Podcast
Questions and Answers
Which severe cutaneous adverse reaction is generally considered less severe than SJS and TEN?
Which severe cutaneous adverse reaction is generally considered less severe than SJS and TEN?
What is a critical treatment step for severe cutaneous adverse reactions?
What is a critical treatment step for severe cutaneous adverse reactions?
Which HLA haplotype is strongly associated with SJS/TEN caused by allopurinol in Han-Chinese patients?
Which HLA haplotype is strongly associated with SJS/TEN caused by allopurinol in Han-Chinese patients?
Involvement of which type of T cells is significant in the pathogenesis of SJS/TEN?
Involvement of which type of T cells is significant in the pathogenesis of SJS/TEN?
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Which form of hypersensitivity syndrome is linked to the HLA-B∗13:01 haplotype?
Which form of hypersensitivity syndrome is linked to the HLA-B∗13:01 haplotype?
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What role do CD8+ resident memory T (TRM) cells play in the recurrence of erythema multiforme-like lesions?
What role do CD8+ resident memory T (TRM) cells play in the recurrence of erythema multiforme-like lesions?
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Which of the following features is characteristic of DiHS/DRESS?
Which of the following features is characteristic of DiHS/DRESS?
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How does abacavir hypersensitivity differ according to the altered peptide model?
How does abacavir hypersensitivity differ according to the altered peptide model?
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What is a major contributor to the breakdown of peripheral tolerance in DiHS/DRESS?
What is a major contributor to the breakdown of peripheral tolerance in DiHS/DRESS?
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Which model proposes that drugs can trigger immune responses through direct interactions with T-cell receptors?
Which model proposes that drugs can trigger immune responses through direct interactions with T-cell receptors?
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Study Notes
Severe Cutaneous Adverse Reactions (SCARs)
- SCARs are life-threatening conditions triggered by aberrant immune responses to drugs.
- They encompass SJS, TEN, DiHS/DRESS, and acute generalized exanthematous pustulosis (AGEP).
- AGEP is generally less severe than SJS/TEN and DiHS/DRESS.
- Prompt drug discontinuation is crucial for treatment.
- Animal models for SCARs are lacking.
Genetic Predisposition to SCARs
- Genetic predisposition to SCARs, including SJS/TEN and DiHS/DRESS, exists and it's dependent on ethnicity.
- Certain HLA haplotypes (e.g., B∗58:01 for allopurinol-induced SJS/TEN, B∗15:02 for carbamazepine-induced SJS/TEN) are strongly associated with SJS/TEN in specific ethnic groups (e.g., Han Chinese).
- The association between genotype and susceptibility varies by drug.
- HLA haplotypes linked to SCARs aren't found in all ethnic groups, highlighting the link between genetics and ethnicity. (Example: HLA-B∗13:01 linked to dapsone hypersensitivity syndrome in Asians, but not Europeans or Africans).
- Genetic predisposition in non-Asians is suspected but not proven.
Pathophysiology of SCARs
- SJS/TEN: Characterized by cytotoxic T cell involvement that causes interface dermatitis and keratinocyte apoptosis. CD8+ T cells are prominent in lesions.
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DiHS/DRESS: Presents with maculopapular or morbilliform lesions, often with peripheral eosinophilia. T cell involvement is suspected, but the role of eosinophils is uncertain. Lymphadenopathy and atypical lymphocytes may suggest T-cell involvement. Regulatory T-cell expansion might lead to immune deficiency.
- Possible reactivation of Herpes viruses (e.g., HHV-6, HHV-7, EBV, CMV), and B-cell targeting occurs in DiHS, as patients often exhibit hypogammaglobulinemia..
- Long-lasting immunologic abnormalities and a potential for autoimmune diseases (e.g., Hashimoto thyroiditis, SLE, Type 1 diabetes) might follow DiHS/DRESS resolution, suggesting peripheral tolerance breakdown.
Mechanisms of Drug-Induced SCARs
- Drugs triggering SCARs are small molecules unlikely to be directly recognized by T cells. Mechanism for epitope recognition and generation isn't fully understood. Several models exist:
- Hapten model: Drugs act as haptens, and create antigens by binding to endogenous protein
- Modified peptide model: Drugs, like abacavir, directly bind to HLA molecules altering presentation of self-peptides, and creating new antigens.
- Pharmacologic interaction model (p-i): Drugs bypass classical immune mechanisms triggering responses by interacting directly with HLA or T-cell receptors.
- Altered T-cell receptor (TCR) model: Drugs directly interact with TCRs, potentially changing TCR specificity toward self-antigens. (Examples: binding to TCRs with Sulfamethoxazole, TCR-VB-11-ISGSY predominant in Carbamazepine-reactive T cells).
Conclusion
- Further research using humanized mouse models is necessary to refine the understanding of SCAR pathophysiology.
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Description
This quiz explores Severe Cutaneous Adverse Reactions (SCARs) and their genetic predispositions. It covers life-threatening conditions like SJS, TEN, and their associations with specific HLA haplotypes across different ethnic groups. Test your knowledge on the implications of drug reactions and genetic factors involved in SCARs.
