Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2024;14(2):e2024123 1 Tape Stripping — Searching for Minimally Invasive Biomarkers in Atopic Dermatitis Weronika Zysk1, Magdalena Trzeciak1 1 Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, Poland Key words: Atopic dermatitis, biomarkers, precise treatment, tape-strips Citation: Zysk W, Trzeciak M. Tape Stripping — Searching for Minimally Invasive Biomarkers in Atopic Dermatitis. Dermatol Pract Concept. 2024;14(2):e2024123. DOI: https://doi.org/10.5826/dpc.1402a123 Accepted: February 4, 2024; Published: April 2024 Copyright: ©2024 Zysk et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: Both the authors have contributed significantly to this publication. Corresponding Author: Prof. Magdalena Trzeciak, Department of Dermatology, Venereology and Allergology, Faculty of Medicine, Medical University of Gdansk, Smoluchowskiego 17 Street, 80-214 Gdansk, Poland. Tel. +48585844014; fax +48585844020 E-mail: mtrzeciak@ gumed.edu.pl Atopic dermatitis (AD) is nowadays entering a new era of more targeted treatments. However, to make personalized medicine, which we are currently striving for, a reality, a reliable set of validated biomarkers is needed. The most practical seem to be biomarkers that can be obtained easily and minimally invasively. Tape stripping (TS) is a method that provides such an opportunity. This review summarizes the potential biomarkers of AD identified by the minimally invasive TS method. Thymic stromal lymphopoietin (TSLP), interleukin (IL)-13, CC chemokine ligand 17 (CCL17)/thymus and activation-regulated chemokine (TARC) and stratum corneum (SC) lipids can be used as predictive biomarkers for AD occurrence. CCL17/TARC also holds great promise for being reliable biomarkers for AD severity as well as treatment response. Nitric oxide synthase 2 (NOS2)/inducible nitric oxide synthase (iNOS) which high expression is specific for psoriasis may be a good biomarker for differen- tial diagnosis between psoriasis and AD in challenging clinical situations. AD children with food al- lergy (FA) have a unique endotype characterized by selectively altered expression of various molecules in the skin that can indicate FA coexistence. Unfortunately, although numerous potential biomarkers have been found, none of these candidates have been validated and implemented into routine clinical practice, which still separates us from the possibility of a precise approach to AD patients. ABSTRACT Introduction Atopic dermatitis (AD) is a chronic and highly hetero- geneous inflammatory skin disorder with severe itching affecting approximately 20% of children and up to 10% of adult patients worldwide [1]. The disease is characterized by different endotypes that drive specific phenotypes [2]. Multi- ple factors such as disease chronicity, age of onset, ethnicity, 2 Review | Dermatol Pract Concept. 2024;14(2):e2024123 immunoglobulin E (IgE) levels, filaggrin mutation status, and underlying molecular mechanisms orchestrate the phenotype of AD [2]. Immune polarization in AD is primarily towards Th2/Th22, with variable Th1 and Th17 components [2]. In the phase of acute lesions, which are erythematous, wet, and highly inflammatory, accumulation of cytokines from the Th2 and Th22 axes and, to a lesser extent, Th17 is ob- served [2]. With disease chronicity, lesions turn lichenified, dry, thick, and hyperpigmented, which is accompanied by the intensification of Th2 and Th22 responses with signif- icant increases in Th1 cytokines but no further increases in Th17 cytokines [2]. Apart from the typical Th2/Th22- dependent immune response, adult AD patients exhibit greater expression of Th1 cytokines than pediatric AD patients, whereas pediatric AD patients have higher involvement of Th17 cytokines than adults [2,3]. Additionally, the morphol- ogy and distribution of AD lesions change as patients age [2,3]. Asian AD patients have higher Th17 and lower Th1 axis activations than European American AD patients, who are characterized by immune polarization mainly towards Th2, Th22, and Th1. African American AD patients exhibit primarily Th2/Th22 axis activation with parallel attenuation of Th1/Th17 [2,4]. According to the IgE levels, AD can be categorized into the IgE-high, extrinsic subtype presented in 80% of patients, and the IgE-normal, intrinsic subtype in the remaining 20% [2,3]. Moreover, extrinsic AD is associated with traditional immune polarization towards Th2, eosino- philia, personal and family atopic background, and a higher percentage of filaggrin (FLG) mutation, whereas greater Th1 and Th17/Th22 immune responses, delayed disease onset, preserved barrier function, and increased metal contact hy- persensitivity characterize patients with intrinsic AD [2,3]. With the development of novel targeted, highly specific therapies for AD over the past few years, we are seeing a revolution in