Tape-strips are a minimally invasive approach to characterize skin biomarkers in atopic dermatitis (AD). However, they have not yet been used for tracking gene expression changes with systemic treatment.
Objective
The aim of the study was to evaluate gene expression changes and therapeutic response biomarkers in AD patients before and after dupilumab (interleukin 4Rα antibody) treatment using tape-strips to obtain epidermal tissue for analysis.
Methods
Lesional and nonlesional tape-stripped skin was sampled from 18 AD patients before and after dupilumab treatment and from 17 healthy subjects and analyzed by RNA-seq.
Results
At baseline, we detected 6745 and 4859 differentially expressed genes between lesional and nonlesional skin versus normal, respectively, whereas 841 and 977 genes were differentially expressed after treatment, respectively (fold change >1.5 and false discovery rate <0.05). Tape-strips captured significant modulation with dupilumab in key AD immune (eg, C-C motif chemokine ligand 13 [CCL13], CCL17, CCL18) and barrier (eg, periplakin, FA2H) biomarkers. Changes in biomarkers (CCL20, interleukin 34, FABP7) were also significantly correlated with clinical disease improvements (Eczema Area and Severity Index; R > 0.5 or R < −0.4, P < 0.05).
Conclusions
This real-life study represents the first comprehensive RNA-seq molecular profiling of tape-strips from moderate to severe AD patients after dupilumab therapy. Analysis of tape strip specimens detected significant gene expression changes in key AD biomarkers with dupilumab treatment, suggesting that this approach may be useful to monitor therapeutic responses in inflammatory skin diseases.
Get full access to this article
View all access options for this article.
References
1.
SilverbergJI, HanifinJM. Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study. J Allergy Clin Immunol, 2013; 132(5):1132–1138.
2.
MalajianD, Guttman-YasskyE. New pathogenic and therapeutic paradigms in atopic dermatitis. Cytokine, 2015; 73(2):311–318.
3.
Guttman-YasskyE, DhingraN, LeungDYM. New era of biologic therapeutics in atopic dermatitis. Expert Opin Biol Ther, 2013; 13(4):549–561.
4.
Guttman-YasskyE, LowesMA, Fuentes-DuculanJ, et al.Major differences in inflammatory dendritic cells and their products distinguish atopic dermatitis from psoriasis. J Allergy Clin Immunol, 2007; 119(5):1210–1217.
5.
NovakN. An update on the role of human dendritic cells in patients with atopic dermatitis. J Allergy Clin Immunol, 2012; 129(4):879–886.
6.
FujitaH, ShemerA, Suárez-FariñasM, et al.Lesional dendritic cells in patients with chronic atopic dermatitis and psoriasis exhibit parallel ability to activate T-cell subsets. J Allergy Clin Immunol, 2011; 128(3):574–582.e1-12.
7.
Dos SantosVG, OrfaliRL, de Oliveira TitzT, et al.Evidence of regulatory myeloid dendritic cells and circulating inflammatory epidermal dendritic cells–like modulated by toll-like receptors 2 and 7/8 in adults with atopic dermatitis. Int J Dermatol, 2017; 56(6):630–635.
8.
BrunnerPM, PavelAB, KhattriS, et al.Baseline IL-22 expression in patients with atopic dermatitis stratifies tissue responses to fezakinumab. J Allergy Clin Immunol, 2019; 143(1):142–154.
9.
Suárez-FariñasM, UngarB, Correa da RosaJ, et al.RNA sequencing atopic dermatitis transcriptome profiling provides insights into novel disease mechanisms with potential therapeutic implications. J Allergy Clin Immunol, 2015; 135(5):1218–1227.
10.
NodaS, Suárez-FariñasM, UngarB, et al.The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization. J Allergy Clin Immunol, 2015; 136(5):1254–1264.
11.
GittlerJK, ShemerA, Suárez-FariñasM, et al.Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol, 2012; 130(6):1344–1354.
12.
