To the Editor,
The extensive therapeutic pipeline for atopic dermatitis (AD) has stemmed from our improved understanding of AD pathogenesis. However, AD is clinically and molecularly heterogeneous, displaying age-specific characteristics with potentially meaningful therapeutic implications that need further investigation.
While full-depth skin biopsies have previously informed about evolving AD-associated biomarkers in pediatric AD during maturation,1 biopsies are not suitable for recurrent assessments. Additionally, although blood studies may represent overall skin involvement, AD-related blood abnormalities are delayed in comparison to skin and difficult to detect. Thus, it is imperative to use minimally invasive techniques to explore the patterns of expression among the different pediatric AD age groups, expanding upon previous tape-strip studies in pediatric patients overall.2
Forty-four moderate-to-severe AD patients in consecutive age groups (19 infants with <6 months disease duration, 0–5 y/o, mean age 1.7 years; 13 children, 6–11 y/o, mean age 8.0 years; and 12 adolescents, 12–17 y/o, mean age 15.0 years), and 52 age-appropriate controls were enrolled after parents and patients ≥12 y/o signed Institutional Review Board-approved informed consents and assents (Table S1). Exclusion criteria included recent use of systemic immunosuppressants and phototherapy (<4 weeks), topical steroids/immunomodulators (<1 week), or moisturizers (<12 h). Tape strips were serially collected from lesional and non-lesional AD and normal skin, as described.3 RT-PCR of 74 AD-related markers from tape-stripped AD and normal skin was performed to compare different age-groups using linear regression.
Lesional and nonlesional tape strips presented upregulations of general inflammation/innate immunity markers (e.g., MMP12, IL-8, IL-6) for most age groups FCH >2, p < .05) (Figures 1 and 2). ICOS, a marker for T-cell activation, was highly upregulated across all ages and AD samples (FCH > 12.5, p < .05). Tape strips captured the Th2-centered inflammation characteristic of AD across all age groups, including key AD-related markers such as CCL17/TARC and IL-13. Moreover, IL-4, a Th2 marker that is not consistently upregulated in AD skin biopsies despite its important role in disease pathogenesis,4 was significantly upregulated in both infant lesional and nonlesional skin and in adolescent lesions using tape strips (p < .05).
FIGURE 1.
Heatmap and fold change (FCH) of immune and barrier genes in tape-stripped lesional (LS) and nonlesional (NL) atopic-dermatitis (AD) vs. normal skin (N) across age-groups using RT-PCR, by criteria of FCH >2 and p < .05. Samples are sorted by hierarchical clustering. Right side of the table (pink headers) shows comparisons (using FCH) between lesional and nonlesional samples across pediatric age-groups. +p < .1, *p< .05, **p < .01, ***p < .001
FIGURE 2.
Word clouds by fold-change (represented by relative letter size) in lesional and non-lesional tape strips across pediatric age-groups.
Consistent with previous biopsy and blood data,1,5 the Th22/Th17-related S100A7/8/9 were upregulated in lesions across most pediatric age-groups, with S100A12 significantly upregulated in both lesional and nonlesional tape strips across all ages. Th17-related markers also presented an overall increase across all age groups, primarily in lesions (CCL20, IL-23A), with IL-19 exclusively upregulated in infants. The negative regulator IL-34 was upregulated across all age groups.
We also assessed barrier-related markers, key markers in AD, shown to be better captured with tape strips than biopsies in psoriasis.6 Despite the recent AD onset in infants, this age group displayed the greatest abnormalities across all evaluated barrier-related markers, with some markers showing significant dysregulations only in infants (such as the terminal differentiation marker periplakin/PPL in both lesional and nonlesional tape strips). Filaggrin/FLG and loricrin/LOR, pivotal terminal differentiation markers implicated in AD pathogenesis, showed greater and more significant downregulations than previously reported in full-depth AD biopsies in the same age groups.1 Moreover, in contrast to biopsied skin,1 a significant down-regulation of these markers was captured by tape strips in nonlesional skin, primarily in infants (e.g., FLG, FLG2, LOR, periplakin/PPL). These findings may be explained by the thinner epidermis of infants,1 resulting in a greater dermis to epidermis ratio and thus a relative dilution of epidermal barrier markers in biopsies as compared to tape strips.6
Our limitations include a cross-sectional nature and the inclusion of moderate-to-severe AD patients with a majority of White participants, potentially limiting the generalizability of these findings to milder patients and other races.