the field of treatment for this disease. However, due to the high heterogeneity of AD, we will not be able to fully benefit from these therapies, which are regrettably also very expensive, without a precise medical approach [2] Therefore, it is essential to search for reliable biomarkers, based on which it will be possible to accurately stratify pa- tients and then apply appropriate preventive strategies or therapy precisely tailored to the patient’s needs, resulting in a medical care system with higher efficacy, less risk to the individual, and lower overall costs [5]. In other words, a validated set of biomarkers is an essential instrument in the toolbox of precision medicine in AD. A recently published review article on behalf of the International Eczema Council highlights the great unmet need for minimally invasive bio- markers, which would enable the implementation of preci- sion medicine in AD [6]. Tape stripping (TS) is a minimally invasive way of ob- taining stratum corneum (SC) and some of the stratum granulosum (SG) samples using adhesive tapes. The tech- nique is simple, painless, and causes neither bleeding nor scarring. It is only associated with mild discomfort and a temporary red mark on the skin [7]. SC samples collected by TS are suitable for detecting several biological entities such as proteins, proteases, lipids, and RNA, providing a wide range of immune and epidermal barrier biomarkers for both lesional and nonlesional skin [8]. Until recently, the only method to obtain biomarkers from the skin was through a painful and scarring skin biopsy, which may also be complicated by infections and poor healing [6]. TS tech- nique appears to be a promising and reliable alternative to skin biopsies in evaluating skin biomarkers in AD patients, especially infants, in whom conventional, painful skin biopsy may be difficult to perform and practically contraindicated [9]. In addition, due to the non-invasive nature of TS, this technique allows repeated skin samples to be taken from the same patient in a short time for various purposes, such as therapy monitoring or clinical trials, and longitudinal studies [9]. Skin biopsies in these cases would be challenging. The main limitation of TS seems to be that only biomarkers pres- ent in or diffuse into the superficial layers of the epidermis can be captured [9]. Moreover, previous tape strip reports in AD described limited sample detection rates [6], but recently global transcriptomic studies in young children and adults with AD have shown improved rates of detection, which were almost 100% per sample and marker [10,11]. Objectives In this review, we provide a summary of potential AD bio- markers identified by the minimally invasive TS method (Table 1). Methods A comprehensive search of the literature using the PubMed electronic database with the search queries,,atopic dermatitis AND tape strips’’, atopic dermatitis AND tape stripping’’, ,,atopic dermatitis AND potential biomarkers’’, ,,atopic dermatitis AND biomarkers’’, ,,atopic dermatitis AND skin biomarkers’’, ,,atopic dermatitis and epidermal biomarkers’’, and ,,atopic dermatitis AND minimally invasive biomarkers’’ was performed. The search period was from the inception of the database to 8 May 2023. Based on the title and abstract analysis, we included articles concerning the potential bio- markers in atopic dermatitis identified by the tape-stripping method. At this step, we excluded records not related to the topic, non-English manuscripts, personal opinions, and du- plicates or related to skin biopsy instead of tape strips. Af- ter reading the full manuscripts, some were excluded (not relevant or providing information concerning only skin Review | Dermatol Pract Concept. 2024;14(2):e2024123 3 biomarkers identified by skin biopsy instead of tape strip- ping). Finally, we also included other suitable records that we found by searching references through other articles we found. Potential minimally invasive skin biomarkers identi- fied by tape stripping were analyzed and summarized. Results Potential Biomarkers for AD Occurrence The identification of biomarkers that can select infants at risk of developing AD would allow the implementation of target preemptive interventions. Currently, the best-known risk factor for AD is FLG mutations, carried by approxi- mately 10% to 40% of these patients [12]. A positive fam- ily history of AD is another well-established risk factor [4]. Since, for instance, the application of emollients from birth has been proposed as a preventive measure in high-risk in- fants [13]. However, two recently published trials did not confirm that daily use of emollients during the first year of life prevents AD in high-risk children [14,15]. Perhaps we may also need additional preventive strategies for AD. How- ever, to establish a primary prevention strategy, it is essential to find biomarkers that