Erythema multiforme (overview) L51.0

Ferdinand v. Hebra first described erythema exsudativum multiforme as a purely cutaneous, polymorphic erythema (exanthema) with a benign course in his textbook in 1860. v. Hebra 1867: "I choose the name "erythema multiforme" to describe this condition [!] The same is characterized [!] above all others [!] by its localization [!]; it always occurs on the back of the hand or foot, and only in more intense cases does it also appear on the forearms, lower legs, upper arms, thighs and very exceptionally on the trunk and face, but is certainly never absent in the last-mentioned cases: on the back of the hand, where the first efflorescences [!] usually appear. These efflorescences [!] consist of flattened nodules or lumps of lentil to bean size, of dark blue or brown-red [!] color and occur in smaller or larger quantities".

In 1876, clinically more severe, similar cases with skin and mucous membrane infestation were then described as erythema multiforme majus.

In 1922, the syndrome described by Stevens and Johnson, a febrile exanthema with stomatitis and purulent conjunctivitis, was published.
In 1950, the British dermatologist Bernard Thomas suggested dividing erythema exsudativum multiforme into a less severe variant without fever with mainly skin involvement (erythema exsudativum multiforme minus) and a severe febrile variant with severe mucosal involvement as erythema exsudativum multiforme majus (Thomas, 1950).

In 1956, the term "toxic epidermal necrolysis" was created by Lyell (Lyell syndrome).

Recently, there has been a tendency to combine Stevens-Johnson syndrome and toxic epidermal necrolysis under the generic term EN - epidermal necrolysis.

Erythema multiforme (EM) is a polyetiologic inflammatory syndrome triggered by an infection-induced, hyperergic, systemic immune reaction that is projected either only onto the skin (erythema multiforme minus), onto skin and mucous membranes (erythema multiforme majus) or exclusively onto mucous membranes close to the surface (Fuchs syndrome).

Erythema multiforme is clinically characterized by an acute to subacute, self-limited exanthema prone to recurrence with characteristic, well-defined, targetoid (cocardia - disc-in-disc structure with heterogeneous ring formations, possibly also central blistering).

The classic erythema multiforme/EM-minus(first described by Ferdinand v. Hebra) is usually mild, skin-accentuated and is mainly caused by herpes simplex viruses but also other viruses and various bacteria (e.g. mycoplasma). Bacteria (e.g. mycoplasma). A few patients suffer a recurrent form (usually triggered by herpes simplex infections) with recurring episodes over months and years.

Erythema multiforme majus is much more severe than EM-minus with skin and varying degrees of mucosal involvement (conjunctiva, lip and oral mucosa, anal and genital mucosa).

A course of EM that is limited to mucous membranes can be referred to as Fuchs syndrome or mucosal EM.

Erythema (exsudativum) multiforme minus: mild (classic) form, which is mainly triggered by herpes simplex infections. Mucosal involvement is not observed in this variant. One part recurs. A recurrent course over many years is possible (recurrent erythema multiforme).

Erythema (exsudativum) multiforme majus: this severe, usually single, extremity variant with varying degrees of erosive mucosal involvement is also predominantly virus-induced. Typical and/or atypical cockades are detectable. In children and adolescents, Mycoplasma pneumoniae can be the trigger (EM strain - see also RIME)

Fuchs syndrome (mucosal EM): In this clinical variant of erythema multiforme major (first described in 1906), there is localized involvement of the conjunctiva (and oral mucosa). By definition, skin symptoms recede completely into the background. No cockades!

Ectodermosis erosiva pluriorificialis (Rendu-Fiessinger): Clinical variant of erythema multiforme major with polytopic involvement of the oral, genital and anal mucosa (a term that is not commonly used today - the changes are essentially assigned to Fuchs syndrome).

Reactive infectious mucocutaneous eruption (RIME): Clinical variant of erythema multiforme major which is mainly caused by Mycoplasmae pneumoniae.

Mycoplasma-induced rash and mucositis (MIRM ), an inflammatory mucocutaneous eruption in children and adolescents associated with infections caused by Mycoplasma pneumoniae. Other associated pathogens that cause this inflammatory symptomatology have since been identified. The name RIME is preferred.

See below for the respective disease binders.

1. Ayangco L et al. (2003) Oral manifestations of erythema multiforme. Dermatol Clin 21: 195-205
2. Das S et al. (2000) Herpes simplex virus type 1 as a cause of widespread intracorneal blistering of the lower limbs. Clin Exp Dermatol 25: 119-121.
3. Grünwald P et al. (2020) Erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis - diagnosis and treatment. J Dtsch Dermatol Ges 18:547-553.
4. Hidajat C et al (2014) Drug-mediated rash: erythema multiforme versus Stevens-Johnson syndrome. BMJ Case Rep 22 PubMed PMID: 25246464.
5. Johnston GA et al (2002) Neonatal erythema multiforme major. Clin Exp Dermatol 27: 661-664
6. Labé P et al (2020) Erythema multiforme and Kawasaki disease associated with COVID-19 infection in children. J Eur Acad Dermatol Venereol 34:e539-e541
7. Lavery MJ et al. (2021) A flare of pre-existing erythema multiforme following BNT162b2 (Pfizer-BioNTech) COVID-19 vaccine. Clin Exp Dermatol 46:1325-7.
8. Molnar I, Matulis M. (2002) Arthritis associated with recurrent erythema multiforme responding to oral acyclovir. Clin Rheumatol 21: 415-417
9. Saleh W et al. (2024) Increased prevalence of erythema multiforme in patients with COVID-19 infection or vaccination. Sci Rep 14:2801.
10. Samim F et al.(2013) Erythema multiforme: a review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin North Am 57:583-96.
11. Seishima M, Oyama Z, Yamamura M (2001) Erythema multiforme associated with cytomegalovirus infection in nonimmunosuppressed patients. Dermatology 203: 299-302
12. Sun J et al. (2014) Stevens-Johnson syndrome and toxic epidermal necrolysis: a multi-aspect comparative 7-year study from the People's Republic of China. Drug Des Devel Ther 8:2539-1547
13. Tatnall FM et al. (1995) A double-blind, placebo-controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 132: 267-270
14. Thielmann CM et al (2022) COVID-19-Triggered EEM-Like Skin Lesions. Dtsch Arztebl Int 119:131.
15. Thomas BA (1950). So-called Stevens--Johnson syndrome. BMJ 1: 1393-1397.
16. Trayes KP et al (2019) Erythema Multiforme: Recognition and Management. Am Fam Physician. 100: 82-88.
17. von Hebra F, Kaposi M (1860) Acute exanthema and skin diseases. Textbook of skin diseases. Volume 1, Enke, Erlangen
18. Wang S et al. (2022) 5-Fluorouracil and actinomycin D lead to erythema multiforme drug eruption in chemotherapy of invasive mole: Case report and literature review. Medicine (Baltimore) 101:e31678