How does dupilumab suppress inflammation and symptoms of atopic dermatitis?
Published online: September 5, 2018
Dupilumab, a monoclonal antibody targeting the interleukin-4Ra that blocks signaling through IL-4 and IL-13, is the first biologic approved for treatment of moderate-to-severe atopic dermatitis patients in the US, and several other countries. While a preliminary short 4-week study reported that dupilumab improved the gene expression profile of lesional skin (Hamilton et al. JACI 2014), the study was conducted in a small number of patients and lacked cellular studies and longer-term evaluations.
Guttman-Yassky and colleagues have recently published the results from a randomized, placebo controlled study in The Journal of Allergy and Clinical Immunology (JACI) characterizing the effects of dupilumab on AD skin tissues after 4 and 16 weeks of treatment. Fifty-four patients were treated with 200 mg of dupilumab or placebo subcutaneously injected every other week for 16 weeks. The safety results and clinical improvement of atopic dermatitis disease severity were comparable to other dupilumab atopic dermatitis trials.
To better understand how dupilumab works in treating atopic dermatitis, the evaluations included gene expression profiles including inflammatory pathways and barrier molecules, epidermal thickness, cellular profiles in skin tissues, as well as circulating markers of inflammation. The study also evaluated how these measures relate to each other and to clinical outcomes.
Treatment with dupilumab (compared with placebo) progressively improved the clinical AD disease and resulted in molecular suppression of AD gene expression, cellular profiles of inflammation and systemic biomarkers as early as week 4, with progressive improvement through 16 weeks of treatment (the latest time point studied). Guttman-Yassky et al. showed that dupilumab reversed the active disease skin phenotype towards that of non-lesional skin. Expression changes with dupilumab extended beyond inflammatory pathways (e.g. type 2/Th2, Th17 and Th22 pathway-related genes), such as genes associated with epidermal barrier functions. Dupilumab improved the barrier function of the skin, with increases in proteins related to lipid metabolism, epidermal terminal differentiation, and cell-to-cell adhesion (tight junctions). In parallel, dupilumab significantly reduced epidermal thickness to a more normal depth after only 4 weeks of treatment, with further decreases at week 16, relative to no significant change with placebo. Dupilumab significantly reduced the presence of inflammatory cell markers known to be present in skin lesions from atopic dermatitis patients. Circulating markers of inflammation were also significantly decreased. Importantly, reductions in inflammatory markers in skin and circulation were correlated with improvements in epidermal barrier measures (thickness, barrier proteins, and others), as well as with clinical measures.
The authors demonstrated that dupilumab suppresses inflammation in atopic dermatitis, both locally in the skin and systemically, as measured by circulating markers. The significant reduction in inflammation paralleled the reversal of the epidermal barrier abnormalities seen in atopic dermatitis, and the clinical improvement of atopic dermatitis disease activity. These results further validate IL-4 and IL-13 as central mediators of the inflammation and barrier dysfunction in atopic dermatitis.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
Dupilumab progressively improves systemic and cutaneous inflammatory abnormalities in atopic dermatitis patients