Knowledge on rare diseases and orphan drugs

On average, the annual incidence is 1/319,000 in Europe; however, it varies worldwide with a higher incidence observed in Asian populations and in the US. Females are more often affected than males.

Onset may occur at any age, but the risk increases after 40 years. Three subforms have been described according to the percentage of the body surface area affected: Stevens-Johnson syndrome (<10%), toxic epidermal necrolysis (≥ 30%; TEN) and an intermediate form, Stevens-Johnson syndrome/toxic epidermal necrolysis overlap syndrome (10-29%). The initial manifestations are nonspecific: a seemingly banal rash, fever, and a burning sensation involving the eyes, mouth and genitalia. The rash rapidly progresses to become vesicular and bullous on the face and body. The cutaneous vesicles aggregate and rupture under mild friction, revealing denuded red skin with seeping and pain. Mucous membrane lesions are present in 85 to 95% of patients with involvement, in order of frequency, of the oropharynx, eyes, genitalia and anus. Lesions are painful and lead to hypersalivation, feeding problems, photophobia, and burns following urination. High fever is a constant feature. Visceral manifestations are also frequent with hematological, respiratory and digestive involvement.

In 85% of cases, the disorder is triggered by a clearly identifiable drug allergy. A dozen high risk drugs have been identified: allopurinol, anti-infective sulphonamide agents, carbamazepine, phenobarbital, phenytoin, lamotrigine, nevirapine, and oxicam-derived nonsteroidal anti-inflammatory drugs. Genetic predisposition is described in some populations. In the other 15% of cases, the disease is associated with infections (in particular, Mycoplasma pneumoniae) or lupus erythematosus (TEN-like lupus). The remaining cases are classed as idiopathic and should be confirmed by skin biopsy.

Diagnosis is suspected on clinical presentation and confirmed by skin biopsy which will reveal full-thickness epidermal necrosis and the absence of antibody deposits by direct immunofluorescence. Medication history will find a suspect drug in 85% of cases. Allergology work-up may help assessing the culprit in case of multiple suspects, and to find alternatives. Assessing possible genetic predisposition may help identifying the culprit drug in predisposed populations (e.g. Chinese Hans for carbamazepine and allopurinol).

The differential diagnosis should include chicken pox during the early stages of the disease, staphylococcal epidermolysis, staphylococcal scalded skin syndrome, generalized bullous fixed drug eruption and, more rarely, severe graft versus host disease, and autoimmune bullous diseases (excluded by examination of skin biopsies). The more limited forms of TEN are still often misdiagnosed as erythema multiforme major.

HLA predisposition should be screened before prescription of carbamazepine (and other aromatic anti-epileptics) and allopurinol in Chinese Hans population; and before prescription of abacavir in all populations.

Patients should be admitted (according to the severity) to a dermatology or an intensive care or burns unit as soon as the diagnosis is suspected. The causative drug, together with any related compounds should be contraindicated for the patient and their close relatives (in case a genetic predisposition). No disease-modifying drugs have been shown to be efficient in the treatment of this disease. The benefits of general corticotherapy, cyclosporine or anti-TNF administration are still under evaluation. High-dose intravenous immunoglobulins appear to be of limited efficacy. Intensive supportive care is essential: a heated environment, analgesia, daily dressing changes, prevention of infections, and symptomatic intensive care measures (especially hydration, nutrition, analgesics, ocular care).

Reepithelialization is usually rapid (2-3 weeks). However, the prognosis for patients with extensive forms is poor (20-25% mortality). Sequelae are reported in over 80% of surviving patients with ocular sequelae being the most problematic as they tend to be severe and progressive. Other sequelae (cutaneous, genital, buccal/dental or bronchial problems) are generally easier to detect and treat.

Last update: June 2022 - Expert reviewer(s): Pr Saskia ORO | ERN-Skin*

* European Reference Network