Improved Systemic, Cutaneous Abnormalities With Dupilumab in Atopic Dermatitis

In patients with moderate to severe atopic dermatitis (AD), the use of dupilumab suppressed cutaneous and systemic measures of inflammation, and improved epidermal pathology and clinical disease severity scores at 4 weeks, according to the results of a placebo-controlled, double-blind study (ClinicalTrials.gov identifier: NCT01979016) published in The Journal of Allergy and Clinical Immunology.

Recognizing that dupilumab is an interleukin (IL)-4Rα monoclonal antibody that inhibits signaling of IL-4/IL-13 — key drivers of type 2–driven inflammation — the investigators sought to assess the efficacy and safety of dupilumab therapy on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers in patients with AD. They obtained skin biopsies and blood samples from a total of 54 patients, who were randomly assigned in a 1:1 ratio to weekly subcutaneous dupilumab 200 mg (n=27) or placebo (n=27) for 16 weeks.

Compared with placebo, dupilumab significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4 to 16). Mean improvements in a meta-analysis-derived AD transcriptome were 68.8% and 110.8% with dupilumab and –10.5% and 55.0% with placebo at weeks 4 and 16, respectively (P <.001).

Treatment with dupilumab significantly decreased the expression of genes involved in type 2 inflammation, epidermal hyperplasia, T cells, dendritic cells, and Th17/Th22 activity. Furthermore, dupilumab increased the expression of epidermal differentiation, barrier, and lipid-metabolism genes. Use of dupilumab also significantly reduced lesional epidermal thickness vs placebo (P =.001 at 4 weeks and P =.0002 at 16 weeks).

Improvements in clinical and histologic measures correlated significantly with the modulation of gene expression. Moreover, dupilumab significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific immunoglobulin Es.

The investigators concluded that dupilumab-modulated inhibition of IL-4/IL-13 signaling via IL-4Rα blockade progressively and significantly improves disease activity, suppresses cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reverses AD-linked epidermal abnormalities. Additional studies are warranted to address possible interactions between the skin microbiome and resolution of clinical disease and tissue inflammation among patients with moderate to severe AD.

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Reference

Guttman-Yassky E, Bissonnette R, Ungar B, et al. Dupilumab progressively improves systemic and cutaneous abnormalities in atopic dermatitis patients [published online September 5, 2018]. J Allergy Clin Immunol. doi: 10.1016/j.jaci.2018.08.022