EsakiH, EwaldDA, UngarB, et al.Identification of novel immune and barrier genes in atopic dermatitis by means of laser capture microdissection. J Allergy Clin Immunol, 2015; 135(1):153–163.
13.
EsakiH, BrunnerPM, Renert-YuvalY, et al.Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin. J Allergy Clin Immunol, 2016; 138(6):1639–1651.
14.
CzarnowickiT, GonzalezJ, ShemerA, et al.Severe atopic dermatitis is characterized by selective expansion of circulating TH2/TC2 and TH22/TC22, but not TH17/TC17, cells within the skin-homing T-cell population. J Allergy Clin Immunol, 2015; 136(1):104–115.e7.
15.
BrunnerPM, Suarez-FarinasM, HeH, et al.The atopic dermatitis blood signature is characterized by increases in inflammatory and cardiovascular risk proteins. Sci Rep, 2017; 7(1):8707.
16.
Guttman-YasskyE, Suárez-FariñasM, ChiricozziA, et al.Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis. J Allergy Clin Immunol, 2009; 124(6):1235–1244.e58.
17.
Suárez-FariñasM, TintleSJ, ShemerA, et al.Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities. J Allergy Clin Immunol, 2011; 127(4):954–964.e1–4.
OlesenCM, FuchsCSK, PhilipsenPA, et al.Advancement through epidermis using tape stripping technique and reflectance confocal microscopy. Sci Rep, 2019; 9(1):12217.
25.
KimBE, GolevaE, KimPS, 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.
26.
Guttman-YasskyE, DiazA, PavelAB, 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.
27.
KoppesSA, BransR, Ljubojevic HadzavdicS, et al.Stratum corneum tape stripping: monitoring of inflammatory mediators in atopic dermatitis patients using topical therapy. Int Arch Allergy Immunol, 2016; 170(3):187–193.
28.
ClausenML, SlotvedHC, KrogfeltKA, et al.Measurements of AMPs in stratum corneum of atopic dermatitis and healthy skin–tape stripping technique. Sci Rep, 2018; 8(1):1666.
29.
AmarbayasgalanT, TakahashiH, DekioI, et al.Interleukin-8 content in the stratum corneum as an indicator of the severity of inflammation in the lesions of atopic dermatitis. Int Arch Allergy Immunol, 2013; 160(1):63–74.
30.
Angelova-FischerI, MannheimerAC, HinderA, et al.Distinct barrier integrity phenotypes in filaggrin-related atopic eczema following sequential tape stripping and lipid profiling. Exp Dermatol, 2011; 20(4):351–356.
31.
MoritaE, TakahashiH, NiiharaH, et al.Stratum corneum TARC level is a new indicator of lesional skin inflammation in atopic dermatitis. Allergy, 2010; 65(9):1166–1172.
32.
SanoY, MasudaK, Tamagawa-MineokaR, et al.Thymic stromal lymphopoietin expression is increased in the horny layer of patients with atopic dermatitis. Clin Exp Immunol, 2013; 171(3):330–337.
33.
YamaguchiJ, AiharaM, KobayashiY, et al.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.
34.
HulshofL, HackDP, HasnoeQCJ, 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.
35.
McAleerMA, JakasaI, HuraultG, et al.Systemic and stratum corneum biomarkers of severity in infant atopic dermatitis include markers of innate and T helper cell–related immunity and angiogenesis. Br J Dermatol, 2019; 180(3):586–596.
36.
GolevaE, CalatroniA, LeBeauP, et al.Skin tape proteomics identifies pathways associated with transepidermal water loss and allergen polysensitization in atopic dermatitis. J Allergy Clin Immunol, 2020; 146:1367–1378.
37.
VoegeliR, RawlingsAV, BreternitzM, et al.Increased stratum corneum serine protease activity in acute eczematous atopic skin. Br J Dermatol, 2009; 161(1):70–77.
38.
LeungDYM, CalatroniA, ZaramelaLS, et al.The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype. Sci Transl Med, 2019; 11(480):eaav2685.
39.
