Atopic dermatitis displays stable and dynamic skin transcriptome signatures

Möbus, Lena; Rodríguez, Elke; Harder, Inken; Stölzl, Dora; Boraczynski, Nicole; Gerdes, Sascha; Kleinheinz, Andreas; Abraham, Susanne; Heratizadeh, Annice; Handrick, Christiane; Haufe, Eva; Werfel, Thomas; Schmitt, Jochen; Weidinger, Stephan

doi:10.1016/j.jaci.2020.06.012

Cited by 96 publications

(94 citation statements)

References 52 publications

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“…Many patients affected by AD show a personal or a familiar history of atopic diseases, such as asthma, allergic rhinitis, and a specific IgE-reactivity [70]. AD is a multifactorial disease based on a genetic predisposition with the contribution of environmental factors, leading to skin barrier impairment and cutaneous inflammation, which is driven by excessive T cell activation and an increased production of inflammatory cytokines [71]. Genetic susceptibility encompasses the keratinocyte differentiation process, such as filaggrin, with a consequent skin barrier weakness, as well as immune dysregulation with a Th2 immune response.…”

Section: Atopic Dermatitismentioning

confidence: 99%

“…Excessive epidermal colonization by S. aureus is involved in pathogenesis, by damaging the skin barrier and inducing inflammatory responses and immune activation. Type 2 inflammation in AD is characterized by the activation of Th2 cells, T-cytotoxic 2 cells, innate lymphoid cells 2, eosinophils and mast cells, while other immune pathways such as Th22, Th17, Th9, and Th1 might contribute to maintain the pathogenic mechanism [71]. Multiple type 2 cytokines, including IL-4, IL-5, IL-9, IL-13, IL-25, IL-31, IL-33, and TSLP are overexpressed in skin and in the peripheral blood [72].…”

Section: Atopic Dermatitismentioning

confidence: 99%

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Pruritus as a Distinctive Feature of Type 2 Inflammation

et al. 2021

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Pruritus is a common symptom of several skin diseases, both inflammatory and neoplastic. Pruritus might have a tremendous impact on patients’ quality of life and strongly interfere with sleep, social, and work activities. We review the role of type-2 inflammation and immunity in the pathogenesis of chronic pruritic conditions of the skin. Type 2 cytokines, including IL-4, IL-13, thymic stromal lymphopoietin, periostin, IL-31, IL-25, and IL-33 are released by mast cells, innate lymphoid cells 2, keratinocytes, and type 2 T lymphocytes, and are master regulators of chronic itch. These cytokines might act as direct pruritogen on primary sensory neurons (pruriceptors) or alter the sensitivity to other itch mediators Type 2 inflammation- and immunity-dominated skin diseases, including atopic dermatitis, prurigo nodularis, bullous pemphigoid, scabies, parasitic diseases, urticaria, and Sézary syndrome are indeed conditions associated with most severe pruritus. In contrast, in other skin diseases, such as scleroderma, lupus erythematosus, hidradenitis suppurativa, and acne, type 2 inflammation is less represented, and pruritus is milder or variable. Th2 inflammation and immunity evolved to protect against parasites, and thus, the scratching response evoked by pruritus might have developed to alert about the presence and to remove parasites from the skin surface.

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Section: Atopic Dermatitismentioning

confidence: 99%

Section: Atopic Dermatitismentioning

confidence: 99%

Pruritus as a Distinctive Feature of Type 2 Inflammation

et al. 2021

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“…Simultaneous blocking of Type I receptor (IL‐4Rα/γc) and Type 2 receptor (IL‐4Rα/IL‐13Rα) inhibit at the same time T2 responses dependent on IL‐4 and IL‐4/IL‐13, respectively, in hematopoietic and non‐hematopoietic cells. Dupilumab targets several important disease mechanisms in the skin of AD patients, including the skin‐barrier defect, the chronic itch, the microbiome, and the T2 inflammation, both in clinical trials and in real life 38,39,63‐67 . Accumulating experience with dupilumab treatment for AD confirmed its effectiveness and safety, by reducing AD severity, reliever and background medication, and improving QoL, both in the paediatric population 12–17 years old and in adults 68‐77 …”

Section: Key Recommendationsmentioning

confidence: 97%

“…Dupilumab targets several important disease mechanisms in the skin of AD patients, including the skin-barrier defect, the chronic itch, the microbiome, and the T2 inflammation, both in clinical trials and in real life. 38,39,[63][64][65][66][67] Accumulating experience with dupilumab treatment for AD confirmed its effectiveness and safety, by reducing AD severity, reliever and background medication, and improving QoL, both in the paediatric population 12-17 years old and in adults. [68][69][70][71][72][73][74][75][76][77] Recent evidence was published for the efficacy and safety in the 6-11 years old population.…”

Section: Ke Y Recommendationsmentioning

confidence: 99%

EAACI Biologicals Guidelines—dupilumab for children and adults with moderate‐to‐severe atopic dermatitis

Agache

Akdiş

et al. 2020

Allergy

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Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co‐morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home‐based), its cost‐effectiveness and long‐term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.

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“…Crucially, the cytokines IL-4, IL-13 and IL-31 require JAK-STAT downstream signaling for their biological function [ 37 , 38 , 39 ] ( Figure 2 ). Furthermore, AD skin transcriptome analysis revealed increased JAK1 expression in lesional and non-lesional tissue [ 40 ]. In addition to inflammation, pruritic cytokines, thymic stromal lymphopoietin (TSLP) and IL-31 use downstream JAK1 and JAK2 signaling [ 39 , 41 ] ( Figure 3 ).…”

Section: Inflammatory Skin Diseasesmentioning

confidence: 99%

Developing a JAK Inhibitor for Targeted Local Delivery: Ruxolitinib Cream

et al. 2021

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Named after the two-faced Roman god of doorways, Janus kinases (JAKs) represent a class of tyrosine kinases. The JAK signaling pathway is pivotal for the downstream signaling of inflammatory cytokines, including interleukins, interferons, and multiple growth factors. This article provides an overview of the JAK pathway and signaling, its significance in immune-mediated dermatologic diseases and the development of a targeted, localized option of a selective JAK inhibitor, ruxolitinib cream. In the early 1990s, various discovery and clinical development programs were initiated to explore pharmaceutical inhibition of the JAK-STAT pathway. Incyte Corporation launched a strategy to identify molecules suitable for both topical as well as oral delivery. Ruxolitinib was designed as a molecule with low nanomolar potency selective for JAK1 and 2 enzymes, but without significant inhibition of non-JAK kinases, as well as physicochemical properties for both topical and oral administration. An oil-in-water emulsified ruxolitinib cream formulation was developed for topical application and was studied in multiple immune-mediated dermatologic diseases including psoriasis, alopecia areata, atopic dermatitis and vitiligo. Ruxolitinib cream represents a novel, JAK1/2 selective therapy that can be delivered directly to the skin to treat a number of cytokine-driven, inflammatory dermatoses.

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Atopic dermatitis displays stable and dynamic skin transcriptome signatures

Cited by 96 publications

References 52 publications

Pruritus as a Distinctive Feature of Type 2 Inflammation

Pruritus as a Distinctive Feature of Type 2 Inflammation

EAACI Biologicals Guidelines—dupilumab for children and adults with moderate‐to‐severe atopic dermatitis

Developing a JAK Inhibitor for Targeted Local Delivery: Ruxolitinib Cream

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