosae.
Promptly consult an ophthalmologist to avoid permanent eye damage if the patient has eye symptoms.
Frequently recurring episodes of EM caused by the Herpes simplex virus may be an indication for prophylactic medication against herpes.
Stevens-Johnson syndrome: immediate referral to hospital
Toxic epidermal necrolysis: the patient needs high dependency/intensive care.
References
Yousefian M, Khadivi A. Occurrence of erythema multiforme following COVID-19 vaccination: a review. Clin Exp Vaccine Res 2023;12(2):87-96 [PubMed]
Daneshgaran G, Dubin DP, Gould DJ. Cutaneous Manifestations of COVID-19: An Evidence-Based Review. Am J Clin Dermatol 2020;21(5):627-639.[PubMed]
Trayes KP, Love G, Studdiford JS. Erythema Multiforme: Recognition and Management. Am Fam Physician 2019;100(2):82-88 [PubMed]
Bassetti M, Massone C, Vena A, et al. Skin manifestations in patients with coronavirus disease 2019. Curr Opin Infect Dis 2022;35(2):88-94 [PubMed]
Mayor-Ibarguren A, Feito-Rodriguez M, González-Ramos J, et al. Mucositis Secondary to Chlamydia pneumoniae Infection: Expanding the Mycoplasma pneumoniae-Induced Rash and Mucositis Concept. Pediatr Dermatol 2017;34(4):465-472 [PubMed]
Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012;51(8):889-902. [PubMed]