Understanding Severe Cutaneous Adverse Reactions

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.
• 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.