Multiple Roles for Cytokines in Atopic Dermatitis: From Pathogenic Mediators to Endotype-Specific Biomarkers to Therapeutic Targets

Abstract

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, which generally presents with intense itching and recurrent eczematous lesions. AD affects up to 20% of children and 10% of adults in high-income countries. The prevalence and incidence of AD have increased in recent years. The onset of AD mostly occurs in childhood, although in some cases AD may persist in adult life or even manifest in middle age (adult-onset AD). AD pathophysiology is made of a complex net, in which genetic background, skin barrier dysfunction, innate and adaptive immune responses, as well as itch contribute to disease development, progression, and chronicization. One of the most important features of AD is skin dehydration, which is mainly caused by filaggrin mutations that determine trans-epidermal water loss, pH alterations, and antigen penetration. In accordance with the “outside-inside” theory of AD pathogenesis, in a context of an altered epidermal barrier, antigens encounter epidermal antigen presentation cells (APCs), such as epidermal Langerhans cells and inflammatory epidermal dendritic cells, leading to their maturation and Th-2 cell-mediated inflammation. APCs also bear trimeric high-affinity receptors for immunoglobulin E (IgE), which induce IgE-mediated sensitizations as part of pathogenic mechanisms leading to AD. In this review, we discuss the role of cytokines in the pathogenesis of AD, considering patients with various clinical AD phenotypes. Moreover, we describe the cytokine patterns in patients with AD at different phases of the disease evolution, as well as in relation to different phenotypes/endotypes, including age, race, and intrinsic/extrinsic subtypes. We also discuss the outcomes of current biologics for AD, which corroborate the presence of multiple cytokine axes involved in the background of AD. A deep insight into the correlation between cytokine patterns and the related clinical forms of AD is a crucial step towards increasingly personalized, and therefore more efficient therapy.

Effect of abrocitinib on skin biomarkers in patients with moderate‐to‐severe atopic dermatitis

“…[28][29][30] Furthermore, previous studies correlated IL-22 and S100A gene expression levels in skin with AD clinical severity and decreased expression was correlated with clinical therapeutic response 31 ; IL-22 expression is also correlated with epidermal hyperplasia, and reduced IL-22 levels may result in reduction in epidermal thickness. 32 Findings from this study were consistent with the efficacy profile of abrocitinib; reduced expression of S100A genes was correlated with itch improvement and skin clearance. Future studies could explore whether the reduction in epidermal thickness observed in abrocitinib-treated patients is correlated with the abrocitinib-mediated reduction of IL-22 and S100A gene expression levels.…”

The JAK–STAT pathway in keloid pathogenesis: a systematic review with qualitative synthesis

“…Even though one disease may be multifactorial, targeting only one pivotal pathway may already be effective. One example is atopic dermatitis, of which the pathogenesis is multifactorial, [57][58][59] with the JAK-STAT pathway being one of the pathways that may be targeted. 24 For this indication, JAK inhibitors as monotherapy are now part of the treatment regimen in many countries.…”

Atopic Dermatitis and Water: Is There an Optimum Water Intake Level for Improving Atopic Skin?

“…Immune system dysregulation, mainly in the expression of type 2 chemokines, such as IL-14 and IL 13, leads to the suppression of antimicrobial peptides and allergic inflammation [58,59]. IL-31 is linked to the induction of itching in patients with AD, by producing a brain-derived natriuretic peptide and coordinating chemokine release from skin cells [60,61].…”