Aetiology

EM is a hypersensitivity response pattern found in susceptible individuals that can be induced by a variety of causes, mostly of an infectious nature.[2][3][4][5][9]​​​ The most common associated infections are herpes simplex virus and Mycoplasma pneumoniae. Other less commonly associated infections include hepatitis B, hepatitis C, influenza, Epstein-Barr virus, cytomegalovirus, histoplasmosis (with concomitant erythema nodosum), orf (a disease of sheep and goats caused by a parapox virus that can be transmitted to humans), coccidioidomycosis, herpes zoster, gardnerella, syphilis, HIV, and SARS-CoV-2.[2][7][10][11][12][13][14]​​​​[15][16]​​​​​​​​ Case reports also suggest an uncommon association with Kawasaki disease, and patients with lymphoma may have a dermatological manifestation of EM on presentation or during treatment.[6][17]​​

Drugs are reported as the cause of EM in less than 10% of cases.[2] ​Drugs that have been associated with EM include certain antibiotics; docetaxel or paclitaxel; immune checkpoint inhibitors; sorafenib; tumour necrosis factor (TNF)-alpha inhibitors; antimalarials; hydroxychloroquine; lenalidomide; methotrexate; anticonvulsants; statins; bisphosphonates; non-steroidal anti-inflammatory drugs (NSAIDs); metamizole; oral contraceptives; imiquimod; lidocaine; triclocarban; barium contrast.[1][18][19][20][21][22][23][24][25][26][27] ​​​​​​Photo-distributed lesions have been noted with phenylbutazone, triclocarban, paclitaxel, and statins.[22][23]

Vaccines against organisms such as hepatitis B, smallpox, varicella, meningococcus, human papillomavirus, and SARS-CoV-2, and allergic response to contact allergens and tattoos, have also been reported to elicit EM.[14][28][29]​​

​​​In many cases the aetiology is not identified. However, possible causes should be carefully investigated before any patient is labelled as having an idiopathic case.[2]​ There are reports of natural extracts triggering EM (e.g., cloves) or aggravating herpes-associated EM (e.g., alpinia galangal).[30][31]

Pathophysiology

The exact pathogenetic mechanism has not been identified. A monocytic inflammatory cell infiltrate is present, suggesting a type 4 cytotoxic hypersensitivity response caused by T lymphocytes reacting to specific antigens and producing cytotoxic immune complexes. Cytotoxic immune complexes cause keratinocyte oedema, necrosis, and blistering; there is no epidermal necrosis and the inflammatory infiltrate is within the dermis.[1][32]​

In the case of photo-distributed lesions the cause of hypersensitivity would be a photo-product or drug activated by ultraviolet radiation, inducing an immune reaction or phototoxic agent destroying cells and releasing antigen into the circulation. This is in distinct contrast to toxic epidermal necrolysis, in which keratinocyte necrosis typifies the histology of sloughing skin.

A clear genetic association has yet to be identified. However, multiple human leukocyte antigen (HLA) subtypes have been linked to the propensity, including HLA-DQw3, DRw53, and Aw33, which are distinct from the subtypes seen in toxic epidermal necrolysis.[3]

Herpes simplex virus (HSV) DNA (by PCR) and HSV-encoded proteins can be found in the majority of tested skin lesions, supporting HSV-hypersensitivity as a leading cause of EM.[33] It is thought that persistence of HSV DNA expression may initiate recruitment of monocytic cells and Th1 cells, inducing local interferon-gamma production and lesions of EM. Dissemination of HSV DNA may occur due to CD34+ Langerhans' cells travelling to distant cutaneous sites.[34][35]

Classification

Standard classification[2][3][4][5]

EM minor has cutaneous manifestations only, while EM major involves one or more mucosal sites.

EM minor:

  • Typical targets or raised oedematous papules, with acral distribution, without involvement of mucosal sites and involving <10% total body surface area.

EM major:

  • Typical targets or raised oedematous papules, with acral distribution, plus involvement of 1 or more mucosal sites and involving <10% total body surface area.

Related dermatitides

  • Stevens-Johnson syndrome: severe macular (atypical target) lesions that coalesce, resulting in epidermal blistering, necrosis, and sloughing. No typical targets. Less than 10% total body surface area affected. May present with only mucosal involvement.

  • Toxic epidermal necrolysis: severe macular (atypical target) lesions that coalesce, resulting in epidermal blistering, necrosis, and sloughing. No typical targets. More than 30% total body surface area affected.

  • Stevens-Johnson/toxic epidermal necrolysis overlap: severe macular (atypical target) lesions that coalesce, resulting in epidermal blistering, necrosis, and sloughing. No typical targets. Between 10% and 30% total body surface area affected. See Stevens-Johnson syndrome and toxic epidermal necrolysis.

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