Xiangyu Peng

The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization

BACKGROUND Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17(+)-producing cell counts in Asian patients with AD. OBJECTIVE We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. METHODS We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). RESULTS Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD (P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. TH2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher TH17 and TH22 (IL17A, IL19, and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower TH1/interferon (CXCL9, CXCL10, MX1, and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. CONCLUSION The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher TH17 activation, and a strong TH2 component. The relative pathogenic contributions of the TH17 and TH2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics.

Alopecia areata profiling shows TH1, TH2, and IL-23 cytokine activation without parallel TH17/TH22 skewing

BACKGROUND Alopecia areata (AA) is a common T cell-mediated disorder with limited therapeutics. A molecular profile of cytokine pathways in AA tissues is lacking. Although studies have focused on TH1/IFN-γ responses, several observations support a shared genetic background between AA and atopy. OBJECTIVE We sought to define the AA scalp transcriptome and associated biomarkers with comparisons with atopic dermatitis (AD) and psoriasis. METHODS We performed microarray and RT-PCR profiling of 27 lesional and 17 nonlesional scalp samples from patients with AA for comparison with normal scalp samples (n = 6). AA gene expression was also compared with samples from patients with lesional or nonlesional AD and those with psoriasis. A fold change of greater than 1.5 and a false discovery rate of less than 0.05 were used for differentially expressed genes (DEGs). RESULTS We established the AA transcriptomes (lesional vs nonlesional: 734 DEGs [297 upregulated and 437 downregulated]; lesional vs normal: 4230 DEGs [1980 upregulated and 2250 downregulated]), including many upregulated immune and downregulated hair keratin genes. Equally impressive as upregulation in TH1/interferon markers (IFNG and CXCL10/CXCL9) were those noted in TH2 (IL13, CCL18, CCL26, thymic stromal lymphopoietin, and periostin), TH9/IL-9, IL-23 (p40 and p19), and IL-16 mediators (all P < .05). There were no increases in TH17/TH22 markers. Hair keratin (KRT) expressions (ie, KRT86 and KRT85) were significantly suppressed in lesional skin. Greater scalp involvement (>25%) was associated with greater immune and keratin dysregulation and larger abnormalities in nonlesional scalp samples (ie, CXCL10 and KRT85). CONCLUSIONS Our data associate the AA signature with TH2, TH1, IL-23, and IL-9/TH9 cytokine activation, suggesting consideration of anti-TH2, anti-TH1, and anti-IL-23 targeting strategies. Similar to psoriasis and AD, clinical trials with selective antagonists are required to dissect key pathogenic pathways.

An IL-17–dominant immune profile is shared across the major orphan forms of ichthyosis

Background: The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis‐based therapy is largely lacking because the underlying molecular basis is poorly understood. Objective: We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. Methods: We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT‐PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI‐E) and scaling (IASI‐S); transepidermal water loss; and pruritus. Results: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T‐cell and dendritic cell infiltrates. Increases of general inflammatory (IL‐2), innate (IL‐1&bgr;), and some TH1/interferon (IFN‐&ggr;) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF‐&agr; levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of TH2 cytokines (IL‐13 and IL‐31) was similar to that seen in control subjects. The striking induction of IL‐17–related genes or markers synergistically induced by IL‐17 and TNF‐&agr; (IL‐17A/C, IL‐19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI‐E scores strongly correlated with IL‐17A (r = 0.74, P < .001) and IL‐17/TNF–synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. Conclusion: Our data associate a shared TH17/IL‐23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL‐17–targeting strategies.

Molecular signatures order the potency of topically applied anti-inflammatory drugs in patients with atopic dermatitis

