Only double-blind randomized clinical trials with topical PDE4 inhibitors vs topical vehicle treatment for patients with mild to moderate AD were included.
As a demonstration of the potential of this strategy, the SD approach recently led to the approval of crisaborole, a soft phosphodiesterase 4 (PDE4) inhibitor, for atopic dermatitis, while other agents are in clinical development.
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.
Randomized, double-blind placebo-controlled trials (RCTs) have demonstrated topical PDE4 inhibitors are effective and safe in the treatment of both children and adults with AD but further evaluations are needed.
In-vivo analysis confirmed that compound 23 effectively alleviated the symptoms of atopic dermatitis in DNCB-treated Balb/c mice by suppressing the synthesis of inflammatory mediators such as TNF-α, and Ig-E. Taken together, this study suggested that compound 23 could be an effective PDE4 inhibitor for the potential treatment of AD.
Over the past decades, numerous PDE4 inhibitors have been designed and synthesized, among which roflumilast, apremilast, and crisaborole were approved for the treatment of inflammatory airway diseases, psoriatic arthritis, and atopic dermatitis, respectively.
Crisaborole 2% ointment, a topical PDE4, is now US Food and Drug Administration-approved for children older than 2 years and adults in the treatment of AD.
Current treatments for AD include topical moisturizers and anti-inflammatory agents (such as corticosteroids, calcineurin inhibitors and cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) inhibitors), phototherapy and systemic immunosuppressants.
In this review, we highlight recent findings of PDE4 inhibitors in atopic dermatitis, alopecia areata, uveitis, rheumatoid arthritis, psoriasis and PsA, systemic lupus erythematosus, vasculitis, systemic sclerosis, multiple sclerosis and inflammatory bowel disease.
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.
This process has been well characterized, and new therapies for AD, such as phosphodiesterase 4 (PDE-4) inhibitors, T<sub>h</sub>2-expressed chemoattractant receptor-homologous molecule antagonists, and Janus kinase inhibitors, work by antagonizing this cellular pathway.
Non-biologic oral therapies are also being developed for AD and include small molecule drugs targeting phosphodiesterase type IV (PDE4) inhibition or Janus Kinase (JAK) inhibition.
Expert commentary: Crisaborole has several key features in its mode of action which distinguish it from existing treatments for atopic dermatitis (AD), notably its activity against the phosphodiesterase E4 (PDE4) pathway, regulating cyclic AMP (cAMP) levels.
AD therapies attempt to correct this pathology, and guidelines suggest suggest basics of AD therapy, which include repair of the skin barrier through bathing practices and moisturizers, infection control, and further lifestyle modifications to avoid and reduce AD triggers.While some patients' AD may be controlled using these measures, inflammatory eczema including acute flares and maintenance therapy in more severe patients are treated with topical pharmacologic agents such as topical corticosteroids, topical calcineurin inhibitors, and, more recently, topical PDE-4 inhibitors.
Crisaborole ointment 2% (Eucrisa™) is a novel, anti-inflammatory inhibitor of phosphodiesterase 4 (PDE4) that is available in the USA for the topical treatment of mild to moderate atopic dermatitis in patients aged ≥ 2 years.