Dupilumab improves skin barrier function in patients with atopic dermatitis
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Key takeaways:
- Patients treated with dupilumab experienced statistically significant improvements in transepidermal water loss.
- Also, patients with AD saw rapid and significant (P < .001) improvement in their ceramide composition.
- These improvements occurred in lesional and non-lesional skin.
By inhibiting IL-4 and IL-13 signaling, dupilumab enabled the restoration of lipid composition and barrier function in the skin of patients with moderate to severe atopic dermatitis, according to a study published in Allergy.
These improvements occurred in lesional and non-lesional skin, Evgeny V. Berdyshev, PhD, an associate professor and a researcher in the division of pulmonary, critical care and sleep medicine at National Jewish Health in Denver, and colleagues wrote in the study.
Skin lipids known as ceramides are vital in providing barrier function in the skin, according to the researchers. Skin ceramides also include ultra-long-chain fatty acids and unique omega-esterified (EO) ceramides that are highly hydrophobic.
IL-4 and IL-13, the major cytokines involved in AD pathogenesis, block the formation of very long-chain fatty acids and EO-type ceramides, interfering with skin barrier function and diminishing total skin ceramide hydrophobicity. Dupilumab (Dupixent, Sanofi Genzyme/Regeneron) targets the alpha subunit on the IL-4 receptor and blocks signaling initiated by IL-4 and IL-13.
The study cohort (42% female; 80.8% white) included 26 patients with moderate to severe AD and 26 healthy volunteers. Each group had 20 adults (median age at baseline, 40.5 years; range, 18-63 years) and six adolescents (median age at baseline, 13.5 years; range, 12-17 years).
Patients with AD received dupilumab 600 mg subcutaneously on the first day followed by 300 mg every other week starting at week 2 through week 14. Patients weighing less than 60 kg had a leading dose of 400 mg and subsequent doses of 200 mg.
The patients treated with dupilumab experienced statistically significant improvements in transepidermal water loss (TEWL), as measured by the area under the curve over 10 consecutive skin tape strips (AUC10). This improvement occurred between baseline and as early as day 15, and it was sustained through week 16 (P < .0001).
The median TEWL AUC10 in the intent-to-treat population was 608 g/m2 × hour (95% CI, 479-737) at baseline and 227 g/m2 × hour (95% CI, 156-299) at week 16, with no significant difference between the patients with AD and healthy volunteers. Similar findings were observed in non-lesional skin.
TEWL results before skin tape strip testing and after five and 10 skin tape strips showed similar improvements as the TEWL AUC10 measurements, with statistically significant improvements seen from day 15 through week 16 on lesional skin (P < .0001) and no significant differences compared with the healthy volunteers.
P < .001) improvement in their ceramide composition, with substantial decreases in the content of ceramides with non-hydroxy fatty acids and sphingosine (NS-ceramides) within 4 weeks of treatment, as well as gradual increases in the proportion of long-chain species and decreases in short-chain species of NS-ceramides in lesional skin.
Additionally, dupilumab brought levels of esterified omega-hydroxy fatty acids and C-18 sphingosine (EO[C18]S-ceramides) up to the levels found in the healthy volunteers within the course of the treatment, with the greatest effects seen within the first month.
Dupilumab also rapidly restored levels of EOS-ceramides with longer sphingoid bases in lesional and non-lesional skin, with some restoration of levels of NS-ceramides with C20-sphingosine and C22-sphingosine in lesional and non-lesional skin as well.
Further, dupilumab significantly improved the ratio between EOS-ceramides and NS-ceramides (P < .0005), which the researchers called a surrogate for skin hydrophobicity, with a tenfold increase in EOS-ceramide to NS-ceramide in lesional skin.
Overall, the researchers wrote, dupilumab restored EOS-ceramide levels and their proportion to corresponding NS-ceramides by restoring the biosynthesis of very long-chain fatty acids, which IL-4 and IL-13 typically impact.
Perspective
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Barrier dysfunction is a known, significant feature of the AD disease process, and normalizing it should be an important goal of treatment. Given the place that dupilumab has as a crucial first-line treatment for moderate to severe AD, having direct evidence of this improvement is very significant.
Although measuring skin barrier function directly is not part of a typical clinical practice, improvement with treatment can at least be inferred based on clinical responses. Dupilumab is often very effective in achieving clinical improvement, and these findings seem very much in line with that.
Doctors can use these findings to feel reassured that treating AD with dupilumab improves multiple aspects of the disease process, including those that have been better established to date, such as inflammation, itching and quality of life, as well as barrier function.
Next steps in this research may be to try to understand characteristics of patients that have different levels of improvement with treatment. AD is a heterogenous disease, so understanding the characteristics that impact clinical responses, including barrier function restoration, is very important.
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