can predict the development of AD. The effective prevention of AD would undoubtedly represent an important public health breakthrough. In the prospective birth cohort study, the expression of epidermal thymic stromal lymphopoietin (TSLP) was pro- posed as a potential early biomarker for predicting AD de- velopment in infants. Children with high TSLP expression at 2 months were 5.3 times more likely to develop AD by age 24 months (95% CI, 1.3-21.4) [16]. Berdyshev et al [17] indicated a panel of biomarkers that predicted the onset of AD by the age of 24 months with an OR of 54.0 (95% CI, 9.2-317.5). It was the combination of a positive fam- ily history of atopic diseases, high IL-13, high 26:1-SM, and low O30:0(C22S)-CER levels in skin tape strips [17]. Rin- nov et al [18] found that children who developed AD in the first 12 months of life had an altered SC lipid composition. Among the examined lipid markers, reduced phytosphin- gosine level may serve as a single predictor of the occurrence of AD with a prediction accuracy of 75.6% [18]. Another study has shown that elevated CCL17/TARC levels in SC at 2 months of age increased the risk of AD development within the first 2 years of life (aHR: 1.85; 95% CI: 1.18- 2.89; P = 0.007) [19]. Noteworthy, all of these studies focus on biomarkers that predict the development of AD in infants. Since we have learned that AD represents a disease that can occur at any age [20,21], the availability of biomarkers predicting adult-onset AD or AD in the elderly would be very useful. Table 1. The table shows the molecules that were tested by the tape stripping (TS) method as potential biomarkers. So far, none of them has been validated and implemented in routine clinical practice. The potential biomarkers of atopic dermatitis (AD) identified by the TS method Biomarkers for AD occurrence TSLP, a panel of biomarkers: positive family history of atopic diseases, IL-13, 26:1-SM, and O30:0(C22S)-CER; phytosphingosine, CCL17/ TARC Diagnostic biomarkers IL-34, FLG, FLG2, LOR, FA2H, NOS2/iNOSa Biomarkers for AD severity IL-18, CXCL8, VEGF-A, Flt-1, IL-33, IL-23p19, IL-19, S100As, PI3, IL-36G, DEFB4B, STAT3, LL-37, IL-17C, K16, IL-4R, CD11b, CD11c, CCL17/TARC, CTACK, IL-8, TSLP, CCL2, Hbd-2, VEGF, MIF, MMP12, ICOS, IL-13, CCL26, IL-22, IL-17F, IL-26, CAMP/LL-37, FOXP3 Biomarkers of barrier function TSLP, Gal-7, SERPINB3, TARC/CCL17, CCL22, IL-22, IL-17A, trihydroxy-linoleic acid Biomarkers for monitoring treatment response TARC/CCL17, IL-8, CSF1, CCL13, CCL23, KYNU, IL-6R, CCL20, IL-34, FABP7, NGF, IL-37 Biomarkers for comorbidities (Food allergy) FLG, KRT5, KRT14, KRT16 AD = atopic dermatitis; IL = interleukin; CCL = CC chemokine ligand; CXCL = C-X-C motif chemokine ligand; CSF1 = colony-stimulating factor 1; CTACK = cutaneous T cell-attracting chemokine; DEFB4B = β-defensin 4B; FABP7 = fatty acid binding protein 7; FA2H = fatty acid 2-hydroxylase; FLG = filaggrin; Flt-1 = vascular endothelial growth factor receptor 1; FOXP3 = forkhead box P3; Gal-7 = galectin-7; ICOS = Inducible T-cell COStimulator; hBD-2 = human b-defensin-2; KRT = keratin; PI3 = phosphoinositide 3-kinase; K16 = keratin 16; KYNU = Kynureninase; iNOS = inducible nitric oxide synthase; S100As = S100 calcium-binding protein A; LL-37 = cathelicidin; LOR = loricrin; MIF = macrophage migration inhibitory factor; MMP12 = matrix metallopeptidase 12; NGF = nerve growth factor; NOS2 = ni- tric oxide synthase 2; STAT3 = signal transducer and activator of transcription 3; TARC = thymus and activation-regulated chemokine; TSLP =thymic stromal lymphopoietin; VEGF = vascular endothelial growth factor. apotential biomarker for differential diagnosis between psoriasis and AD 4 Review | Dermatol Pract Concept. 2024;14(2):e2024123 Potential Biomarkers for AD Severity In the era of more targeted therapies for AD, knowing the exact severity of the disease seems crucial for planning the appropriate timing, and intensity of treatment. In the study by McAleer et al [24], among the examined SC markers, the levels of IL‐18, CXCL8, VEGF‐A, and Flt‐1 in non-lesional skin showed the highest correlation with AD severity and barrier function among AD infants [24]. The investigation by Guttman-Yassky et al [11] among children with early-onset AD showed the greatest number of signifi- cant correlations between disease severity and lesional bio- markers, including the expression of Th2 (IL-33, IL-4R) and Th17 (IL-23p19) cytokines, Th17/Th22 (IL-19, S100As, PI3, IL-36G, β-defensin 4B (DEFB4B), STAT 3, and cathelicidin LL-37), innate (IL-17C), hyperplasia (epidermal prolifer- ation marker K16), Th2 (IL-4R), and cellular (CD11b and CD11c) biomarkers. In another assessment of biomarkers, the levels of CCL17/TARC, CTACK, IL-8, and IL-18 in both lesional and non-lesional tape-stripped skin were indicated as crucial biomarkers of AD severity in children [25]. Cy- tokines such