Erythema multiforme majus L51.1

Acute, usually severe (up to max. 3% of KOF) mucocutaneous inflammatory syndrome characterized by a self-limited exanthema with characteristic, well-defined, targetoid (disc-in-disc structure with heterogeneous ring formations, possibly also central blistering) and a pronounced, usually monotopic mucosal infestation (oral mucosa/conjunctiva/genital and anal mucosa). A transition to toxic epidermal necrolysis is excluded.

With regard to the statements on the etiology of extremity-emphasized EM-majus, it must be borne in mind that most studies do not distinguish between minus and majus variants in erythema multiforme. See below Erythema multiforme

Other possible triggers include topically and systemically applied medications, malignant diseases, autoimmune diseases, UV radiation, X-rays, chronic inflammatory diseases and hormonal fluctuations due to pregnancy or menstruation. Reproducible evidence is usually lacking.

In the case of erythema multiforme majus, the herpes simplex virus is a possible trigger. An infection with Mycoplasma pneumoniae is also repeatedly mentioned as a trigger in studies. EMM in adults in particular often appears to be associated with a herpes eruption (Kaiser P et al. 2012). In an international, prospective case-control study of severe skin reactions, EEMM was associated with an outbreak of herpes labialis in 29% of all cases (Auquier-Dunant A et al. 2002). In various studies, HSV was detected in skin lesions of EM patients. This was achieved in nine out of 13 herpes-associated cases of EEM and also in nine out of twelve EEM cases that had not been associated with herpes. Herpes may therefore also have played a role in triggering the disease in EEM cases in which no herpes labialis was clinically visible (Jester J et al. 1989). Other research groups found HSV DNA in skin samples from EEM patients in 74% of cases. In recurrent EEM, herpes virus DNA was even detected in 87.5% of cases (Aslanzadeh J et al. 1992).

In children, adolescents and young adults, a high percentage of Mycoplasma pneumoniae must be expected as the trigger - see also Mycoplasma-induced rash and mucositis. Infections with mycoplasma usually manifest themselves in the form of tracheobronchitis or atypical pneumonia. Mycoplasma infections. They can occur at any age. Known extrapulmonary manifestations include vasculitis and thrombosis, encephalitis, Guillain-Barré syndrome, aseptic meningitis, urticaria, thrombotic thrombocytopenic purpura, the formation of cold agglutinins, myositis and pericarditis and rhabdomyolysis (Waites KB et al. (2017). In children, adolescents and young adults, infection with Mycoplasma pneumoniae is a common trigger for EMM (Kaiser et al. 2012). Mycoplasma-associated cases of EEMM often manifest as atypical EMM and may be associated with giant cocardia in childhood.

Other infections such as hepatitis C infection, recurrent vulvovaginal candidiasis play only a minor role.

Medication: Medication has long been considered an important trigger of EEMM. In the large cohort study of 1999 cited above, 9% of all cases of typical EEMM and 13% of all cases of atypical EEMM involved exposure to highly suspected drug triggers such as allopurinol, certain anticonvulsants, certain sulphonamides, chlormezanone and non-steroidal anti-inflammatory drugs of the oxicam type (Schröder et al., 1999). However, exposure to a drug cannot be equated with a causal relationship. Compared to exposure to medication, infections are much more frequently found as triggers (Roujeau CJ et al. 2019).

The formation of antibodies against desmoplakin I/II postulated in earlier years could not be verified in later studies (Komorowski L et al. 2013).

Extremities (often accentuated on the extensor side), in children and adolescents (Mycoplasma pneumomiae as trigger) also trunk accentuation; involvement of the mucous membranes close to the surface (conjunctiva, labial and oral mucous membranes, anal and genital mucous membranes).

The skin-mucous membrane lesions may be preceded by a non-specific prodromal phase lasting two to three days. Many patients report fever, rhinitis and other mucosal symptoms. EMM is often accompanied by a pronounced general feeling of illness and fever. Mild to severe mucosal involvement is just as possible as mild or severe skin involvement. The general condition of patients is also influenced by an infection that is often present in addition to the skin reaction. It is not uncommon for a respiratory tract infection, pneumonia or cold sores to be present at the same time as EEMM.

In patients with mucosal involvement, erosive changes occur in one or more mucous membranes. The oral mucosa is most frequently affected, most often the tongue and buccal mucosa. The oral mucosal lesions are usually covered with fibrin and blisters are visible (Roujeau and Mockenhaupt, 2019). There are not only aphthous changes, but also extensive detachment of larger areas of mucosa. Both the skin changes and the mucosal lesions develop rapidly within a few days. The mucosal lesions are perceived by patients as clearly painful.

Eye involvement can manifest itself in the form of redness, burning and tearing of the eyes and even purulent conjunctivitis. Corneal, conjunctival and eyelid complications can occur, which can cause severe damage if left untreated (Chronopoulos et al., 2012).

The nasal, anal and genital mucosa are also frequently involved. The mucous membranes of the larynx, pharynx and oesophagus are rarely affected.

See below Erythema multiforme

Pityriasis lichenoides et varioliforms acuta (PLEVA ): Very polymorphic, only moderately itchy, possibly burning, but often (in 50% of patients) also completely asymptomatic, trunk-accentuated exanthema. No mucosal infestation! The recurrent and relapsing course of the disease leads to a coexistence of different efflorescences, with a correspondingly colorful (as in varicella) overall pattern. Healing with the formation of varioliform scars.

