Toxic epidermal necrolysis and Stevens-Johnson syndrome

Toxic epidermal necrolysis (TEN) and Stevens Johnson Syndrome (SJS) are severe adverse cutaneous drug reactions that predominantly involve the skin and mucous membranes. Both are rare, with TEN and SJS affecting approximately 1or 2/1,000,000 annually, and are considered medical emergencies as they are potentially fatal. They are characterized by mucocutaneous tenderness and typically hemorrhagic erosions, erythema and more or less severe epidermal detachment presenting as blisters and areas of denuded skin. Currently, TEN and SJS are considered to be two ends of a spectrum of severe epidermolytic adverse cutaneous drug reactions, differing only by their extent of skin detachment. Drugs are assumed or identified as the main cause of SJS/TEN in most cases, but Mycoplasma pneumoniae and Herpes simplex virus infections are well documented causes alongside rare cases in which the aetiology remains unknown. Several drugs are at "high" risk of inducing TEN/SJS including: Allopurinol, Trimethoprim-sulfamethoxazole and other sulfonamide-antibiotics, aminopenicillins, cephalosporins, quinolones, carbamazepine, phenytoin, phenobarbital and NSAID's of the oxicam-type. Genetic susceptibility to SJS and TEN is likely as exemplified by the strong association observed in Han Chinese between a genetic marker, the human leukocyte antigen HLA-B*1502, and SJS induced by carbamazepine. Diagnosis relies mainly on clinical signs together with the histological analysis of a skin biopsy showing typical full-thickness epidermal necrolysis due to extensive keratinocyte apoptosis. Differential diagnosis includes linear IgA dermatosis and paraneoplastic pemphigus, pemphigus vulgaris and bullous pemphigoid, acute generalized exanthematous pustulosis (AGEP), disseminated fixed bullous drug eruption and staphyloccocal scalded skin syndrome (SSSS). Due to the high risk of mortality, management of patients with SJS/TEN requires rapid diagnosis, evaluation of the prognosis using SCORTEN, identification and interruption of the culprit drug, specialized supportive care ideally in an intensive care unit, and consideration of immunomodulating agents such as high-dose intravenous immunoglobulin therapy. SJS and TEN are severe and life-threatening. The average reported mortality rate of SJS is 1-5%, and of TEN is 25-35%; it can be even higher in elderly patients and those with a large surface area of epidermal detachment. More than 50% of patients surviving TEN suffer from long-term sequelae of the disease

Toxidermies

RésuméLes toxidermies correspondent aux effets indésirables médicamenteux à expression cutanéo-muqueuse. Elles présentent une grande variabilité sémiologique, non spécifique de l’étiologie médicamenteuse. L’exanthème maculo-papuleux est la présentation la plus fréquente suivie de l’urticaire et des vascularites. L’érythème pigmenté fixe est une toxidermie plus rare dans les pays occidentaux. La fréquence des formes sévères (décès, séquelles graves) est de 2 % : toxidermies bulleuses (syndrome de Stevens-Johnson, nécrolyse épidermique toxique ou syndrome de Lyell), DRESS (drug reaction with eosinophilia and systemic symptoms ou syndrome d’hypersensibilité), pustulose exanthématique aiguë généralisée (PEAG). Elles doivent être rapidement identifiées afin d’orienter la prise en charge. Les principaux facteurs de risque des toxidermies sont l’immunodépression, les pathologies auto-immunes ainsi que certains génotypes du système HLA dans les toxidermies bulleuses et le syndrome d’hypersensibilité. Toutes les classes médicamenteuses peuvent être à l’origine de toxidermies, en particulier les antibactériens, les anticonvulsivants, les antinéoplasiques, les anti-inflammatoires non stéroïdiens, l’allopurinol et les produits de contraste. Les mécanismes physiopathologiques comprennent les réactions immunologiques/immuno-allergiques immédiates ou retardées, classiquement non dose-dépendantes, et les mécanismes toxiques/pharmacologiques dose-dépendants ou temps-dépendants, incluant les réactions dites « paradoxales ». En cas de toxidermie de mécanisme immuno-allergique, un bilan allergologique est possible pour préciser l’imputabilité du/des médicament(s) suspect(s) avec une sensibilité variable selon les médicaments et le type de toxidermie. Il comprend les tests épicutanés (ou patch tests) et les tests intradermiques (prick test et intradermoréactions). Cependant aucun test in vivo ou in vitro ne permet d’affirmer la responsabilité médicamenteuse devant une toxidermie. Le diagnostic repose donc sur une démarche d’imputabilité prenant en compte la présentation clinique, la chronologie des événements et des prises médicamenteuses et l’élimination des diagnostics différentiels. Cette démarche diagnostique, complétée par une recherche bibliographique, permet dans la majeure partie des cas d’établir un lien de causalité entre le(s) médicament(s) et l’éruption cutanée. Une déclaration en pharmacovigilance est indispensable en cas de toxidermie grave quel que soit le médicament impliqué, et dans tous les cas s’il s’agit d’un médicament récent ou non classiquement associé à un risque cutané.AbstractCutaneous adverse drug reactions (CADR) represent a heterogeneous field including various clinical patterns without specific features suggesting drug causality. Exanthematous eruptions, urticaria and vasculitis are the most common forms of CADR. Fixed eruption is uncommon in western countries. Serious reactions (fatal outcome, sequelae) represent 2% of CADR: bullous reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), DRESS (drug reaction with eosinophilia and systemic symptoms or drug-induced hypersensitivity syndrome) and acute generalized exanthematous pustulosis (AGEP). These forms must be quickly diagnosed to guide their management. The main risk factors are immunosuppression, autoimmunity and some HLA alleles in bullous reactions and DRESS. Most systemic drugs may induce cutaneous adverse reactions, especially antibiotics, anticonvulsivants, antineoplastic drugs, non-steroidal anti-inflammatory drugs, allopurinol and contrast media. Pathogenesis includes immediate or delayed immunologic mechanism, usually not related to dose, and pharmacologic/toxic mechanism, commonly dose-dependent or time-dependent. In case of immunologic mechanism, allergologic exploration is possible to clarify drug causality, with a variable sensitivity according to the drug and to the CADR type. It includes epicutaneous patch testing, prick test and intradermal test. However, no in vivo or in vitro test can confirm the drug causality. To determine the cause of the eruption, a logical approach based on clinical characteristics, chronologic factors and elimination of differential diagnosis is required, completed with a literature search. A reporting to pharmacovigilance network is essential in case of a serious CADR whatever the suspected drug and in any case if the involved drug is a newly marketed one or unusually related to cutaneous reactions