The role of phosphodiesterase 4 in the pathophysiology of atopic dermatitis and the perspective for its inhibition.

Abstract

Atopic dermatitis (AD) is a highly prevalent, chronic inflammatory skin disease that affects children and adults. The pathophysiology of AD is complex and involves skin barrier and immune dysfunction. Many immune cytokine pathways are amplified in AD, including T helper (Th) 2, Th22, Th17 and Th1. Current treatment guidelines recommend topical medications as initial therapy; however, until recently, only two drug classes were available: topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs). Several limitations are associated with these agents. TCSs can cause a wide range of adverse effects, including skin atrophy, telangiectasia, rosacea and acne. TCIs can cause burning and stinging, and the prescribing information lists a boxed warning for a theoretical risk of malignancy. Novel medications with new mechanisms of action are necessary to provide better long-term control of AD. Phosphodiesterase 4 (PDE4) regulates cyclic adenosine monophosphate in cells and has been shown to be involved in the pathophysiology of AD, making it an attractive therapeutic target. Several PDE4 inhibitors are in clinical development for use in the treatment of AD, including crisaborole, which recently became the first topical PDE4 inhibitor approved for treatment of mild to moderate AD. This review will further describe the pathophysiology of AD, explain the possible role of PDE4 in AD and review PDE4 inhibitors currently approved or being investigated for use in AD.

• Authors: Emma Guttman-Yassky, Jon M Hanifin, Mark Boguniewicz, Andreas Wollenberg, Robert Bissonnette, Vivek Purohit, Iain Kilty, Anna M Tallman, Michael A Zielinski
• Journal: Experimental dermatology (Exp Dermatol) Vol. 28 Issue 1 Pg. 3-10 (01 2019) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 30332502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• 2-(6-(2-(3,5-dichloro-4-pyridyl)acetyl)-2,3-dimethoxyphenoxy)-N-propylacetamide
• Acetamides
• Boron Compounds
• Bridged Bicyclo Compounds, Heterocyclic
• Cytokines
• Phosphodiesterase Inhibitors
• Phthalic Acids
• Pyridines
• Quinazolines
• methyl 4-(((3-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)amino)carbonyl)benzoate
• Thalidomide
• Cyclic Nucleotide Phosphodiesterases, Type 4
• PDE4A protein, human
• crisaborole
• apremilast

Topics

• Acetamides (pharmacology)
• Boron Compounds (pharmacology)
• Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (physiology)
• Cytokines (metabolism)
• Dermatitis, Atopic (metabolism, physiopathology, prevention & control)
• Drug Approval
• Humans
• Immune System
• Inflammation
• Phosphodiesterase Inhibitors (pharmacology)
• Phthalic Acids (pharmacology)
• Pyridines (pharmacology)
• Quinazolines (pharmacology)
• Risk
• Skin (pathology)
• Thalidomide (analogs & derivatives, pharmacology)