as IL-8, IL-18, and TSLP have demonstrated a positive correlation with SCORAD in lesional AD skin in the study conducted by Lyubchenko et al [26]. Furthermore, IL-8 appears to be a useful biomarker of local severity in both acute and chronic AD lesions [27]. Hulshof et al [28] has pointed out CCL17/TARC, CXCL8, and CCL2 as the most promising biomarkers to assess the severity of AD in children. In non-lesional AD skin, all 3 biomarkers signifi- cantly correlated with objective SCORing AD (oSCORAD), whereas in lesional AD skin, only CXCL8 significantly cor- related with oSCORAD. Clausen et al [29] found a signifi- cant positive correlation between hBD-2 in lesional skin and both disease severity (SCORAD) and skin barrier function (TEWL) [29]. VEGF has been proposed as an indicator of the acute inflammatory condition of skin lesions in patients with AD [30]. Macrophage migration inhibitory factor (MIF) was suggested to be a marker of the local severity of AD, as its level in SC significantly correlated with the sever- ity of the local skin lesion [31]. Other suggested biomarkers by He et al in lesional skin that may reflect the clinical sever- ity of AD (according to TSS and IGA score) included mark- ers of general inflammation (matrix metallopeptidase 12 (MMP12) ), T-cell activation (inducible T-cell COStimulator (ICOS)), Th2 (IL-13, CCL17/TARC, and CCL26/ eotaxin-3), Th22 (IL-22), Th17 (IL-17F, IL-26, and cathelicidin antimicrobial peptide (CAMP)/LL37), and T-regs (FOXP3). [10] CCL17/TARC may be useful in the evaluation severity of lesions of AD, especially in acute ones as its level in SC was strongly correlated with acute phase parameters of le- sions such as erythema, edema/papule, and oozing/crusts but not with itching and excoriation or chronic parameters such as lichenification and xerosis [32]. Additionally, CCL17/ Moreover, childhood AD can have periods of long remission and then recur in later stages of life [20,21]. Such prognostic biomarkers would be also very helpful in terms of the pre- vention of AD. Potential Diagnostic Biomarkers of AD To date, the diagnosis of AD is most commonly based on Hanifin and Rajka criteria, which were primarily developed based on the pediatric population. The clinical picture of AD in adult patients is characterized by marked heteroge- neity. Reliable biomarkers for the diagnosis are lacking, and a diagnosis of AD, especially adult-onset AD, can be chal- lenging [20]. Furthermore, there is a range of diseases that can mimic AD in both children and adults [22]. For this rea- son, there are unmet needs for biomarkers to confirm the diagnosis or distinguish AD from other diseases with similar manifestations, which would be incredibly useful in chal- lenging cases. Guttman-Yassky et al [11] has described IL-34 as a per- fect single-gene classifier to discriminate early-onset AD skin from normal skin with almost 100% accuracy. Moreover, they found that epidermal barrier markers, such as FLG, FLG2, loricrin (LOR), and fatty acid 2-hydroxylase (FA2H), were also effective discriminators. A comprehensive tran- scriptome analysis in patients with AD and psoriasis iden- tified nitric oxide synthase 2 (NOS2)/inducible nitric oxide synthase (iNOS) expression as a single gene biomarker that can differentiate these two conditions with 100% accuracy (AUC = 1.0) by quantitative PCR and almost perfectly (AUC = 0.97) using the RNA-seq data [10]. Psoriasis skin exhibited significantly elevated levels of NOS2/iNOS expres- sion, whereas AD skin exhibited no discernible increase in expression [10]. Thus, the differential expression of NOS2/ iNOS between psoriasis and AD skin suggests its potential utility as a valuable biomarker for distinguishing between these two dermatological conditions, particularly in chal- lenging clinical situations. The usefulness of TS for differential diagnosis in pa- tients with overlapping features of AD and psoriasis also finds reflection in real-life clinical practice. In patient pre- senting with concurrent psoriasis and AD, the analysis of tape strips revealed pronounced expression of Th17-related products, along with NOS2/iNOS, which is specific for pso- riasis, as well as Th2-related products characteristic of AD confirming the overlap of the two diseases. The coexistence of these two conditions was also previously confirmed by a skin biopsy [23]. This suggests that TP can serve as a diag- nostic tool in challenging clinical situations, replacing the need for invasive skin biopsies to distinguish between AD and psoriasis. However, there are still numerous biomarkers differentiating AD from many other diseases that need to be discovered. Review | Dermatol Pract Concept. 