Immunological and molecular signatures of carbamazepine-induced maculopapular exanthema

Cutaneous adverse drug reactions to carbamazepine range from mild maculopapular exanthema to life-threatening syndromes such as Stevens-Johnson syndrome/toxic epidermal necrolysis. While the immunological basis for HLA-B*15:02-restricted carbamazepine-induced SJS/TEN has received greater attention, mechanisms underlying mild maculopapular exanthema remain poorly understood. In this study, we examined circulating T-cell immune recognition and transcriptomic signatures in the blood of patients with carbamazepine-induced maculopapular exanthema during active and resolved disease and compared these profiles with severe reactions. Peripheral blood was collected from patients with active (< 9 days post-diagnosis; n = 5) or resolved (> 2 months post-resolution; n = 10) carbamazepine-induced maculopapular exanthema, carbamazepine-tolerant controls (n = 11), and resolved carbamazepine-induced Stevens-Johnson syndrome cases (n = 11). T-cell reactivity, T-cell receptor clonotypes, and global transcriptional profiles were assessed using cytokine assays, sequencing, and bulk RNA transcriptomics. Both active and resolved maculopapular exanthema patients exhibited polyclonal CD8⁺ T-cell activation. Resolved cases displayed recognition of related tricyclic compounds and private CD8⁺ T-cell receptor clonotypes. Transcriptomics revealed enrichment of complement, interferon, and CD4⁺ T-cell-associated chemokine pathways in active disease, with persistent TNF and NF-κB signalling in resolved cases. Both disease states showed reduced IGHA2 expression, indicating IgA⁺ B-cell dysregulation. Compared with severe hypersensitivity reactions, maculopapular exanthema lacked sustained proinflammatory signalling, highlighting divergent long-term immune activation. Together, we demonstrated that carbamazepine-induced maculopapular exanthema is driven by polyclonal CD8⁺ T-cell responses in conjunction with innate immune activation and exhibits distinct molecular signatures from severe reactions, providing mechanistic insight into the milder clinical phenotype.