Dupilumab Improves Skin and Systemic Symptoms of Atopic Dermatitis

Burden Associated with Atopic Dermatitis

Atopic dermatitis (AD) is an inflammatory skin disease. One-third of patients have moderate to severe forms and many require systemic treatment. Both skin symptoms and systemic inflammation, alongside potential comorbidities, represent a significant burden for patients and their families. Therapeutic options for patients who do not respond adequately to topical treatments are currently limited and often have undesirable side effects.

Mechanism of Action of Dupilumab

Dupilumab is the first targeted biological treatment approved in the European Union, the United States, Japan, and other countries for adults with inadequately controlled moderate to severe AD. It is a fully human monoclonal antibody (mAb) targeting the IL-4α receptor, a shared subunit of IL-4 and IL-13 cytokines, inhibiting the signaling of both cytokines. Clinical studies have shown that dupilumab is highly effective and has an acceptable safety profile in adults with moderate to severe AD, asthma, or chronic rhinosinusitis with nasal polyposis, supporting the view that these atopic disorders share a type 2 inflammatory response pathogenesis.

Study Methodology and Progress

A placebo-controlled double-blind study evaluated the safety and efficacy of dupilumab in patients with moderate to severe AD. Molecular and cellular phenotypes of skin from eczematous lesions and unaffected skin were analyzed. Systemic biomarkers of type 2 inflammatory response were also tested. Skin biopsy and blood samples from 54 patients randomized 1 : 1 to either subcutaneous 200 mg dupilumab or placebo once weekly for 16 weeks were used for evaluation. Participants were monitored for a total of 32 weeks.

Results

Compared to placebo, dupilumab significantly improved the clinical signs and symptoms of AD, was well tolerated, and progressively shifted lesional transcriptome towards non-lesional phenotype (weeks 4-16). Significant modulation of gene expression was observed. Dupilumab significantly reduced the expression of genes involved in type 2 inflammation, epidermal hyperplasia processes, T cell and dendritic cell activation, and TH₁₇/TH₂₂ lymphocyte activity. Concurrently, it increased the expression of genes affecting epidermal differentiation, skin barrier formation, and lipid metabolism.

By week 4, patients on dupilumab achieved an average of 68.8% improvement in AD transcriptome derived from a meta-analysis of genes differentially expressed in lesional versus non-lesional skin compared to −10.5% for patients on placebo. By week 16, average improvement reached 110.8% in the dupilumab arm compared to 55.0% in the placebo group. Dupilumab reduced lesional epidermal thickness compared to placebo (week 4 p = 0.001; week 16 p = 0.0002).

Improvement in clinical and histological outcomes significantly correlated with gene expression modulation. Dupilumab also significantly suppressed serum markers of type 2 inflammation, including CCL17, CCL18, periostin, and total and allergen-specific IgE.

Conclusion

Targeted dual inhibition of IL-4 and IL-13 signaling through IL-4Rα blockade by dupilumab rapidly and progressively suppressed cellular and molecular skin markers of inflammation and reversed related epidermal abnormalities. It also improved disease severity scores and symptoms in patients with moderate to severe AD. There was also a reduction in systemic biomarkers of type 2 inflammation.

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Source: Guttman-Yassky E., Bissonnette R., Ungar B. et al. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis. J Allergy Clin Immunol 2019; 143 (1): 155–172, doi: 10.1016/j.jaci.2018.08.022.