Divergent cytotoxic and immunomodulatory immune programs distinguish morbilliform drug eruption from SDRIFE.

Cutaneous drug eruptions, including morbilliform drug eruption (MDE) and the less common symmetrical drug-related intertriginous and flexural exanthema (SDRIFE), are characterized by an erythematous rash following medication exposure, often to beta-lactam antibiotics. While MDE is thought to involve tissue-resident memory T cells, the immunopathogenesis of SDRIFE remains poorly understood. We sought to define the inflammatory patterns in SDRIFE compared to MDE, and to elucidate the spatial localization of immune cells within skin. To address these questions, we performed single-cell RNA sequencing, exploratory spatial transcriptomics, and immunohistochemistry to compare skin from patients with MDE and SDRIFE. MDE lesions featured a predominance of CD8+ cytotoxic T cells and Th1-type CD4+ T cells, high expression of CXCL9-11, and upregulation of interferon-responsive genes. In contrast, SDRIFE showed limited CD8+ infiltration, enrichment for CD4+ T cells with modest Th2 skewing and macrophages with an immunomodulatory profile. Exploratory spatial transcriptomics revealed substantial T cell and macrophage presence in the superficial dermis in both conditions. We conclude that MDE and SDRIFE display distinct immune landscapes: MDE is characterized by cytotoxic and interferon-mediated inflammation, while SDRIFE involves an immunomodulatory, non-classical response. These findings reveal inflammatory patterns in SDRIFE and highlight potential diagnostic and therapeutic targets.