Dupilumab Inhibits Vascular Leakage of Blood Proteins Into Atopic Dermatitis Skin

Abstract

Atopic dermatitis (AD) skin lesions are associated with oozing, bleeding, and erythema. This suggests AD is associated with vascular changes. Dupilumab is an antibody to the alpha-subunit of interleukin (IL) 4 receptor that demonstrates strong efficacy in the treatment of AD. IL-4 is known to reduce the permeability barrier function of vascular endothelium. To examine the effects of dupilumab on vascular barrier function in AD skin. Using proteomic analysis, we evaluated the plasma protein composition in skin tapes of lesional and non-lesional skin of adults and adolescents with moderate-to-severe AD over the course of a 16-week treatment with dupilumab and compared those to matched healthy subjects. At baseline, 115 plasma proteins were detected in AD skin and globally increased (1.5-fold or greater) compared to healthy skin. Functionally, these proteins included immunoglobulins, proteins involved in the coagulation process, enzymes, protease inhibitors, transport proteins, acute-phase proteins, complement proteins, and other pleiotropic proteins. Noteworthy, fibrinogens, fibronectin, and heme-binding proteins haptoglobin and hemopexin were among the top proteins originating from plasma and were increased in AD lesional versus healthy skin at baseline (p<0.0001). Dupilumab treatment resulted in significantly reduced levels of plasma proteins in AD skin (p<0.0001), with the majority dropping to levels seen in healthy skin or no longer detectable at week 16. Inhibition of IL-4/IL-13 action by dupilumab significantly reduces the efflux of plasma proteins into AD skin. Several of these proteins, such as fibrinogens and fibronectin, are known to enhance Staphylococcus aureuscolonization and are associated with AD skin severity.