BerdyshevE, GolevaE, BronovaI, et al.Lipid abnormalities in atopic skin are driven by type 2 cytokines. JCI insight, 2018; 3(4):e98006.
40.
DyjackN, GolevaE, RiosC, et al.Minimally invasive skin tape strip RNA sequencing identifies novel characteristics of the type 2–high atopic dermatitis disease endotype. J Allergy Clin Immunol, 2018; 141(4):1298–1309.
41.
OlesenCM, PavelAB, WuJ, et al.Tape-strips provide a minimally-invasive approach to track therapeutic response to topical corticosteroids in atopic dermatitis patients. J Allergy Clin Immunol Pract, 2020; 9(1):576–579.
42.
PavelAB, SongT, KimH-J, et al.Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis. J Allergy Clin Immunol, 2019; 144(4):1011–1024.
43.
KhattriS, ShemerA, RozenblitM, et al.Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology. J Allergy Clin Immunol, 2014; 133(6):1626–1634.
44.
BissonnetteR, PavelAB, DiazA, et al.Crisaborole and atopic dermatitis skin biomarkers: an intrapatient randomized trial. J Allergy Clin Immunol, 2019; 144(5):1274–1289.
45.
KhattriS, BrunnerPM, GarcetS, et al.Efficacy and safety of ustekinumab treatment in adults with moderate-to-severe atopic dermatitis. Exp Dermatol, 2017; 26(1):28–35.
46.
TintleS, ShemerA, Suárez-FariñasM, et al.Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response. J Allergy Clin Immunol, 2011; 128(3):583–593.e1–4.
47.
BrunnerPM, KhattriS, GarcetS, et al.A mild topical steroid leads to progressive anti-inflammatory effects in the skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol, 2016; 138(1):169–178.
48.
HamiltonJD, Suárez-FariñasM, DhingraN, et al.Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis. J Allergy Clin Immunol, 2014; 134(6):1293–1300.
49.
TofteS, GraeberM, CherillR, et al.Eczema Area and Severity Index (EASI): a new tool to evaluate atopic dermatitis. J Eur Acad Dermatol Venereol, 1998; 11:S197.
50.
HeH, BissonnetteR, WuJ, et al.Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis. J Allergy Clin Immunol, 2020; 147(1):199–212.
51.
PavelAB, Renert-YuvalY, WuJ, et al.Tape-strips from early-onset pediatric atopic dermatitis highlight disease abnormalities in non-lesional skin. Allergy, 2020; 76(1):314–325.
LawCW, ChenY, ShiW, et al.voom: precision weights unlock linear model analysis tools for RNA-seq read counts. Genome Biol, 2014; 15(2):R29.
54.
WittkowskiKM, LeeE, NussbaumR, et al.Combining several ordinal measures in clinical studies. Stat Med, 2004; 23(10):1579–1592.
55.
FangH, KnezevicB, BurnhamKL, et al.XGR software for enhanced interpretation of genomic summary data, illustrated by application to immunological traits. Genome Med, 2016; 8(1):129.
56.
KanehisaM, GotoS, FurumichiM, et al.KEGG for representation and analysis of molecular networks involving diseases and drugs. Nucleic Acids Res, 2010; 38(Database issue):D355–D360.
57.
NishimuraD. BioCarta. Biotech Software Internet Rep, 2001; 2(3):117–120.
DhingraN, ShemerA, Correa da RosaJ, et al.Molecular profiling of contact dermatitis skin identifies allergen-dependent differences in immune response. J Allergy Clin Immunol, 2014; 134(2):362–372.
60.
HeH, OlesenCM, PavelAB, et al.Tape-strip proteomic profiling of atopic dermatitis on dupilumab identifies minimally invasive biomarkers. Front Immunol, 2020; 11:1768.
61.
HeH, LiR, ChoiS, et al.Increased cardiovascular and atherosclerosis markers in blood of older patients with atopic dermatitis. Ann Allergy Asthma Immunol, 2020; 124(1):70–78.
62.
