Dupilumab-associated head and neck dermatitis shows a pronounced type 22 immune signature mediated by oligoclonally expanded T cells

Background: Dupilumab, an IL4R-blocking antibody, has shown clinical efficacy for atopic dermatitis (AD) treatment. In addition to conjunctivitis/blepharitis, the _de novo_ appearance of head/neck dermatitis is now recognized as a distinct side effect, occurring in up to 10% of patients. Histopathological features distinct from AD suggest a drug effect, but exact underlying mechanisms remain unknown. Methods: We profiled punch biopsies from dupilumab-associated head and neck dermatitis (DAHND) by using single-cell RNA sequencing and compared data with untreated AD and healthy control skin. Results: We show that dupilumab treatment was accompanied by normalization of IL-4/IL-13 downstream activity markers such as _CCL13, CCL17_, _CCL18 _and_ CCL26_. By contrast, we found strong increases in type 22-associated markers (_IL22, AHR_) especially in oligoclonally expanded T cells, accompanied by enhanced keratinocyte activation and IL-22 receptor upregulation. Conclusions: Taken together, we demonstrate that dupilumab effectively dampens conventional type 2 inflammation in DAHND lesions, with concomitant hyperactivation of _IL22_-associated responses. Comparison of skin cells obtained from DAHND, Head/neck AD, Trunk AD and HC donors. Submitter declares "Due to patient privacy concerns raw data is not provided."