Phosphodiesterase 4 inhibitors

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Historically, drugs available for treating atopic dermatitis (AD) have been limited to topical corticosteroids and topical calcineurin inhibitors, with systemic immunosuppressants and phototherapy reserved for severe AD. Despite their efficacy and infrequent adverse events, phobia about the use of topical steroids and calcineurin inhibitors has limited their use. More targeted options with fewer systemic and cutaneous side effects are needed for treating AD. Phosphodiesterase 4 (PDE4) is involved in the regulation of proinflammatory cytokines via the degradation of cyclic adenosine monophosphate. PDE4 activity is increased in the inflammatory cells of patients with AD, leading to increased production of proinflammatory cytokines and chemokines. Targeting PDE4 reduces the production of these proinflammatory mediators in AD. Both topical and oral PDE4 inhibitors have a favorable safety profile. 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. Crisaborole 2% ointment shows early and sustained improvement in disease severity and pruritus and other AD symptoms, with burning and/or stinging upon application as the only related adverse event. Other PDE4 inhibitors are currently in trials with promising efficacy and safety.

Section snippets

PDE4 activity is increased in AD and associated with proinflammatory cytokines

Alterations in nucleotide metabolism in atopic disease were first described in 1968 by Szentivanyia et al.16 Elevated phosphodiesterase (PDE) activity in a variety of inflammatory cells involved in AD has been described in adults with AD17, 18, 19, 20 and the cord blood of children born to atopic parents.21 Intracellular cyclic adenosine monophosphate (cAMP) levels depend on the relative rate of cAMP production and degradation. PDE 4 (PDE4) degrades cAMP, a negative regulator of the production

Clinical studies of PDE4 inhibitors

During the past 2 decades, several oral and topical PDE4 inhibitors have been studied and approved for the treatment of a variety of inflammatory disorders, including AD, asthma, chronic obstructive pulmonary disease, psoriasis and psoriatic arthritis, and rheumatoid arthritis.43

Oral PDE4 inhibitors are minimally immunosuppressive, in contrast to other systemically administered medications for inflammatory skin disease, but they have a narrow therapeutic window, with nausea, vomiting, abdominal

Conclusions

There is a need for additional topical treatments for AD. PDE4 activity is increased in inflammatory cells of patients with AD, leading to degradation of intracellular cAMP, with subsequent increased production of proinflammatory cytokines. PDE4 inhibitors are a promising targeted treatment option for children and adults with mild-to-moderate AD. Future studies will be needed explore the efficacy and safety of PDE4 compounds beyond crisaborole and in pediatric patients younger than 2 years.

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  • Cited by (0)

    Publication of this article was supported by Leo Pharma, Bayer, and Sanofi/Regeneron.

    Funding sources: Supported by Bayer, LEO Pharma, and Sanofi.

    Disclosure: Dr Paller has received funds for serving as an investigator for Anacor and as a consultant for Pfizer. Dr Zebda disclosed no conflicts of interest.

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