2024;14(2):e2024123 5 biomarkers predicting treatment response to a particular drug, which is essential in the current era of new targeted therapies in AD. Based on these biomarkers we would be able to identify patients who will likely benefit most from partic- ular drugs and stratify them before treatment initiation. The TS technique was applied to assess the effect of top- ical therapy in a few studies. The results put CCL17/ TARC and IL-8 in the light of promising biomarkers for monitor- ing topical therapy effect. After 6 weeks of using emollient, CCL17/TARC, and IL-8 expression decreased in moderate AD patients, which was correlated with reduced disease severity [38]. Additionally, it has been demonstrated that the expression of IL-8 in SC was significantly reduced after topical corticosteroid treatment and correlated with visual improvements in symptoms of AD [39]. Moreover, TS may be useful for assessing treatment response to systemic tar- geted drugs such as dupilumab. He et al [40] found that many key immune proteins were significantly decreased in lesional skin after dupilumab treatment, further correlat- ing with the improvement of clinical symptoms of AD, as measured by EASI. These included markers of immune cell infiltration such as macrophages (CSF1), immune markers related to Th2 (CCL13, CCL23), Th17 (KYNU), and innate immunity (IL-6R) [40]. CCL20, IL-34, and FABP7 were also observed to be useful in monitoring therapeutic response to dupilumab treatment [41]. Quantitative analysis of nerve growth factor (NGF) in AD stratum corneum has found that the level of NGF reflects the severity of the disease and may also help assess the therapeutic effects of AD [42]. The expression of NGF has been significantly downregulated after antihistamine and/or topical steroid treatment and correlated with the decrease in the severity of AD lesions and laboratory severity parameters of the disease, such as eosinophil count, and LDH level [42]. IL-37, an anti- inflammatory cytokine, is also believed to be a reliable biomarker to monitor cutaneous therapeutic response. An association between SCORAD score improvement and up- regulation of IL-37 following treatment of mometasone has been observed [43]. TS method can be a useful tool for treatment response. Traditional monitoring methods for treatment response of- ten rely on subjective assessments or clinical observations. TS method provides objective evidence of changes occurring in the skin, allowing for a more accurate assessment of the efficacy of a treatment and tracking changes over time. Fur- thermore, the procedure can be easily repeated at different time points to monitor the progression of treatment response over time. The data obtained from TS can help us make in- formed decisions about treatment regimens and determine whether to escalate or reduce the intensity of the treatment or change medications resulting in ultimately improved pa- tient outcomes. TARC has been considered an indicator of AD’s systemic disease severity, as it correlated with laboratory parameters reflecting the systemic severity of the disease, such as the se- rum IgE level and the blood eosinophil count [32]. It should be mentioned that serum CCL17/TARC levels according to many studies, appear to be the most reliable biomarker for AD severity in both adult and pediatric patients currently available [6]. Biomarkers of Barrier Function in AD Sano et al [33] found that the TSLP expression level was correlated significantly with SCORAD and epidermal barrier functions, such as TEWL. Importantly, among items within SCORAD, a significant correlation was shown only with the itching score and xerosis score, which is regarded as a reflec- tion of epidermal barrier dysfunction in AD [33]. According to these results, the hypothesis was put forward that the ex- pression level of TSLP in SC might be a useful biomarker of AD severity, especially epidermal barrier status. In addition, it seems to be applicable for estimating the effects of the use of moisturizing products on skin dryness because, after treat- ment with moisturizer, the level of TSLP was reduced [33]. Using an in vivo model of skin barrier disruption, it has been shown that the level of galectin-7 (Gal-7), which plays a role in maintaining epidermal homeostasis, was significantly cor- related with TEWL [34]. Skin tape strip proteomic analysis has shown that among 45 identified proteins in non-lesional AD skin, SERPINB3 expression had the highest positive correlation with TEWL, while KRT10 expression had the highest negative correlation with TEWL [35]. Lyubchenko et al [26] has found that the levels of CCL17, CCL22, TSLP, IL-22, and IL-17A in lesional AD skin positively correlated with skin TEWL measurements in the pediatric cohort. According to results obtained by Chiba et al.