The immunology of atopic dermatitis and its reversibility with broad-spectrum and targeted therapies

Abstract

Atopic dermatitis (AD), the most common chronic inflammatory skin disease, is driven by both terminal keratinocyte differentiation defects and strong type 2 immune responses. In contrast to chronic plaque-type psoriasis, AD is now understood to be a much more heterogeneous disease, with additional activation of T_H22, T_H17/IL-23, and T_H1 cytokine pathways depending on the subtype of the disease. In this review we discuss our current understanding of the AD immune map in both patients with early-onset and those with chronic disease. Clinical studies with broad and targeted therapeutics have helped to elucidate the contribution of various immune axes to the disease phenotype. Importantly, immune activation extends well beyond lesional AD because nonlesional skin and the blood component harbor AD-specific inflammatory changes. For this reason, future therapeutics will need to focus on a systemic treatment approach, especially in patients with moderate-to-severe disease.

Keywords: Atopic dermatitis; T helper cell; eczema; immune; keratinocyte; skin immune map; targeted therapy.

Figure 1

Schematic representation/activation levels of selected immune pathways and epidermal responses in lesional and non-lesional skin in (A) infant, (B) early-onset AD and (C) Asian AD, (D) compared to psoriasis. AMP Antimicrobial peptide. K16 Keratin 16.

Figure 1

Schematic representation/activation levels of selected immune pathways and epidermal responses in lesional and non-lesional skin in (A) infant, (B) early-onset AD and (C) Asian AD, (D) compared to psoriasis. AMP Antimicrobial peptide. K16 Keratin 16.

Figure 1

Schematic representation/activation levels of selected immune pathways and epidermal responses in lesional and non-lesional skin in (A) infant, (B) early-onset AD and (C) Asian AD, (D) compared to psoriasis. AMP Antimicrobial peptide. K16 Keratin 16.

Figure 2

Targets of (A) biologics and (B) small molecules recently published or currently being assessed in clinical trials. AMP adenosine monophosphate; cAMP cyclic adenosine monophosphate; CREB cAMP response element-binding protein; CRTH2 Prostaglandin DP2 receptor; FFA Free fatty acids; H4R Histamine H4 receptor; JAK Janus kinase; NF-kB Nuclear factor kappa-light-chain-enhancer of activated B cells; PGD₂ Prostaglandin D₂; PKA Protein kinase A; STAT signal transducer and activator of transcription.

Figure 2

Targets of (A) biologics and (B) small molecules recently published or currently being assessed in clinical trials. AMP adenosine monophosphate; cAMP cyclic adenosine monophosphate; CREB cAMP response element-binding protein; CRTH2 Prostaglandin DP2 receptor; FFA Free fatty acids; H4R Histamine H4 receptor; JAK Janus kinase; NF-kB Nuclear factor kappa-light-chain-enhancer of activated B cells; PGD₂ Prostaglandin D₂; PKA Protein kinase A; STAT signal transducer and activator of transcription.

Figure 3

Clinical responses in an AD patient before (A) and after (B) treatment with dupilumab 300mg eow. Hallmarks of AD such as widely distributed erythema and excoriations are largely relieved after 16 weeks of treatment.

Figure 4

Effects of dupilumab on lesional AD skin. (A) Schematic representation of pathways influenced by dupilumab treatment. (B) Summary heat map of quantitative RT-PCR mRNA expression changes in placebo, 150mg and 300mg dupilumab after 4 weeks of treatment. Values represent mean fold change (FCH) +/− SEM. *p<0.1, **p<0.05, ***p<0.01. Figure reproduced with permission of publisher from Hamilton et al. FLG Filaggrin; K16 Keratin 16; LOR Loricrin; MMP12 Matrix metalloproteinase-12; PI3 Peptidase inhibitor 3; TSLPR: Thymic stromal lymphopoietin receptor.

Figure 4

Effects of dupilumab on lesional AD skin. (A) Schematic representation of pathways influenced by dupilumab treatment. (B) Summary heat map of quantitative RT-PCR mRNA expression changes in placebo, 150mg and 300mg dupilumab after 4 weeks of treatment. Values represent mean fold change (FCH) +/− SEM. *p<0.1, **p<0.05, ***p<0.01. Figure reproduced with permission of publisher from Hamilton et al. FLG Filaggrin; K16 Keratin 16; LOR Loricrin; MMP12 Matrix metalloproteinase-12; PI3 Peptidase inhibitor 3; TSLPR: Thymic stromal lymphopoietin receptor.