Blood transcriptome profiling identifies 2 candidate endotypes of atopic dermatitis.

BACKGROUND: Few studies have analyzed the blood transcriptome in atopic dermatitis (AD). OBJECTIVE: We explored blood transcriptomic features of moderate to severe AD. METHODS: Blood messenger RNA sequencing on 60 adults from the TREATgermany registry including 49 patients before and after dupilumab treatment, as well as from an independent cohort of 31 patients and 43 controls was performed. Patient clustering, differential expression, correlation and coexpression network analysis, and unsupervised learning were conducted. RESULTS: AD patients showed pronounced inflammatory expression signatures with increased myeloid and IL-5-related patterns, and clearly segregated into 2 distinct clusters, with striking differences in particular for transcripts involved in eosinophil signaling. The eosinophil-high endotype showed a more pronounced global dysregulation, a positive correlation between disease activity and signatures related to IL-5 signaling, and strong correlations with several target proteins of antibodies or small molecules under development for AD. In contrast, the eosinophil-low endotype showed little transcriptomic dysregulation and no association between disease activity and gene expression. Clinical improvement with receipt of dupilumab was accompanied by a decrease of innate immune responses and an increase of lymphocyte signatures including B-cell activation and natural killer cell composition and/or function. The proportion of super responders was higher in the eosinophil-low endotype (32% vs 11%). Continued downregulation of IL18RAP, IFNG, and granzyme A in the eosinophil-high endotype suggests a residual disturbance of natural killer cell function despite clinical improvement. CONCLUSION: AD can be stratified into eosinophilic and noneosinophilic endotypes; such stratification may be useful when assessing stratified trial designs and treatment strategies.

Elevated NK-cell transcriptional signature and dysbalance of resting and activated NK cells in atopic dermatitis.

BACKGROUND: Altered quantities, activity, and composition of natural killer (NK) cells in blood as well as expression changes of genes involved in NK-cell function in skin lesions of patients with atopic dermatitis (AD) were recently reported. OBJECTIVES: We sought to comprehensively analyze cutaneous NK-cell transcriptomic signatures in AD, and to examine changes under treatment. METHODS: We analyzed NK-cell signatures in skin transcriptome data from 57 patients with moderate to severe AD and 31 healthy controls. In addition, changes after 12 weeks of systemic treatment (dupilumab n = 21, cyclosporine n = 8) were analyzed. Deconvolution of leucocyte fractions was conducted. Immunofluorescence staining of NK cells was performed on paraffin-embedded skin sections. RESULTS: Immunofluorescence staining revealed a relatively high abundance of both NK cells and CD3+CD56+ cells in lesional as compared with nonlesional and healthy skin. Lesional and to a lesser extent nonlesional skin showed a strong upregulation of NK-cell markers together with a dysbalanced expression of inhibitory and activating receptors, which was not reverted under treatment. Digital cytometry showed a decrease in activated and an increase in resting NK cells in both lesional and nonlesional skin, which was reverted by both treatment with dupilumab and cyclosporine. The NK-cell transcriptomic signature remained upregulated after treatment, but there was a shift on the qualitative level, indicating a compositional change in NK-cell subsets toward CD56bright NK cells. CONCLUSIONS: Lesional AD skin shows a NK-cell dysregulation, which despite clinical improvement under systemic therapy was only partially reverted, and which may represent a yet underappreciated disease mechanism.

Atopic dermatitis displays stable and dynamic skin transcriptome signatures.

BACKGROUND: Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as "improvement" under therapy. These observations were mainly made in trials and based on microarray data. OBJECTIVES: Our aim was to explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry. METHODS: Biopsy specimens from 59 patients with moderate-to-severe AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab [n = 22] or cyclosporine [n = 8]) and from 31 healthy controls were subjected to mRNA sequencing. Differential expression, pathway enrichment, correlation, and coexpression network analysis were conducted. RESULTS: Both lesional and nonlesional skin showed a stable "core" signature characterized by disturbed epidermal differentiation and activation of IL-31/IL-1 signaling. A second dynamic signature showed progressive enrichment for type 2 inflammation, TH17 signaling, and natural killer cell function. Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation. IL4RA was among the top 3 central dysregulated genes. Cyclosporine led to a more pronounced global transcriptome reversion and normalized TH17 cell/IL23 signaling, whereas dupilumab led to a stronger increase in level of epidermal differentiation markers. Both treatments strongly decreased levels of type 2 markers, but overall the residual profile was still profoundly different from that of healthy skin. Lower levels of IL4RA and IL13 and high IL36A expression were related to a stronger clinical response to dupilumab. CONCLUSION: The AD core signature is characterized by dysregulation of genes related to keratinocyte differentiation and itch signaling. A dynamic signature reflects progressive immune responses dominated by type 2 cytokines with an additional role of TH17 and natural killer cell signaling.

Effectiveness of secondary prevention in metalworkers with work-related skin diseases and comparison with participants of a tertiary prevention program: A prospective cohort study.

BACKGROUND: In Germany, a multistep approach has been established to prevent work-related skin diseases (WRSDs). OBJECTIVES: To evaluate the effect of a secondary individual prevention program (SIP) in metalworkers with WRSD and to compare their characteristics with those of participants of a tertiary individual prevention program (TIP). PATIENTS AND METHODS: In a prospective cohort study, metalworkers with WRSD of the hands participating either in the SIP (n = 114) or in the TIP (n = 83) were recruited. At baseline and at the respective follow-up 8-12 weeks after the SIP or at dismissal from the TIP (3-4 weeks later), questionnaires were completed and the severity of WRSD was assessed. Saliva samples were collected for assessment of filaggrin (FLG) mutations and an explorative genome-wide association study (GWAS). RESULTS: Ninety-three SIP patients (81.6%) attended the follow-up. Disease severity was significantly reduced, and knowledge and protective behavior were significantly improved compared to baseline. Significant differences between SIP and TIP patients were found regarding duration and severity of symptoms, work absenteeism, tobacco smoking, and presence of atopic dermatitis, but not regarding FLG mutations and by GWAS. CONCLUSIONS: The SIP was effective in metalworkers with WRSDs. Individual factors may influence the course of the disease and the need for the TIP.