[36], the trihydroxy-linoleic acid levels in the SC significantly cor- related with TEWL, which makes it another possible bio- marker of barrier function in AD easily measured by TS. Potential Biomarkers for Monitoring Treatment Response of AD The effective treatment of AD is a highly desirable goal. According to the data, up to over 55% of adult patients with moderate to severe AD complain of inadequate disease control [37]. Considering the high heterogeneity of AD, the ‘‘one-size-fits-all’’ approach may not be successful in these patients because treatment response may differ depending on immune differences in particular AD endotypes/ phenotypes [3]. Biomarkers for monitoring treatment response may pro- vide objective information on how effective a particular drug is in each patient. This would have significance in terms of selecting appropriate therapies for patients and consequently ensuring successful treatment outcomes. We greatly need 6 Review | Dermatol Pract Concept. 2024;14(2):e2024123 References 1. Laughter MR, Maymone MBC, Mashayekhi S, et al. The global burden of atopic dermatitis: lessons from the Global Burden of Disease Study 1990-2017. Br J Dermatol. 2021;184(2):304-309. DOI: 10.1111/bjd.19580. PMID: 33006135. 2. Czarnowicki T, He H, Krueger JG, Guttman-Yassky E. Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol. 2019;143(1):1-11. DOI: 10.1016/j.jaci .2018.10.032. PMID: 30612663. 3. Tokura Y, Hayano S. Subtypes of atopic dermatitis: From phe- notype to endotype. Allergol Int. 2022;71(1):14-24. DOI: 10.1016/j.alit.2021.07.003. PMID: 34344611. 4. Sroka-Tomaszewska J, Trzeciak M. Molecular Mechanisms of Atopic Dermatitis Pathogenesis. Int J Mol Sci. 2021;22(8):4130. DOI: 10.3390/ijms22084130. PMID: 33923629. PMCID: PMC8074061. 5. Mastraftsi S, Vrioni G, Bakakis M, et al. Atopic Dermatitis: Striving for Reliable Biomarkers. J Clin Med. 2022;11(16):4639. DOI: 10.3390/jcm11164639. PMID: 36012878. PMCID: PMC9410433. 6. Renert-Yuval Y, Thyssen JP, Bissonnette R, et al. Biomarkers in atopic dermatitis-a review on behalf of the International Eczema Council. J Allergy Clin Immunol. 2021147(4):1174-1190.e1. DOI: 10.1016/j.jaci.2021.01.013. PMID: 33516871. 7. Hughes AJ, Tawfik SS, Baruah KP, O’Toole EA, O’Shaugh- nessy RFL. Tape strips in dermatology research. Br J Dermatol. 2021;185(1):26-35. DOI: 10.1111/bjd.19760. PMID: 33370449. 8. Keurentjes AJ, Jakasa I, Kezic S. Research Techniques Made Simple: Stratum Corneum Tape Stripping. J Invest Dermatol. 2021;141(5):1129-1133.e1. DOI: 10.1016/j.jid.2021.01.004. PMID: 33888213. 9. Kim BE, Goleva E, Kim PS, et al. Side-by-Side Comparison of Skin Biopsies and Skin Tape Stripping Highlights Abnormal Stratum Corneum in Atopic Dermatitis. J Invest Dermatol. 2019;139(11): 2387-2389.e1. DOI: 10.1016/j.jid.2019.03.1160. PMID: 31176708. PMCID: PMC6814531. 10. He H, Bissonnette R, Wu J, Diaz A, et al. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol. 2021;147(1):199-212. DOI: 10.1016/j.jaci.2020.05.048. PMID: 32709423. 11. 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 Der- matol. 2019;155(12):1358-1370. DOI: 10.1001/jamaderma- tol.2019.2983. PMID: 31596431. PMCID: PMC6802262. 12. Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common loss-of-function variants of the epidermal barrier protein filag- grin are a major predisposing factor for atopic dermatitis. Nat Genet. 2006;38(4):441-446. DOI: 10.1038/ng1767. PMID: 16550169. 13. Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient enhance- ment of the skin barrier from birth offers effective atopic derma- titis prevention. J Allergy Clin Immunol. 2014;134(4):818-823. DOI: 10.1016/j.jaci.2014.08.005. PMID: 25282563. PMCID: PMC4180007. 14. Chalmers JR, Haines RH, Bradshaw LE, et al. Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial. Lancet. 2020;395(10228):962-972. DOI: 10.1016/S0140-6736(19)32984-8. PMID: 32087126. PMCID: PMC7086156. Potential Biomarkers for Comorbidities of AD Patients with AD often have not only allergic comorbidities but also others such as neuropsychiatric, autoimmune, met- abolic diseases, or cardiovascular diseases [44]. There is a great need to seek biomarkers associated with comorbidities in AD. Evaluation of candidate biomarkers for comorbidities in AD by TS is limited; there are a few reports regarding food allergy (FA) in AD patients. Skin tape strip proteomic analysis has shown that AD children with FA have a unique endotype characterized by selectively altered expression of keratins, proteases, in- flammatory mediators, alarmins, glycolytic enzymes, and antioxidant defense proteins in non-lesional skin in compar- ison to children without FA as well as nonatopic children [35]. FLG breakdown products FA together with keratin 5 (KRT5), KRT14, and KRT16 have been proposed as prog- nostic biomarkers for coexisting food allergy in children with AD [45]. Studies that identify candidates for biomarkers predict- ing the development of diseases such as neuropsychiatric, au- toimmune, gastrointestinal, malignant, and cardiovascular in AD patients are generally underdeveloped [46]. Identifying who is at risk of comorbidity may ensure a more holistic ap- proach to