Skip to main content
SpringerLink
Log in

Phosphodiesterase 4 Inhibitor Therapies for Atopic Dermatitis: Progress and Outlook

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Abstract

Phosphodiesterase 4 (PDE4) is a cyclic AMP degrading enzyme in leukocytes. Several decades ago, increased PDE activity was demonstrated in patients with atopic dermatitis (AD). Currently, several PDE4 inhibitors in both topical and oral formulation have been developed to target the inflammatory cascade of AD. This review shows the pathogenic rationale behind these inhibitors, and discusses multiple PDE4 inhibitors that are under evaluation or in the market. PDE4 inhibitors may be considered as favorable agents in the repertoire of current interventions for AD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. J Am Acad Dermatol. 2014;71(1):116–32. doi:10.1016/j.jaad.2014.03.023 .

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sidbury R, Davis DM, Cohen DE, American Academy of Dermatology, et al. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents. J Am Acad Dermatol. 2014;71(2):327–49. doi:10.1016/j.jaad.2014.03.030.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wittmann M, Helliwell PS. Phosphodiesterase 4 inhibition in the treatment of psoriasis, psoriatic arthritis and other chronic inflammatory diseases. Dermatol Ther (Heidelb). 2013;3(1):1–15. doi:10.1007/s13555-013-0023-0.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Eyerich K, Novak N. Immunology of atopic eczema: overcoming the Th1/Th2 paradigm. Allergy. 2013;68(8):974–82. doi:10.1111/all.12184.

    Article  CAS  PubMed  Google Scholar 

  5. Samrao A, Berry TM, Goreshi R, Simpson EL. A pilot study of an oral phosphodiesterase inhibitor (apremilast) for atopic dermatitis in adults. Arch Dermatol. 2012;148(8):890–7.

    Article  CAS  Google Scholar 

  6. Maurice DH, Ke H, Ahmad F, Wang Y, Chung J, Manganiello VC. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014;13(4):290–314. doi:10.1038/nrd4228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hanifin JM, Chan SC, Cheng JB, Tofte SJ, Henderson WR Jr, Kirby DS, Weiner ES. Type 4 phosphodiesterase inhibitors have clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol. 1996;107(1):51–6.

    Article  CAS  Google Scholar 

  8. Felding J, Sørensen MD, Poulsen TD, Larsen J, Andersson C, Refer P, Engell K, Ladefoged LG, Thormann T, Vinggaard AM, Hegardt P, Søhoel A, Nielsen SF. Discovery and early clinical development of 2-{6-[2-(3,5-dichloro-4-pyridyl)acetyl]-2,3-dimethoxyphenoxy}-N-propylacetamide (LEO 29102), a soft-drug inhibitor of phosphodiesterase 4 for topical treatment of atopic dermatitis. J Med Chem. 2014;57(14):5893–903. doi:10.1021/jm500378a.

    Article  CAS  PubMed  Google Scholar 

  9. Grewe SR, Chan SC, Hanifin JM. Elevated leukocyte cyclic AMP-phosphodiesterase in atopic disease: a possible mechanism for cyclic AMP-agonist hyporesponsiveness. J Allergy Clin Immunol. 1982;70(6):452–7.

    Article  CAS  Google Scholar 

  10. Butler JM, Chan SC, Stevens S, Hanifin JM. Increased leukocyte histamine release with elevated cyclic AMP-phosphodiesterase activity in atopic dermatitis. J Allergy Clin Immunol. 1983;71(5):490–7.

    Article  CAS  Google Scholar 

  11. Heskel NS, Chan SC, Thiel ML, Stevens SR, Casperson LS, Hanifin JM. Elevated umbilical cord blood leukocyte cyclic adenosine monophosphate-phosphodiesterase activity in children with atopic parents. J Am Acad Dermatol. 1984;11(3):422–6.

    Article  CAS  Google Scholar 

  12. Zane LT, Chanda S, Jarnagin K, Nelson DB, Spelman L, Gold LS. Crisaborole and its potential role in treating atopic dermatitis: overview of early clinical studies. Immunotherapy. 2016;8(8):853–66. doi:10.2217/imt-2016-0023.

    Article  CAS  PubMed  Google Scholar 

  13. Jarnagin K, Chanda S, Coronado D, Ciaravino V, Zane LT, Guttman-Yassky E, Lebwohl MG. Crisaborole topical ointment, 2%: a nonsteroidal, topical, anti-inflammatory phosphodiesterase 4 inhibitor in clinical development for the treatment of atopic dermatitis. J Drugs Dermatol. 2016;15(4):390–6.

    CAS  PubMed  Google Scholar 

  14. Tom WL, Van Syoc M, Chanda S, Zane LT. Pharmacokinetic profile, safety, and tolerability of crisaborole topical ointment, 2% in adolescents with atopic dermatitis: an open-label phase 2a study. Pediatr Dermatol. 2016;33(2):150–9. doi:10.1111/pde.12780.

    Article  PubMed  Google Scholar 

  15. Paller AS, Tom WL, Lebwohl MG, et al. Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis (AD) in children and adults. J Am Acad Dermatol. 2016;75(3):494–503.e4. doi:10.1016/j.jaad.2016.05.046.

