Delayed Drug Hypersensitivity: Mechanistic Advances and Emerging Therapies

Delayed drug hypersensitivity reactions span mild cutaneous eruptions, severe cutaneous adverse reactions (SCARs), and internal-organ injury. We review how pharmacogenomic, single-cell, and spatial methods have shown that these syndromes are driven by shared effector mechanisms, and how identifying which one predominates opens the way to targeted treatment. HLA associations are necessary but not sufficient to explain who reacts. Susceptibility is increasingly attributed to a pre-existing, often virus-shaped T-cell repertoire and to where tissue-resident memory T cells reside. Multiomic profiling of SJS/TEN identifies a cytotoxic CD8⁺ resident-memory population shared across HLA alleles and culprit drugs and implicates interferon and JAK-STAT signaling in keratinocyte death. AGEP and generalized pustular psoriasis show concordant transcriptomic signatures, placing AGEP within a targetable IL-36-driven spectrum. The IL-5 axis and herpesvirus reactivation are reframing DRESS, generalized bullous fixed drug eruption is increasingly recognized as a SCAR, and the same effector signature recurs in checkpoint inhibitor toxicity. Diagnostic testing remains unstandardized, and no biomarker reliably identifies the dominant mechanism. Because the dominant mechanism determines the phenotype more than the culprit drug does, therapy can be directed at the effector, with TNF-α, IL-36, IL-5, and JAK inhibitors. Rarity makes randomized trials difficult, so registry-based and adaptive designs are more realistic.