these patients and targeted preventative strategies development. Unfortunately, this ability remains a key unmet need in patients with AD. Conclusions Numerous potential biomarkers have been proposed as a result of extensive work. But so far, none of these can- didates have been validated and implemented into rou- tine clinical practice. Reliability, clinical validity, a high positive predictive value, prediction of the therapeutic response, and disease progression are the seven most es- sential features that future validated biomarkers should fulfill, according to members of the BIOMAP project [47]. Currently, CCL17/TARC holds great promise for being reliable biomarkers for AD severity as well as treatment response in children and adults. In Japan, CCL17/TARC serves as a useful clinical biomarker for monitoring treat- ment efficacy, and since 2008 its serum levels have been commercially measured under health insurance support [6]. The TS technique allows us to obtain this biomarker in a minimally invasive way, both in children and adults. Considering the complex and heterogeneous nature of AD, it appears that in clinical practice, we need multiple sets of biomarkers rather than a single biomarker. The concept of personalized medicine in AD seems to be within reach. However, reliable biomarkers are essential to moving a step forward, without which we won’t fully benefit even from the most expensive therapy. Review | Dermatol Pract Concept. 2024;14(2):e2024123 7 29. Clausen ML, Jungersted JM, Andersen PS, Slotved HC, Krog- felt KA, Agner T. Human β-defensin-2 as a marker for disease severity and skin barrier properties in atopic dermatitis. Br J Der- matol. 2013;169(3):587-593. DOI: 10.1111/bjd.12419. PMID: 23647067. 30. Amarbayasgalan T, Takahashi H, Dekio I, Morita E. Content of vascular endothelial growth factor in stratum corneum well correlates to local severity of acute inflammation in patients with atopic dermatitis. Int Arch Allergy Immunol. 2012;157(3): 251-258. DOI: 10.1159/000327556. PMID: 22042099. 31. Yasuda C, Enomoto A, Ishiwatari S, et al. Macrophage migration inhibitory factor (MIF) in the stratum corneum: a marker of the local severity of atopic dermatitis. Exp Dermatol. 2014;23(10): 764-766. DOI: 10.1111/exd.12520. PMID: 25056219. 32. Morita E, Takahashi H, Niihara H, et al. Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis. Allergy. 2010;65(9):1166-1172. DOI: 10.1111/j.1398-9995.2010.02361.x. PMID: 20374230. 33. Sano Y, Masuda K, Tamagawa-Mineoka R, et al. Thymic stromal lymphopoietin expression is increased in the horny layer of pa- tients with atopic dermatitis. Clin Exp Immunol. 2013;171(3): 330-337. DOI: 10.1111/cei.12021. PMID: 23379440. PMCID: PMC3569541. 34. Niiyama S, Yoshino T, Yasuda C, et al. Galectin-7 in the stratum corneum: a biomarker of the skin barrier function. Int J Cosmet Sci. 2016;38(5):487-495. DOI: 10.1111/ics.12326. PMID: 27028525. 35. Goleva E, Calatroni A, LeBeau P, Berdyshev E, et al. Skin tape proteomics identifies pathways associated with transepidermal water loss and allergen polysensitization in atopic dermatitis. J Allergy Clin Immunol. 2020;146(6):1367-1378. DOI: 10.1016 /j.jaci.2020.04.022PMID: 32360271. PMCID: PMC7606732. 36. Chiba T, Nakahara T, Kohda F, Ichiki T, Manabe M, Furue M. Measurement of trihydroxy-linoleic acids in stratum corneum by tape-stripping: Possible biomarker of barrier function in atopic der- matitis. PLoS One. 2019;14(1):e0210013. DOI: 10.1371/ journal. pone.0210013. PMID: 30608955. PMCID: PMC6319710. 37. Simpson EL, Guttman-Yassky E, Margolis DJ, et al. Associa- tion of Inadequately Controlled Disease and Disease Severity With Patient-Reported Disease Burden in Adults With Atopic Dermatitis. JAMA Dermatol. 2018;154(8):903-912. DOI: 10.1001/jamadermatol.2018.1572. PMID: 29971354. PMCID: PMC6143024. 38. Koppes SA, Brans R, Ljubojevic Hadzavdic S, Frings-Dresen MH, Rustemeyer T, Kezic S. Stratum Corneum Tape Stripping: Monitoring of Inflammatory Mediators in Atopic Dermati- tis Patients Using Topical Therapy. Int Arch Allergy Immu- nol. 2016;170(3):187-193. DOI: 10.1159/000448400. PMID: 27584583. PMCID: PMC5296885. 39. Murata S, Kaneko S, Morita E. Interleukin-8 Levels in the Stratum Corneum as a Biomarker for Monitoring Therapeutic Effect in Atopic Dermatitis Patients. Int Arch Allergy Immu- nol. 2021;182(7):592-606. DOI: 10.1159/000512965. PMID: 33486487. PMCID: PMC8315684. 40. He H, Olesen CM, Pavel AB, et al. Tape-Strip Proteomic Profiling of Atopic Dermatitis on Dupilumab Identifies Minimally Inva- sive Biomarkers. Front Immunol. 2020;11:1768. DOI: 10.3389/ fimmu.2020.01768. PMID: 32849633. PMCID: PMC7423990. 41. Mikhaylov D, Del Duca E, Olesen CM, et al. Transcriptomic Profiling of Tape-Strips From Moderate to Severe Atopic Dermatitis Patients Treated With Dupilumab. Dermatitis. 