What are the triggers for Toxic Epidermal Necrolysis (TEN)?

From the Guidelines

Toxic epidermal necrolysis (TEN) is most commonly triggered by medications, particularly those started within the previous 8 weeks, with the most frequent culprits including sulfonamide antibiotics, aromatic anticonvulsants, allopurinol, nevirapine, and certain NSAIDs. The most recent and highest quality study, 1, highlights that implicated medications in children are anticonvulsants and antibiotics, with paracetamol and ibuprofen having an unclear association. Key triggers for TEN include:

• Medications such as sulfonamide antibiotics (e.g., sulfamethoxazole), aromatic anticonvulsants (e.g., phenytoin, carbamazepine, lamotrigine), allopurinol, nevirapine, and certain NSAIDs like piroxicam, as listed in 1.
• Infections, particularly Mycoplasma pneumoniae and herpes simplex virus, which are common causes of SJS/TEN in the pediatric population, as reported in 1.
• Vaccinations, or rarely, malignancies or graft-versus-host disease, as mentioned in the example answer. Genetic factors also play a role in susceptibility, with certain HLA types (like HLA-B*15:02 in Han Chinese patients taking carbamazepine) increasing risk significantly, as noted in 1. The pathophysiology involves an immune reaction where cytotoxic T cells and natural killer cells attack keratinocytes, causing massive apoptosis and the characteristic epidermal detachment. Early recognition of triggers and immediate discontinuation of the offending agent is crucial for management, as mortality rates for TEN can reach 30-40%, emphasizing the importance of prompt action, as discussed in 1. It is essential to investigate the triggering role of HSV, mycoplasma, or chlamydia infections, as suggested in 1, and to record all medicines taken and vaccinations received over the preceding 2 months, including over-the-counter and complementary/alternative therapies, to determine the causal drug, as recommended in 1. The ALDEN algorithm can be used to predict likely causality of a drug reaction, as mentioned in 1. Any suspected medication should be withdrawn as soon as possible, as this decreases the risk of death, as stated in 1. Referral for diagnostic testing to a specialist center with expertise in drug allergy should be considered in severe cases, especially where avoidance of the causal drug is medically compromising or difficult for the patient, as suggested in 1.

From the FDA Drug Label

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported with carbamazepine treatment. The risk of these events is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations However, the risk in some Asian countries is estimated to be about 10 times higher. SJS/TEN and HLA-B1502 Allele Retrospective case-control studies have found that in patients of Chinese ancestry there is a strong association between the risk of developing SJS/TEN with carbamazepine treatment and the presence of an inherited variant of the HLA-B gene, HLA-B1502 The occurrence of higher rates of these reactions in countries with higher frequencies of this allele suggests that the risk may be increased in allele-positive individuals of any ethnicity. Over 90% of carbamazepine treated patients who will experience SJS/TEN have this reaction within the first few months of treatment. Hypersensitivity Reactions and HLA-A3101 Allele Retrospective case-control studies in patients of European, Korean, and Japanese ancestry have found a moderate association between the risk of developing hypersensitivity reactions and the presence of HLA-A3101, an inherited allelic variant of the HLA-A gene, in patients using carbamazepine These hypersensitivity reactions include SJS/TEN, maculopapular eruptions, and Drug Reaction with Eosinophilia and Systemic Symptoms ( see DRESS/Multiorgan hypersensitivity below)

The triggers for toxic epidermal necrolysis (TEN) include:

• Genetic predisposition: Presence of the HLA-B*1502 allele, particularly in patients of Asian ancestry, which increases the risk of developing TEN.
• Genetic predisposition: Presence of the HLA-A*3101 allele, which has been found to have a moderate association with the risk of developing hypersensitivity reactions, including TEN, in patients of European, Korean, and Japanese ancestry.
• Carbamazepine treatment: The risk of TEN is estimated to be about 1 to 6 per 10,000 new users in countries with mainly Caucasian populations, and about 10 times higher in some Asian countries.
• Time of treatment: Over 90% of carbamazepine-treated patients who will experience TEN have this reaction within the first few months of treatment 2 2.

From the Research

Triggers for Toxic Epidermal Necrolysis

Toxic epidermal necrolysis (TEN) is a life-threatening condition that is often triggered by certain factors. The key triggers for TEN include:

• Drugs, with certain medications being more commonly associated with TEN than others 3, 4, 5, 6
• Specific drug structures, drug metabolism, HLA alleles, and T cell clonotypes can contribute to the development of TEN 3
• Immune reactions, involving CD8+ T lymphocytes, monocytes/macrophages, and natural killer cells, play a role in the pathogenesis of TEN 3

Drug-Induced TEN

Certain drugs are known to be more likely to induce TEN, including:

• Antipsychotics
• Antiepileptics, such as phenytoin 5, 6
• Sulfonamides
• Carbamazepine, particularly in individuals of East Asian descent 4
• Abacavir, for which human leukocyte antigen testing is recommended before initiation 4

Mechanism of TEN

The precise mechanism of TEN is still not fully understood, but it is thought to involve:

• Apoptosis or necroptosis of keratinocytes, leading to loss of shape and adhesion 3
• Immune reactions involving various cell types and cytokines, such as tumor necrosis factor α and granulysin 3
• Complex interactions between drug metabolites, immune cells, and skin cells 3