The Dawn of a New Era in Atopic Dermatitis Treatment

Abstract

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, and the condition is typified by barrier dysfunction and immune dysregulation. Recent studies have characterized various phenotypes and endotypes of AD and elucidated the mechanism. Numerous topical and systemic narrow targeting therapies for AD have been developed according to these findings. Topical medications, including Janus kinase (JAK) inhibitors, phosphodiesterase 4 inhibitors, and the aryl hydrocarbon receptor agonist tapinarof, are effective and safe for AD compared to topical corticosteroids. Oral JAK inhibitors and monoclonal antibodies targeting interleukin (IL)-4, IL-13, IL-31, IL-33, OX40, thymic stromal lymphopoietin, and sphingosine 1-phosphate signaling have displayed outstanding efficacy against moderate-to-severe AD. We are currently in a new era of AD treatment.

Keywords: atopic dermatitis; biologics; small-molecule inhibitors; therapy.

Figure 1

Therapies based on the pathogenesis of atopic dermatitis. Disrupted epidermal barrier function and microbial dysbiosis induce the production of pro-inflammatory mediators. Keratinocyte-produced TSLP and IL-33 enhance type 2 inflammatory responses through the activation of Th2 cells and ILC2s. Th2 cells and ILC2s produce the key inflammatory cytokines (IL-4 and/or IL-13) of AD. The ligation of OX40L and OX40 augments Th2 immune responses. IL-31 is a T cell-derived cytokine associated with pruritus. IL-31 transmits itch sensations via IL-31R in peripheral neurons. The lipid mediator S1P regulates various cell activities, including cell growth, differentiation, apoptosis, migration, inflammation, metabolism, and angiogenesis, through S1PRs. TSLP, thymic stromal lymphopoietin; IL, interleukin; Th, T-helper cells; ILC2s, group 2 innate lymphoid cells; OX40L, OX40 ligand; IL-31R, IL-31 receptor; S1P, sphingosine 1-phosphate.

Figure 2

JAK–STAT signaling and oral/topical JAK inhibitors in atopic dermatitis. The JAK protein family (JAK1, JAK2, JAK3, and TYK2) mediates IL-4, IL-13, and IL-31 cytokine signaling via cognate receptors. Activation of JAKs results in the phosphorylation of downstream STAT proteins, followed by their nuclear translocation and activation of target genes. JAK inhibitors inhibit the activity of one or more JAKs, thereby interfering with the JAK–STAT signaling pathway. JAK, Janus kinase; STAT, signal transducer and activator of transcription; TYK2, tyrosine kinase 2; IL, interleukin.