Elevated Cutaneous Interleukin‐21 Links Eczematous Eruption to Interleukin‐17A Inhibitor Treatment in Psoriasis

ABSTRACT Background Eczematous eruption (EE) is an adverse effect observed in psoriasis patients undergoing interleukin (IL)‐17A inhibitor therapy, with reported incidence rates ranging from 2.2% to 12.1%. In some cases, this reaction leads to discontinuation of treatment. However, the underlying mechanism of EE development remains unclear. Therefore, we aimed to elucidate the pathogenesis of EE associated with anti‐IL‐17A treatment and identify pathogenic molecules involved. Methods Skin samples were collected from psoriasis patients both before and after anti‐IL‐17A treatment, and the treated skin included those with and without EE. Transcriptomic profiling was performed using bulk RNA‐seq and scRNA‐seq, which were further validated by histopathological analysis and protein assay. In addition, in vitro experiments were conducted to explore the underlying mechanisms. Results Bulk RNA‐seq analysis revealed significantly elevated IL‐21 expression in EE lesions, along with marked enrichment of Th2/Th22 pathways and activation of JAK–STAT signaling compared to baseline and non‐EE samples. Immunohistochemistry confirmed increased expression of IL‐21, pJAK1, and pSTAT3 in EE lesions. ELISA and LEGENDplex assays detected higher levels of IL‐21, IL‐13, and IL‐22, with positive correlations between IL‐21 and the latter two cytokines. ScRNA‐seq localized IL‐21 expression predominantly to T cells within EE lesions, which co‐expressed high levels of IL‐13 and IL‐22. In vitro, rhIL‐21 stimulation activated JAK1/STAT3 signaling and increased IL‐13 and IL‐22 secretion, which were suppressed by JAK1 inhibition. These findings identify IL‐21 as an important regulator of Th2/Th22 responses and JAK–STAT signaling in EE pathogenesis. Conclusion IL‐21 is an important inflammatory mediator contributing to the development of EE.