Background: Atopic dermatitis (AD) presents a large unmet need for treatments with better safety and efficacy. To facilitate development of topical therapeutics, we need an efficient model for assessing different formulations and concentrations. The “plaque model” has been successfully implemented in patients with psoriasis, another common inflammatory disease, to assess the efficacy of topical treatments. This model has not been validated for AD, which has higher placebo responses and less stable lesions than psoriasis. Objective: We aimed to assess changes in molecular signatures of intrapatient target lesions treated with topical therapeutics. Methods: We enrolled 30 patients with mild‐to‐moderate AD in a randomized, double‐blind, intraindividual comparison of 3 approved agents applied blindly at the investigator site daily for 14 days: pimecrolimus, betamethasone dipropionate, clobetasol propionate, and a vehicle/emollient control. Changes in total sign scores (TSSs), transepidermal water loss, and tissue biomarkers (determined by using RT‐PCR and immunohistochemistry) were evaluated. Results: TSSs showed improvements of 30%, 40%, 68%, and 76% at 2 weeks with vehicle, pimecrolimus, betamethasone, and clobetasol, respectively, with parallel changes in transepidermal water loss (P < .05). Significant differences versus vehicle values were limited to steroids (P < .0001). Steroids (particularly clobetasol) restored epidermal hyperplasia and terminal differentiation versus minimal changes with vehicle or pimecrolimus (P < .001). Levels of cellular infiltrates and cytokines (IL‐13, IL‐22, and S100As) were similarly reduced only by steroids (P < .001). TSS improvement correlated with changes in hyperplasia, infiltrates, and differentiation markers. Conclusion: We detected significant clinical and tissue differences between agents, providing a novel approach to study the differential effects of topical formulations using a limited sample size.

Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features

Our data established the molecular fingerprints of AD and psoriasis in Han Chinese patients, and identified tissue biomarkers of disease that correlated with clinical severity.

Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature

Background: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much‐needed pathogenesis‐based therapy. Objective: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. Methods: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age‐matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). Results: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL‐17 and TNF‐&agr;–coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity‐related manner, patients with Netherton syndrome showed the greatest T‐cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN‐&ggr;, OASL, and TH2/IL‐4 receptor/IL‐5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL‐17–regulated gene expression (IL17F and IL36A/IL36B/IL36G). Conclusion: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis‐like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL‐17/IL‐36–targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.

Dupilumab progressively improves systemic and cutaneous abnormalities in atopic dermatitis patients

Background: Dupilumab is an IL‐4 receptor &agr; mAb inhibiting signaling of IL‐4 and IL‐13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective: This placebo‐controlled, double‐blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate‐to‐severe atopic dermatitis (AD). Methods: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta‐analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL‐22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P = .001; week 16, P = .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen‐specific IgEs. Conclusion: Dupilumab‐mediated inhibition of IL‐4/IL‐13 signaling through IL‐4 receptor &agr; blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD‐associated epidermal abnormalities.

Atopic dermatitis in African American patients is TH2/TH22-skewed with TH1/TH17 attenuation

BACKGROUND African Americans (AA) are disproportionately impacted by atopic dermatitis (AD), with increased prevalence and therapeutic challenges unique to this population. Molecular profiling data informing development of targeted therapeutics for AD are derived primarily from European American (EA) patients. These studies are absent in AA, hindering development of effective treatments for this population. OBJECTIVE We sought to characterize the global molecular profile of AD in the skin of AA patients as compared with that of EA AD and healthy controls. METHODS We performed RNA-Seq with reverse transcription polymerase chain reaction validation and immunohistochemistry studies in lesional and nonlesional skin of AA and EA AD patients vs healthy controls. RESULTS African American AD lesions were characterized by greater infiltration of dendritic cells (DCs) marked by the high-affinity immunoglobulin E (IgE) receptor (FcεR1+) compared with EA AD (P < .05). Both AD cohorts showed similarly robust up-regulation of Th2-related (CCL17/18/26) and Th22-related markers (interleukin [IL]-22, S100A8/9/12), but AA AD featured decreased expression of innate immune (tumor necrosis factor [TNF], IL-1β), Th1-related (interferon gamma [IFN-γ], MX1, IL-12RB1), and Th17-related markers (IL-23p19, IL-36G, CXCL1) vs EA AD (P < .05). The Th2 (IL-13) and Th22-related products (IL-22, S100A8/9/12) and serum IgE were significantly correlated with clinical severity (Scoring of Atopic Dermatitis [SCORAD]) in AA. Fillagrin (FLG) was exclusively down-regulated in EA AD, whereas loricrin (LOR) was down-regulated in both AD cohorts and negatively correlated with SCORAD in AA. CONCLUSION The molecular phenotype of AA AD skin is characterized by attenuated Th1 and Th17 but similar Th2/Th22-skewing to EA AD. Our data encourages a personalized medicine approach accounting for phenotype-specific characteristics in future development of targeted therapeutics and clinical trial design for AD.