Therapeutic pipeline for atopic dermatitis: End of the drought?

Abstract

Until the past year, our therapeutic armamentarium for treating atopic dermatitis (AD) was still primarily topical corticosteroids and, for more severe disease, systemic immunosuppressants. The pipeline of more targeted topical and systemic therapies is expanding based on our growing understanding of the mechanism for AD and is particularly focused on suppressing the skewed immune activation. Most agents are in phase 2 clinical trials. Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, became available in late 2016 in the United States for mild-to-moderate AD, with other PDE4 inhibitors, an agonist of the aryl hydrocarbon receptor, Janus kinase inhibitors, and commensal organisms also in trials for topical application. The first highly effective mAb for AD, dupilumab, targets the IL-4/IL-13 receptor and was approved in early 2017 in the United States for moderate-to-severe adult AD. Other biologics similarly inhibit T2 cytokines (thymic stromal lymphopoietin, IL-4, IL-5, IL-13, and the itch-specific cytokine IL-31 and their receptors) or T22/T17 cytokines, levels of which are increased in lesional skin. Orally administered small-molecule inhibitors that suppress inflammation (targeting chemoattractant receptor-homologous molecules expressed on T2 lymphocytes, PDE4, the histamine 4 receptor, and Janus kinase) or specifically itching (eg, NK1R inhibitors) are also being studied. Comparing biomarkers with individual responses to experimental agents will help to determine subphenotypes within AD that predict prognosis and treatment responses.

Atopic dermatitis in adults: An Australian management consensus

“…Its aetiology involves a complex interaction of a dysfunctional skin barrier, immune dysregulation, individual genetics and environmental factors. There is now focused research interest on the interplay of the epidermis and immune system in patients with AD; multiple molecular targets are being explored with agents in development that target specific components of the immune system and inflammation‐related itch . This has prompted several international updates, and consensus ‘best practice’ recommendations have been published .…”

Translational drug discovery and development with the use of tissue‐relevant biomarkers: Towards more physiological relevance and better prediction of clinical efficacy

“…[56] Co-morbidities are also a common feature in AD presentation, with propensity for other allergic diseases (e.g food allergy, asthma, eosinophilic esophagitis and nasal allergies) and infections, particularly Staphylococcus aureus and herpes viruses. [57] The economic burden of AD is therefore high, with annual costs in the USA estimated to be $5.3 billion. [58] While many patients with AD are able to effectively manage their disease with topical therapies alone, those who cannot are progressed onto more systemic approaches, [59] especially if phototherapy (narrowband ultraviolet light exposure) is ineffective or not appropriate.…”

The complex role of mast cells in fungal infections

“…These Malassezia species have been associated with dermatological diseases such as seborrhoeic dermatitis, pityriasis versicolor, atopic dermatitis (AD) and folliculitis . AD is one of the most common chronic inflammatory diseases of the skin . Malassezia sympodialis ( M. sympodialis ) is frequently isolated from AD patients and healthy individuals .…”