Dupilumab, a therapeutic antibody that blocks the eczematous type 2 immune response in atopic dermatitis (AD), has shown efficacy in many clinical trials and real-life observational studies. Besides blepharitis and conjunctivitis, the de novo appearance of head-neck dermatitis is recognized as a distinct side effect, occurring in up to 10% of patients at any time after dupilumab initiation. Histopathological features distinct from conventional AD such as psoriasiform hyperplasia or increased numbers of ectatic capillaries suggest a drug effect, but exact underlying mechanisms remain largely unknown. We have thus profiled punch biopsies from dupilumab-associated face and neck dermatitis (DAFND) by using single-cell RNA sequencing, and compared data with untreated AD of the same region and of the trunk, as well as healthy control individuals. We found that dupilumab treatment was accompanied by normalization of IL-4/IL-13 activity markers such as CCL17, CCL18 and CCL26 in antigen-presenting cells and myofibroblasts, confirming effective inhibition of type 2 inflammation within DAFND lesions. Nevertheless, IL13 itself was still considerably increased in all AD groups, including DAFND skin. In addition, IL22, a type17/type22-associated cytokine, was significantly increased in helper T cells of DAFND compared to untreated head-neck AD and AD from the trunk. By contrast, other type 17-associated mediators such as IL17A or IL26 were neither elevated in DAFND nor untreated head-neck dermatitis, while lesional skin of the trunk showed upregulation of IL26. Our data suggest that dupilumab effectively dampens conventional type 2 inflammation downstream of the IL4 receptor in a broad range of leukocytes and stromal cells within DAFND lesions, but with concomitant upregulation of type 22-associated T-cell derived inflammation, which might be the key drivers of this dupilumab-associated side effect.
© 2022 Published by Elsevier Inc.