Demystifying Hand Eczema

Clinical Implications•Heterogeneity of chronic hand eczema (CHE) poses a diagnostic and therapeutic challenge.•Tape stripping is a minimally invasive technique to obtain skin tissue samples from acral sites.•Proteomic analysis revealed molecular differences in underlying CHE etiologies.View Large Image Figure ViewerDownload Hi-res image Download (PPT) •Heterogeneity of chronic hand eczema (CHE) poses a diagnostic and therapeutic challenge.•Tape stripping is a minimally invasive technique to obtain skin tissue samples from acral sites.•Proteomic analysis revealed molecular differences in underlying CHE etiologies. The central dogma of molecular biology states that genetic information flows from DNA to RNA to protein, with DNA replication (DNA copied to DNA), transcription (DNA to RNA), and ribosomal translation (RNA to protein) comprising the key biological processes regulating this information. Advances in biomedical research techniques over the past 1-2 decades have progressively enabled the ability to use these biological processes to understand disease pathogenesis, clinical diagnosis, and disease-specific treatments. In particular, whole-genome sequencing (genomics), RNA sequencing (transcriptomics), and protein expression analysis (proteomics) are revolutionizing at a rapid pace the integration of cell and/or tissue analysis with clinical management decisions, making personalized or precision medicine a greater reality for patients. In “the proteome of hand eczema assessed by tape stripping,” Sølberg et al. used protein expression analysis to evaluate a common clinical problem in dermatology (Sølberg et al., 2023Sølberg J.B.K. Quaade A.S. Drici L. Sulek K. Ulrich N.H. Løvendorf M.B. et al.The proteome of hand eczema assessed by tape stripping.J Invest Dermatol. 2023; ([e-pub ahead of print]) (accessed February 9, 2023)https://doi.org/10.1016/j.jid.2022.12.024Abstract Full Text Full Text PDF Scopus (1) Google Scholar). One of the challenges to advancing personalized medicine is reducing a common phenotype (e.g., rash on the hands) into distinct molecular endotypes (e.g., different pathogenic etiologies driving atopic dermatitis (AD), irritant contact dermatitis (ICD), allergic contact dermatitis (ACD), psoriasis, etc.) that may share a common phenotypic presentation. Dermatologists know that patients with a chronic hand rash can be challenging to treat because the precise diagnosis is not always apparent from clinical morphology alone. Shave or punch skin biopsies are routinely used to narrow down a differential diagnosis, but biopsies on acral sites are more difficult, with pain, bleeding, and loss of function being potential adverse events. Because hand rashes comprise a very heterogeneous group of skin disorders, there is an unmet need in dermatology for a simple, non- to minimally invasive technique to endotype or stratify patients into the correct diagnostic and treatment groups. In Sølberg et al., directly tackle this unmet need for chronic hand eczema (CHE) by using tape stripping to characterize the proteome of patients with CHE (with and without AD) using lesional, non-lesional, and healthy skin samples. Tape stripping is a practical method to obtaining superficial skin tissue samples. This technique involves applying adhesive tape to the affected skin and then removing it, along with the top dead layers of the skin (i.e., the stratum corneum). The stratum corneum samples are then evaluated using a variety of devices depending on the purpose; in Sølberg et al., that technique was liquid chromatography-mass spectrometry. Tape strips have been used to broadly characterize immune and epidermal barrier biomarkers of the lesional and nonlesional skin of AD and psoriasis, providing a useful approach not only for clinical trials and longitudinal studies but potentially for routine clinical practice. According to transcriptome analysis in The Human Protein Atlas, 2022The Human Protein Atlashttps://www.proteinatlas.org/Date: 2022Date accessed: February 10, 2023Google Scholar, 71% of the human proteome is expressed in the skin; 612 of these genes showed elevated protein expression in the skin compared to other tissue types (2022). This supports the use of tape stripping to generate a molecular signature or fingerprint of corneocytes and establish disease-specific stratum corneum protein signatures for the dorsal and palmar skin of the hands. However, a question Sølberg et al. address is whether proteomic analysis of stratum corneum can accurately differentiate the immunology of CHE subtypes. Although CHE is a common inflammatory dermatosis, it is an umbrella term that is often used to encompass AD, ICD, and ACD, yet these disorders can be driven by different immune responses. Moreover, hand rashes that mimic CHE, such as tinea manuum, psoriasis, and more rarely cutaneous T-cell lymphoma, can be mislabeled as CHE (Yumeen et al., 2020Yumeen S. Mirza F.N. Lewis J.M. Carlson K.R. King B. Cowper S. et al.CD8+ mycosis fungoides palmaris et plantaris with peripheral blood involvement.JAAD Case Rep. 2020; 6: 434-437Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar). Previous studies investigating the immunology of hand rashes have shown that AD-related CHE presents with a T helper (Th) type Th2/Th22 immune profile. ACD, depending on the allergen, can be driven by the Th2/Th22 response for rubber and fragrance or Th1/Th17 response for metals (nickel). ICD presents with a Th1/Th17 immune profile and is mainly driven by an innate immune response (IL-1α, IL-1β, TNF-α, GM-CSF, and IL-8) (Lee et al., 2013Lee H.Y. Stieger M. Yawalkar N. Kakeda M. Cytokines and chemokines in irritant contact dermatitis.Mediators Inflamm. 