Improvement of Nonlesional Skin Tone and Skin Barrier in Severe Atopic Dermatitis after Dupilumab Treatment

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Introduction
Atopic dermatitis (AD) is a heterogeneous disease that has diferences among various ethnic and racial groups [1].Clinical presentation can also vary among racial subgroups; darker-skinned patients tend to have postinfammatory hyperpigmentation [2].Dupilumab, which is approved for the treatment of moderate-to-severe AD, appears to provide signifcant improvement of skin barrier function and hyperpigmentation in nonlesional skin [3] and for clinical improvement of hyperpigmentation on nonlesional skin [2] as well as for treating AD symptoms.However, to our knowledge, no previous study has evaluated changes of skin tone, erythema, pigmentation, and transepidermal water loss (TEWL) after dupilumab treatment.

Materials and Methods
A total of 19 patients with severe AD (14 males, 5 females) aged 20-41 years (mean age, 28.95) received a 600 mg loading dose of dupilumab and continued to 300 mg every two weeks.Te baseline eczema area and severity index (EASI) score of the patients was above 21.Written informed consent was obtained from all patients.Before and after treatment with dupilumab, measurements of skin tone, erythema, pigmentation, and TEWL were taken every month for fve months and were approved by the institutional review board (KHUH 2022-04-051).A spectrophotometer (CM-2600d, Konica Minolta, Japan), L * , a * , b * , and the narrow-band refectance spectrophotometer (Cortex Technology, Hadsund, Denmark), erythema index, and melanin index were used to measure the skin tone, erythema, and pigmentation in three sites of the nonlesional skin: the cheek, forearm, and lower abdomen.Te Tewameter TM300 probe (Courage + Khazaka, Köln, Germany) was used to measure TEWL.An alternative skin color type classifcation tool was developed using the individual typology angle (ITA).Tis classifcation is based on colorimetric parameters of the Commision Internationale de l'Eclairage (CIE) L * , a * , b * system.In this system, any color can be represented by three variables: L * the lightness axis, a * the red-green axis, and b * the yellow-blue axis [4].L * ranges from black (value 0) to white (value 100).a * refects the intensity and nature of basic melanic pigmentation as well as the level of natural vascularity of the individual.b * is related to the intensity of basic pigmentation.It is also refected in the carotene content and the nature of melanin [5].Narrow-band refectance spectrophotometer was developed to measure hemoglobin and melanin in the skin.Te red refectance yields an estimate of the melanin content and allows the calculation of the melanin index.Subtracting the red absorbance due to melanin from the green refectance estimates the erythema and gives the erythema index [6].
We calculated the relative percentage change from the baseline.Correlations between data were analyzed using Pearson's correlation coefcients.Data were analyzed using the Wilcoxon's rank-sum test.A Bonferroni correction was used to compare the diferences between baseline and treatment duration.Te statistical signifcance level was set at p < 0.05.

Results and Discussion
Tese results showed an improvement in skin tone, erythema, hyperpigmentation, and TEWL after dupilumab treatment (Figure 1).All the anatomical regions were brightened (Supplementary Figure 1).Comparing the anatomical regions, skin tone showed a relatively large improvement in the trunk, erythema index in the arm, and melanin index in the face.TEWL was correlated with the erythema index (r � 0.51, p < 0.0001), melanin index (r � 0.45, p < 0.0001), and a * (r � 0.50, p < 0.0001) and negatively correlated with L * (r � −0.48, p < 0.0001), but weakly correlated with b * (r � 0.28, p � 0.0059) (Supplementary Table 1).In this study, the L * and a * showed signifcant diferences from two months after dupilumab on both the arms and trunk and from three months on the face.In all anatomical regions, b * signifcantly decreased after one month, and TEWL showed a signifcant diference from two months (Supplementary Table 2).Nonlesional AD skin is distinct from normal skin with respect to epidermal diferentiation and immune abnormalities, suggesting that the overall skin in AD is abnormal [7].Dupilumab normalized lipid composition and increased ceramide chain length in lesional and nonlesional stratum corneum, thus allows restoration of the skin lipid composition and barrier function [8].In our study, all results showed continuous improvement as dupilumab treatment continued.

Conclusion
In conclusion, this study demonstrates that the skin tone, erythema, hyperpigmentation, and TEWL of nonlesional skin signifcantly improved after dupilumab initiation.Tese changes may be more clinically noticeable in Asians with melanin pigmentation.