BaurechtH, HotzeM, BrandS, et al.Genome-wide comparative analysis of atopic dermatitis and psoriasis gives insight into opposing genetic mechanisms. Am J Hum Genet, 2015; 96(1):104–120.
63.
MansouriY, Guttman-YasskyE. Immune pathways in atopic dermatitis, and definition of biomarkers through broad and targeted therapeutics. J Clin Med, 2015; 4(5):858–873.
64.
MalikK, HeH, HuynhTN, et al.Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature. J Allergy Clin Immunol, 2019; 143(2):604–618.
65.
BrunnerPM, IsraelA, ZhangN, et al.Early-onset pediatric atopic dermatitis is characterized by TH2/TH17/TH22-centered inflammation and lipid alterations. J Allergy Clin Immunol, 2018; 141(6):2094–2106.
66.
EwaldDA, MalajianD, KruegerJG, et al.Meta-analysis derived atopic dermatitis (MADAD) transcriptome defines a robust AD signature highlighting the involvement of atherosclerosis and lipid metabolism pathways. BMC Med Genomics, 2015; 8(1):60.
67.
VargaT, CzimmererZ, NagyL. PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim Biophys Acta, 2011; 1812(8):1007–1022.
68.
SertznigP, ReichrathJ. Peroxisome proliferator-activated receptors (PPARs) in dermatology: challenge and promise. Dermatoendocrinol, 2011; 3(3):130–135.
69.
SanyalRD, PavelAB, GlickmanJ, et al.Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation. Ann Allergy Asthma Immunol, 2019; 122(1):99–110.e6.
70.
RojahnTB, VorstandlechnerV, KrausgruberT, et al.Single-cell transcriptomics combined with interstitial fluid proteomics defines cell type–specific immune regulation in atopic dermatitis. J Allergy Clin Immunol, 2020; 146:1056–1069.
71.
Guttman-YasskyE, PavelAB, ZhouL, et al.GBR 830, an anti-OX40, improves skin gene signatures and clinical scores in patients with atopic dermatitis. J Allergy Clin Immunol, 2019; 144(2):482–493.e7.
72.
LyubchenkoT, CollinsHK, GolevaE, et al.Skin tape sampling technique identifies proinflammatory cytokines in atopic dermatitis skin. Ann Allergy Asthma Immunol, 2020.
73.
UngarB, PavelAB, LiR, et al.Phase 2 randomized, double-blind study of IL-17 targeting with secukinumab in atopic dermatitis. J Allergy Clin Immunol, 2020.
74.
HeH, SuryawanshiH, MorozovP, et al.Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis. J Allergy Clin Immunol, 2020; 145(6):1615–1628.
75.
WollenbergA, KraftS, HanauD, et al.Immunomorphological and ultrastructural characterization of Langerhans cells and a novel, inflammatory dendritic epidermal cell (IDEC) population in lesional skin of atopic eczema. J Invest Dermatol, 1996; 106(3):446–453.
76.
ShinJ-S, GreerAM. The role of FcεRI expressed in dendritic cells and monocytes. Cell Mol Life Sci, 2015; 72(12):2349–2360.
77.
UngarB, GarcetS, GonzalezJ, et al.An integrated model of atopic dermatitis biomarkers highlights the systemic nature of the disease. J Invest Dermatol, 2017; 137(3):603–613.
78.
EckertRL, BroomeAM, RuseM, et al.S100 proteins in the epidermis. J Invest Dermatol, 2004; 123(1):23–33.
79.
CzarnowickiT, HeH, KruegerJG, et al.Atopic dermatitis endotypes and implications for targeted therapeutics. J Allergy Clin Immunol, 2019; 143(1):1–11.
80.
BrunnerPM, Guttman-YasskyE, LeungDY. The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol, 2017; 139(4S):S65–S76.
81.
MartelBC, LitmanT, HaldA, et al.Distinct molecular signatures of mild extrinsic and intrinsic atopic dermatitis. Exp Dermatol, 2016; 25(6):453–459.