2013; 2013: 916497Crossref PubMed Scopus (78) Google Scholar; Ungar et al., 2017Ungar B. Correa da Rosa J.C. Shemer A. Czarnowicki T. Estrada Y.D. Fuentes-Duculan J. et al.Patch testing of food allergens promotes Th17 and Th2 responses with increased IL-33: a pilot study.Exp Dermatol. 2017; 26: 272-275Crossref PubMed Scopus (11) Google Scholar). ICD reactions are often the first step in the activation process in ACD (Leonard and Guttman-Yassky, 2019Leonard A. Guttman-Yassky E. The unique molecular signatures of contact dermatitis and implications for treatment.Clin Rev Allergy Immunol. 2019; 56: 1-8Crossref PubMed Scopus (37) Google Scholar). Importantly, the authors found that the proteomic differences between CHE subtypes were restricted to lesional skin areas and, indeed, there were differences in the immune-related proteome. Compared to healthy skin, the lesional samples from patients with CHE exhibited increased expression of immune-related markers and a decreased expression of structural barrier proteins. In agreement with previous studies, the pro-inflammatory cytokine IL-34 was highly expressed in non-lesional CHE skin (regardless of etiology) than in healthy skin. IL-34 is an epidermal negative immune regulator cytokine and has been considered the best single-gene classifier, discriminating non-lesional from lesional skin in patients with AD with almost 100% accuracy (Guttman-Yassky et al., 2019Guttman-Yassky E. Diaz A. Pavel A.B. Fernandes M. Lefferdink R. Erickson T. 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: 1358-1370Crossref PubMed Scopus (84) Google Scholar). In total, the authors identified 908 differentially expressed proteins (DEPs) between lesional and healthy skin. Key elevated DEPs included several pro-inflammatory signatures: skin alarmins (keratins 6a, 16, and 17), CD44 (associated with activation of dendritic cells and has been shown to be increased in contact dermatitis) (Lugović-Mihić et al., 2020Lugović-Mihić L. Novak-Bilić G. Vučić M. Japundžić I. Bukvić I. CD44 expression in human skin: high expression in irritant and allergic contact dermatitis and moderate expression in psoriasis lesions in comparison with healthy controls.Contact Dermatitis. 2020; 82: 297-306Crossref PubMed Scopus (8) Google Scholar), complement proteins C3 and C5, IL-18 (migration of antigen-presenting cells and production of antigen-specific T-cells), fibrinogen A and G (which help form protective biofilms following skin wounding), and nicotinamide phosphoribosyltransferase. Increased expression of chaperonin subunits belonging to the T-complex protein Ring Complex suggests misfolded cytoskeleton proteins in CHE lesional skin. In contrast, lower expression of structural proteins (filaggrin 2, loricrin), antimicrobial peptides (dermcidin), complement pathway inhibitors (CD55, CD59), and anti-inflammatory cytokines (IL-37) depict CHE as an inflammatory process with compromised barrier integrity and reduced ability to combat microbial infection or dysbiosis. How soon will dermatologists use tape stripping in their clinic? Although not implemented routinely for hand rashes yet, adhesive technologies exist and are used to evaluate the need to biopsy a nevus (melanoma test evaluating LINC and PRAME expression levels and TERT DNA mutations) (Ferris et al., 2017Ferris L.K. Jansen B. Ho J. Busam K.J. Gross K. Hansen D.D. et al.Utility of a noninvasive 2-gene molecular assay for cutaneous melanoma and effect on the decision to biopsy.JAMA Dermatol. 2017; 153: 675-680Crossref PubMed Scopus (55) Google Scholar), classify melanoma risk (for the need for sentinel lymph node biopsy and subsequent level of clinical surveillance) (Jarell et al., 2022Jarell A. Gastman B.R. Dillon L.D. Hsueh E.C. Podlipnik S. Covington K.R. et al.Optimizing treatment approaches for patients with cutaneous melanoma by integrating clinical and pathologic features with the 31-gene expression profile test.J Am Acad Dermatol. 2022; 87: 1312-1320Abstract Full Text Full Text PDF PubMed Scopus (7) Google Scholar), and aid the selection of biologic therapy categories for patients with plaque psoriasis (transcriptomic analysis on ∼ 7,000 RNAs isolated from stratum corneum) (Bagel et al., 2021Bagel J. Wang Y. Montgomery III, P. Abaya C. Andrade E. Boyce C. et al.A machine learning-based test for predicting response to psoriasis biologics.SKIN The Journal of Cutaneous Medicine. 2021; 5: 621-638Crossref Scopus (5) Google Scholar). The work by Sølberg et al. represents another significant effort to use tape stripping and proteomics to advance our scientific understanding of CHE. This work begins the important and much-needed differentiation of hand rash (labeled as CHE) based on pathobiology. Ultimately, tape stripping appears to be a viable tool not only for research purposes but also for point-of-care diagnostics in dermatology patients. AG declares no relevant conflict of interest. CGB has served as an investigator for Almirall, Timber, and Palvella and a consultant for AbbVie, Almirall, Arcutis, Eli Lilly, EPI Health, LEO Pharma, Novartis, Pfizer, Sanofi-Regeneron, and UCB. The Proteome of Hand Eczema Assessed by Tape StrippingJournal of Investigative DermatologyPreviewHand eczema (HE) is a prevalent skin disease. However, the classification of HE into different subtypes remains challenging. A limited number of previous studies have employed invasive biopsy–based strategies; yet, studies of the HE proteome using noninvasive tape-stripping methodology have not been reported. In this study, we wanted to assess whether global proteomic analysis of skin tape strip samples can be used for subclassification of patients with HE. Tape strips were collected from patients with HE and healthy skin. Full-Text PDF