15. Skjerven HO, Rehbinder EM, Vettukattil R, et al. Skin emol- lient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster- randomised trial. Lancet. 2020;395(10228):951-961. DOI: 10.1016/S0140-6736(19)32983-6. PMID: 32087121. 16. Kim J, Kim BE, Lee J, et al. Epidermal thymic stromal lympho- poietin predicts the development of atopic dermatitis during in- fancy. J Allergy Clin Immunol. 2016;137(4):1282-1285.e4. DOI: 10.1016/j.jaci.2015.12.1306. PMID: 26879860. 17. Berdyshev E, Kim J, Kim BE, et al. Stratum corneum lipid and cytokine biomarkers at age 2 months predict the future onset of atopic dermatitis. J Allergy Clin Immunol. 2023;151(5):1307- 1316. DOI: 10.1016/j.jaci.2023.02.013. PMID: 36828081. 18. Rinnov MR, Halling AS, Gerner T, et al. Skin biomarkers pre- dict development of atopic dermatitis in infancy. Allergy. 2023;78(3):791-802. DOI: 10.1111/all.15518. PMID: 36112082. 19. Halling AS, Rinnov MR, Ruge IF, et al. Skin TARC/CCL17 in- crease precedes the development of childhood atopic dermati- tis. J Allergy Clin Immunol. 2023;151(6):1550-1557.e6. DOI: 10.1016/j.jaci.2022.11.023. PMID: 36572354. 20. Silvestre Salvador JF, Romero-Pérez D, Encabo-Durán B. Atopic Dermatitis in Adults: A Diagnostic Challenge. J Investig Allergol Clin Immunol. 2017;27(2):78-88. DOI: 10.18176/jiaci.0138. PMID: 28071589. 21. Bieber T, D’Erme AM, Akdis CA, et al. Clinical phenotypes and endophenotypes of atopic dermatitis: Where are we, and where should we go? J Allergy Clin Immunol. 2017;139(4S):S58-S64. DOI: 10.1016/j.jaci.2017.01.008. PMID: 28390478. 22. Fishbein AB, Silverberg JI, Wilson EJ, Ong PY. Update on Atopic Dermatitis: Diagnosis, Severity Assessment, and Treatment Selection. J Allergy Clin Immunol Pract. 2020;8(1):91-101. DOI: 10.1016/j.jaip.2019.06.044. PMID: 31474543. PMCID: PMC7395647. 23. Gargiulo L, Ibba L, Pavia G, et al. Upadacitinib for the treat- ment of concomitant psoriasis and atopic dermatitis: a case se- ries. J Dermatolog Treat. 2023;34(1):2183729. DOI: 10.1080 /09546634.2023.2183729. PMID: 36809172. 24. McAleer MA, Jakasa I, Hurault G, et al. Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis in- clude markers of innate and T helper cell-related immunity and angiogenesis. Br J Dermatol. 2019;180(3):586-596. DOI: 10.1111/bjd.17088. PMID: 30132823. PMCID: PMC6446820. 25. Andersson AM, Sølberg J, Koch A, et al. Assessment of biomark- ers in pediatric atopic dermatitis by tape strips and skin biop- sies. Allergy. 2022;77(5):1499-1509. DOI: 10.1111/all.15153. PMID: 34695223. 26. Lyubchenko T, Collins HK, Goleva E, Leung DYM. Skin tape sam- pling technique identifies proinflammatory cytokines in atopic dermatitis skin. Ann Allergy Asthma Immunol. 2021;126(1): 46-53.e2. DOI: 10.1016/j.anai.2020.08.397. PMID: 32896640. PMCID: PMC8782053. 27. Amarbayasgalan T, Takahashi H, Dekio I, Morita E. Interleukin-8 content in the stratum corneum as an indicator of the severity of inflammation in the lesions of atopic dermatitis. Int Arch Al- lergy Immunol. 2013;160(1):63-74. DOI: 10.1159/000339666. PMID: 22948248. 28. Hulshof L, Hack DP, Hasnoe QCJ, et al. A minimally invasive tool to study immune response and skin barrier in children with atopic dermatitis. Br J Dermatol. 2019;180(3):621-630. DOI: 10.1111/bjd.16994. PMID: 29989151. 8 Review | Dermatol Pract Concept. 2024;14(2):e2024123 45. Leung DYM, Calatroni A, Zaramela LS, et al. The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype. Sci Transl Med. 2019;11(480):eaav2685. DOI: 10.1126/scitranslmed.aav2685. PMID: 30787169. PMCID: PMC7676854. 46. Broderick C, Ziehfreund S, van Bart K, et al. Biomarkers asso- ciated with the development of comorbidities in patients with atopic dermatitis: A systematic review. Allergy. 2023;78(1): 84-120. DOI: 10.1111/all.15578PMID: 36366871. PMCID: PMC10107168. 47. Ziehfreund S, Tizek L, Hangel N, et al. Requirements and expec- tations of high-quality biomarkers for atopic dermatitis and pso- riasis in 2021-a two-round Delphi survey among international experts. J Eur Acad Dermatol Venereol. 2022;36(9):1467-1476. DOI: 10.1111/jdv.18178. PMID: 35470457. 2021;32(1S):S71-S80. DOI: 10.1097/DER.0000000000000764. PMID: 34405829. 42. Yamaguchi J, Aihara M, Kobayashi Y, Kambara T, Ikezawa Z. Quantitative analysis of nerve growth factor (NGF) in the atopic dermatitis and psoriasis horny layer and effect of treatment on NGF in atopic dermatitis. J Dermatol Sci. 2009;53(1):48-54. DOI: 10.1016/j.jdermsci.2008.08.011. PMID: 18922683. 43. Olesen CM, Pavel AB, Wu J, et al. Tape-strips provide a minimally invasive approach to track therapeutic response to topical corti- costeroids in atopic dermatitis patients. J Allergy Clin Immunol Pract. 2021;9(1):576-579.e3. DOI: 10.1016/j.jaip.2020.08.037. PMID: 32889222. 44. Paller A, Jaworski JC, Simpson EL, et al. Major Comorbidities of Atopic Dermatitis: Beyond Allergic Disorders. Am J Clin Der- matol. 2018;19(6):821-838. DOI: 10.1007/s40257-018-0383-4. PMID: 30168085.