Gianotti-Crosti syndrome: Reactive, intermittent, symmetrical, acrally accentuated, papular, self-limited exanthema in infants (!), which has been described primarily in association with HBV infection (!), but can also be observed in connection with numerous other viral diseases (e.g. EBV infection, Coxsackie virus infection).

Kawasaki syndrome: Immunologically mediated, diffuse vasculitis (vasculitis of medium-sized vessels) occurring predominantly in childhood, which is clinically characterized by high fever, enlarged cervical lymph nodes, skin and mucous membrane involvement and is complicated in 15-25% of cases by the addition of myocarditis and coronariitis with consecutive thrombus and aneurysm formation in the coronary vessels.

Acute febrile neutrophilic dermatosis (Sweet syndrome): Clinically and morphologically similar in the early phase of the disease. However, the typical cocardia (iris lesions) are absent in Sweet's syndrome. Always fever, severe feeling of illness and neutrophilic leukocytosis.

Polymorphic light dermatosis: Occurs after UV exposure (solar pattern!); severe itching, never involving the mucous membranes.

Acute urticaria: Clinical determination of wheals (prove volatility by marking). No typical wheals.

Urticarial vasculitis: markedly intermittent chronicity. Small-spotted, maculo-papular, itchy or painful exanthema accompanied by fever attacks. Neutrophilic leukocytosis is possible. Frequent arthralgias and arthritides; no erythema exsudativum multiforme cocardia. Swelling of lymph nodes. Possibly positive ANA and signs of systemic lupus erythematosus. Histologically, signs of vasculitis are diagnostic. They are always absent in EM.

Subacute cutaneous lupus erythematosus: A picture similar to erythema exsudativum multiforme may develop (Rowell syndrome), particularly in the case of a highly acute course with disseminated plaques. Histology and immunohistology are diagnostic.

Drug exanthema (maculo-papular-bullous): No real DD, as erythema exsudativum multiforme can be triggered by drugs. A maculo-papular drug exanthema can be diagnosed if a connection can be established with altered or intercurrent drug administration.

Bullous pemphigoid: In some cases, especially in the initial phase of bullous pemphigoid, the pioneering blisters may be absent. This eliminates the leading clinical symptom of "bulging (firm) blisters" and the clear clinical classification as a blistering disease. Histology and IF are conclusive.

Stevens-Johnson syndrome: Initial febrile, catarrhal prodromal symptoms, generalized lymphadenopathy, liver and spleen involvement. Always mucosal manifestations. Skin manifestations of varying extent: from a few atypical cockades with a maximum of two zones to an extensive, scarlatiniform exanthema. Stevens-Johnson syndrome, in contrast to EEM, shows no(!) shooting-disk-like efflorescences, but rather trunk-emphasized, so-called "atypical cockades" with a maximum of two zones. In addition, unlike erythema multiforme, it can develop into toxic epidermal necrolysis (TEN).

RIME/MIRM differs from erythema multiforme majus in its relatively sparse skin symptoms, its prevalence in younger patients and its excellent prognosis. There is a clear association with Mycoplasma pneumoniae infections.

Involvement of the urethral mucosa can lead to problems with micturition (Roujeau and Mockenhaupt, 2019). There are few reports of involvement of the oesophageal, tracheal and laryngeal mucosa. (Hirsch et al., 2016). Older patients > 65 years seem to be less frequently affected by mucosal involvement.

Mucosal erosions are the main cause of pain and high levels of suffering in patients. Oral mucosal erosions can make drinking and eating almost impossible temporarily and require parenteral nutrition.

The course of erythema multiforme majus is characterized by the sudden appearance of shooting disc-shaped, non-painful (possibly slightly itchy erythema and/or plaques), the cockades, especially on the face and extremities. The cockades can vary greatly in size, ranging from a few millimeters to approx. 3 cm in diameter. The center of the cockades often becomes necrotic or forms central blisters. In erythema exsudativum majus, mainly raised typical cockades and raised, atypical cockades occur. The Nikolski phenomenon is usually negative in EM-majus (Bastuji-Garin et al. 1993; Roujeau JC et al. 2019).

Atypical EMM is often associated with giant cocardia and mainly affects young children. In some cases, the perioral or periocular skin is affected, which can give the impression of a "clown face". However, the skin involvement is usually limited to approximately one to three percent of the body surface. Extensive skin detachment is not to be expected.

As a rule, the skin and mucous membrane lesions of EEMM heal without scarring within a few weeks. Hypo- or hyperpigmentation may persist, especially on darker skin. Temporary or permanent hair loss may also occur. In patients with eye involvement, scarring, symblepharon or trichiasis may persist.

Based on the clinical picture and the age of the patient, conclusions can be drawn as to the most likely trigger. It has been observed that a herpes simplex virus eruption is more frequently associated with a typical course of EMM.

Atypical EMM is usually associated with mycoplasma infections. The mucosal involvement is superficial in this case.

Recurrent courses are observed in EMM (as in the classic form), sometimes over several years. Reports of persistent EM of the major or minor form are more likely to be associated with close recurrences.

The mycoplasma-induced rash and mucositis (MIRM) variant is characterized by a predominance of enanthema, blistering, erosion and crusting, with the oral mucosa (94%), the eye region (82%) and the urogenital area (63%) being particularly affected. Infestation of the nasal introitus and anus is less common. Mucosal lesions are generally characterized as ulcerative or haemorrhagic and can cause symptoms. Involvement of the nose can manifest itself in the form of firm hemorrhagic crusts. Anal lesions can lead to pain during bowel movements.

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