Atopic dermatitis: an expanding therapeutic pipeline for a complex disease

Abstract

Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti-IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease.

Fig. 1. A multidimensional model of atopic dermatitis.

A high-level schematic view of the complex interactions that underlie the immunological heterogeneity of atopic dermatitis (AD). This multidimensional disease model generates an ‘immunological march’, which can schematically and tentatively be dissected in several, potentially overlapping phases: first, an asymptomatic preclinical phase (phase 0); second, activation of skin innate immunity (phase 1), rapidly followed by activation of the adaptive immune response (phase 2) starting with a core T helper 2 (T_H2) response accompanied by IgE sensitization to environmental allergens, and a widening of the adaptive immunity with T_H1, T_H17 and T_H22 responses. This widening of the immune response paves the way for the development of atopic and non-atopic comorbidities (phase 3). Each putative phase offers opportunities for preventive and targeted therapeutic intervention, including disease modification. In this scenario, the composition of the skin microbiome and the itch–scratch cycle potentially have a crucial role in directing the adaptive immunity and the development of sensitization to self proteins, atopic and non-atopic comorbidities.

Fig. 2. Therapeutic strategies for atopic dermatitis.

Multiple strategies aimed at correcting the skin dysbiosis by microbiome manipulation are currently in development either by topical application or by oral administration. The aim is to reduce the overgrowth of Staphylococcus aureus (S.a.) and/or to favour the recovery of the commensals Staphylococcus hominis (S.h.) and Staphylococcus epidermidis (S.e.). The innate immune response is assumed to be instrumental at the very early stage of AD, and targeting the aryl-hydrocarbon receptor (AhR) and alarmins represents an appealing strategy of intervention. The complexity of the adaptive immune response offers multiple opportunities for targeted therapies using biologics against cytokines and their respective receptors. As T cells are the effectors in the inflammatory reaction, impacting on their migratory activity from the lymph nodes via modulation of the sphingosine 1-phosphate receptor (S1PR) or into the skin via the C-C chemokine receptor 4 (CCR4) is an emerging approach. Besides biologics, another strategy to affect the pathways involved in the generation of inflammation is the use of kinase inhibitors that are differentially selective for Janus kinases (JAKs) (JAKi) involved in the signal transduction of cytokine receptors. Other inhibitors address kinases involved in pathways related to the nerve growth factor, such as the tropomyosin receptor kinase (TRK) or Bruton tyrosine kinase (BTK) involved in the signal transduction of the B cell receptor or the high-affinity receptor for IgE expressed in mast cells and dendritic cells. Histamine receptor 4 (H4R) is widely expressed and is an interesting target as it is involved in immunomodulatory mechanisms. Another popular approach to reduce inflammation in AD is to use inhibitors of phosphodiesterase 4 (PDE4) as they increase the cellular levels of cAMP and thereby contribute to the generation of anti-inflammatory cytokines. As sensing neurons in the skin can be activated by multiple mediators generated during the inflammatory reaction, several strategies targeting the generation of itching have been developed, including blockade of IL-31 receptor (IL-31R), neurokinin 1 receptor (NK1R) and purinoreceptor 3 (P2X3). LXR, liver X receptor; mIgE, membrane form of IgE; OX40L, OX40 ligand; T_H cell, T helper cell; TSLP, thymic stromal lymphopoietin.