PDE4 Inhibitors: Bridging Molecular Insights With Clinical Impact

June 2025 | Volume 24 | Issue 6 | 631 | Copyright © June 2025


Published online May 29, 2025

doi:10.36849/JDD.9089Citation: Issa NT, Obagi S, Damiani G, et al. PDE4 inhibitors: bridging molecular insights with clinical impact. J Drugs Dermatol. 2025;24(6):631-633. doi:10.36849/JDD.9089

Naiem T Issa MD PhDa,b,c, Sabine Obagi BAd, Giovanni Damiani MD PhDe, Jimin Wang PhDf,g, Christopher G Bunick MD PhDf,g,h

aForefront Dermatology, Vienna, VA
bDr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL
cDepartment of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC
dCollege of Medicine, University of Arizona, Tucson, AZ
eDepartment of Biomedical, Surgical, and Dental Sciences, University of Milan, Milan, Italy
fDepartment of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT
gDepartment of Dermatology, Yale School of Medicine, New Haven, CT
hProgram in Translational Biomedicine, Yale School of Medicine, New Haven, CT

Abstract
Phosphodiesterase-4 (PDE4) inhibitors are reshaping the treatment landscape for chronic inflammatory skin diseases by offering effective, non-steroidal options for conditions like psoriasis, atopic dermatitis, and seborrheic dermatitis. This perspective translates recent structural biology and biochemical findings into clinically meaningful guidance. Among available agents, roflumilast stands out for its high potency and selectivity, with a half-maximal inhibitory concentration of 0.7 nM compared to 140 nM for apremilast (200-fold less) and 750 nM for crisaborole (1071-fold less). This higher potency enables lower dosing and improved tolerability, particularly in topical formulations. Unlike earlier PDE4 inhibitors, roflumilast's structural similarity to the second signal messenger cyclic adenosine monophosphate (cAMP) results in stronger binding to and inhibition of PDE4 and more effective suppression of inflammation. Clinically, this translates into rapid improvements in skin erythema, scaling, and itch, with minimal systemic side effects. Roflumilast is especially valuable for patients who are steroid-averse, pediatric, elderly, or have contraindications to systemic therapy. It can also be integrated into combination regimens, offering flexibility for refractory cases. As ongoing research explores its use in other skin conditions such as vitiligo and lichen planus, understanding the molecular differences among PDE4 inhibitors becomes increasingly relevant to the practicing dermatology provider. By connecting molecular pharmacology with therapeutic decision-making, this article supports dermatology clinicians in selecting targeted therapies that improve patient outcomes, adherence, and quality of life.

J Drugs Dermatol. 2025;24(6):631-633. doi:10.36849/JDD.9089

Citation: Issa NT, Obagi S, Damiani G, et al. PDE4 inhibitors: bridging molecular insights with clinical impact. J Drugs Dermatol. 2025;24(6):631-633. doi:10.36849/JDD.9089

INTRODUCTION

Phosphodiesterase-IV (PDE4) inhibitors represent a burgeoning frontier in dermatological care, offering targeted solutions to inflammatory skin diseases such as psoriasis, atopic dermatitis, and seborrheic dermatitis. PDE4 inhibitors function by increasing cyclic adenosine monophosphate (cAMP), leading to reduced inflammation via cytokine suppression.1 This perspective highlights the practical implications of a recent study2 analyzing the chemical, biochemical, and structural nuances of PDE4 inhibitors - roflumilast, apremilast, and crisaborole - and translates these insights for dermatology clinicians aiming to optimize patient outcomes.

Why PDE4 Inhibition Matters in Dermatology
Inflammatory skin diseases arise from complex immune dysregulation involving Th1, Th2, Th22, and Th17 cytokine pathways.3 PDE4 is a key enzyme expressed in immune and epithelial cells that regulates these pathways by breaking down cAMP, a molecule integral to anti-inflammatory signaling.4 PDE4 inhibitors extend cAMP’s action, thereby reducing inflammation and restoring immune balance.

The introduction of roflumilast, a potent and selective PDE4 inhibitor, offers distinct clinical advantages. Unlike earlier PDE4 inhibitors such as apremilast (oral) and crisaborole (topical), roflumilast boasts significantly higher potency, allowing for more effective treatment of inflammatory skin conditions (Figure 1).2
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