Our results suggest that tape strips are an ideal tool to assess epidermal biomarkers across pediatric age groups, capturing immune and barrier-related markers in both lesional and nonlesional skin. In AD, which is associated with systemic dysregulations across all age groups,5 nonlesional skin may represent the AD-related systemic activity, even in patients with minimally visible lesions, suggesting that normalization of nonlesional skin abnormalities may represent an ultimate therapeutic target. As new therapeutic options become available, tape strips may prove to be a painless technology to monitor and potentially predict response, particularly in pediatric patients of all ages.
Future studies should further investigate tape strips in AD in both mild and severe patients, and in response to different therapeutics across various pediatric races and age groups.
Supplementary Material
FUNDING INFORMATION
Supported by a research grant from the LEO Foundation and Regeneron. Yael Renert-Yuval was supported in part by the National Center for Advancing Translational Sciences, National Institutes of Health, through Rockefeller University, Grant #UL1TR001866.
Abbreviations:
- AD
atopic dermatitis
- FCH
fold-change
- FLG
filaggrin
- IL
interleukin
- qRT-PCR
quantitative real-time polymerase chain reaction
- Th
T helper cell type
Footnotes
CONFLICT OF INTEREST
EGY has served as a consultant for AbbVie, Amgen, Allergan, Asana Bioscience, Celgene, Concert, Dermira, DS Bio-pharma, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharmaceuticals, Lilly, Mit-subishi Tanabe, Novartis, Pfizer, Regeneron, Sanofi, and Union Therapeutics; a member of advisory boards of Allergan, Asana Bioscience, Celgene, DBV, Dermavant, Dermira, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Lilly, Novartis, Pfizer, Regeneron, and Sanofi; and a recipient of research grants from AbbVie, AnaptysBio, AntibioTx, Asana Bioscience, Boehringer-Ingelheim, Celgene, DBV, Dermavant, DS Biopharma, Galderma, Glenmark, Innovaderm, Janssen Biotech, Kiniska Pharma, LEO Pharmaceuticals, Lilly, Medimmune, Sienna Biopharmaceuticals, Novan, Novartis, Ralexar, Regeneron, Pfizer, UCB, and Union Therapeutics. ASP has received research support (grants paid to her institution) from AbbVie, Anaptysbio, Celgene, Eli Lilly, Galderma, Incyte, Leo, Janssen, Novartis, and Regeneron. She has been a consultant for Almirall, Amgen, Asana, Boehringer-Ingelheim, Castle Creek, Celgene, Dermavant, Dermira, Eli Lilly, Exicure, Forte, Galderma, Lenus, Leo, MEDA Corp, Meiji Seika, Novan, Novartis, Pfizer, Regeneron, Sanofi-Genzyme, and Sol Gel. ASP has served as an investigator (grants to institution) for AbbVie, AnaptysBio, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, Regeneron, UCB; consultant with honorarium for Abbvie, Acrotech, Almirall, Amgen, Amryt, Arcutis, Arena, Azitra, BioCryst, BiomX, Boeringer Ingelheim, Botanix, Bridgebio, Bristol Myers Squibb, Castle Biosciences, Catawba, Eli Lilly, Exicure, Gilead, Incyte, Janssen, Kamari, Leo, Novan, Novartis, Pfizer, Pierre Fabre, RAPT, Regeneron, Sanofi/Genzyme, Seanergy, UCB, and Union, and on the Data Safety Monitoring Board for AbbVie, Abeona, Bausch, Galderma, Inmed, and Novan. All other authors declare no competing interests.
SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.
REFERENCES
- 1.Renert-Yuval Y, Del Duca E, Pavel AB, et al. The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults. J Allergy Clin Immunol. 2021;148(1):148–163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Andersson AM, Solberg J, Koch A, et al. Assessment of biomarkers in pediatric atopic dermatitis by tape strips and skin biopsies. Allergy. 2021;77:1499–1509. [DOI] [PubMed] [Google Scholar]
- 3.Guttman-Yassky E, Diaz A, Pavel AB, et al. Use of tape strips to detect immune and barrier abnormalities in the skin of children with early-onset atopic dermatitis. JAMA Dermatol. 2019;155:1358–1370. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Tsoi LC, Rodriguez E, Degenhardt F, et al. Atopic dermatitis is an IL-13-dominant disease with greater molecular heterogeneity compared to psoriasis. J Invest Dermatol. 2019;139(7):1480–1489. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Czarnowicki T, He H, Canter T, et al. Evolution of pathologic T-cell subsets in patients with atopic dermatitis from infancy to adulthood. J Allergy Clin Immunol. 2020;145(1):215–228. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Tsoi LC, Xing X, Xing E, et al. Noninvasive tape-stripping with high-resolution RNA profiling effectively captures a preinflammatory state in nonlesional psoriatic skin. J Invest Dermatol. 2022;142(6):1587–1596.e2. [DOI] [PMC free article] [PubMed] [Google Scholar]
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