Severe cutaneous adverse reactions to drugs (SCARs) are rare but life-threatening delayed allergies. While they primarily affect the skin, they can also affect internal organs. Accordingly, they present with diverse clinical symptoms that vary not only between SCARs subtypes but also among patients. Despite the availability of topical and systemic treatments, these only address the symptoms and not the cause. To develop more effective therapies, it is necessary to elucidate the complexity of the pathophysiology of SCARs in relation to their severity. In line with the new type IV hypersensitivity reactions nomenclature proposed by the European Academy of Allergy and Clinical Immunology (EAACI), this review highlights the current insights into the intricate immune mechanisms engaged, the interplay between the culprit drug and genetic predisposition in drug presentation mechanisms, but also how external factors, such as viruses, are implicated in SCARs. Their relevance to the development of targeted medicine is also discussed.
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