    Article  CAS  PubMed  Google Scholar 

  16. Freund YR, Akama T, Alley MR, Antunes J, et al. Boron-based phosphodiesterase inhibitors show novel binding of boron to PDE4 bimetal center. FEBS Lett. 2012;586(19):3410–4. doi:10.1016/j.febslet.2012.07.058.

    Article  CAS  PubMed  Google Scholar 

  17. Murrell DF, Gebauer K, Spelman L, Zane LT. Crisaborole topical ointment, 2% in adults with atopic dermatitis: a phase 2a, vehicle-controlled, proof-of-concept study. J Drugs Dermatol. 2015;14(10):1108–12.

    CAS  PubMed  Google Scholar 

  18. Zane LT, Kircik L, Call R, Tschen E, Draelos ZD, Chanda S, Van Syoc M, Hebert AA. Crisaborole topical ointment, 2% in patients ages 2 to 17 years with atopic dermatitis: a phase 1b, open-label, maximal-use systemic exposure study. Pediatr Dermatol. 2016;33(4):380–7. doi:10.1111/pde.12872.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Kircik L, Call R, Tschen E, Draelos Z, Syoc M, Zane L, Hebert A. Maximal use systemic exposure (MUSE) study evaluating AN2728, a novel boron-based small molecule, for the treatment of pediatric and adolescent subjects with mild-to-moderate atopic dermatitis. Paper presented at: 10th annual Maui Derm conference, 2014 Jan 26–30, Maui Hawaii.

  20. Stein Gold LF, Spelman L, Spellman MC, Hughes MH, Zane LT. A, Phase 2, randomized, controlled, dose-ranging study evaluating crisaborole topical ointment, 0.5% and 2% in adolescents with mild to moderate atopic dermatitis. J Drugs Dermatol. 2015;14(12):1394–9.

    PubMed  Google Scholar 

  21. Silverberg JI, Nelson DB, Yosipovitch G. Addressing treatment challenges in atopic dermatitis with novel topical therapies. J Dermatol Treat. 2016;27(6):568–76.

    Article  CAS  Google Scholar 

  22. Eichenfield LF, Tom WL, Chamlin SL, et al. Guidelines of care for the management of atopic dermatitis: section 1. Diagnosis and assessment of atopic dermatitis. J Am Acad Dermatol. 2014;70(2):338–51. doi:10.1016/j.jaad.2013.10.010.

    Article  PubMed  Google Scholar 

  23. Barbier N, Paul C, Luger T, et al. Validation of the eczema area and severity index for atopic dermatitis in a cohort of 1550 patients from the pimecrolimus cream 1% randomized controlled clinical trials programme. Br J Dermatol. 2004;150(1):96–102.

    Article  CAS  Google Scholar 

  24. Hanifin JM, Ellis CN, Frieden IJ, et al. OPA-15406, a novel, topical, nonsteroidal, selective phosphodiesterase-4 (PDE4) inhibitor, in the treatment of adult and adolescent patients with mild to moderate atopic dermatitis (AD): a phase-II randomized, double-blind, placebo-controlled study. J Am Acad Dermatol. 2016;75(2):297–305. doi:10.1016/j.jaad.2016.04.001.

    Article  CAS  PubMed  Google Scholar 

  25. Andoh T, Yoshida T, Kuraishi Y. Topical RVT-501, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch-related responses in mice with chronic atopy-like dermatitis. Exp Dermatol. 2014;23(5):359–61. doi:10.1111/exd.12377.

    Article  CAS  PubMed  Google Scholar 

  26. Nemoto O, Hayashi N, Kitahara Y, Furue M, Hojo S, Nomoto M, Shima S, Japanese RVT-501 Study Investigators. Effect of topical phosphodiesterase 4 inhibitor RVT-501 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial. J Dermatol. 2016;43(8):881–7. doi:10.1111/1346-8138.13231.

    Article  CAS  PubMed  Google Scholar 

  27. Ohba F, Matsuki S, Imayama S, Matsuguma K, Hojo S, Nomoto M, Akama H. Efficacy of a novel phosphodiesterase inhibitor, RVT-501, in patients with atopic dermatitis: an investigator-blinded, vehicle-controlled study. J Dermatol Treat. 2016;27(5):467–72. doi:10.3109/09546634.2016.1157257.

    Article  CAS  Google Scholar 

  28. Furue M, Kitahara Y, Akama H, Hojo S, Hayashi N, Nakagawa H, JAPANESE RVT-501 Study Investigators. Safety and efficacy of topical RVT-501, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: results of a randomized, vehicle-controlled, multicenter clinical trial. J Dermatol. 2014;41(7):577–85. doi:10.1111/1346-8138.12534.

    Article  CAS  PubMed  Google Scholar 

  29. Seldon PM, Giembycz MA. Suppression of granulocyte/macrophage colony-stimulating factor release from human monocytes by cyclic AMP-elevating drugs: role of interleukin-10. Br J Pharmacol. 2001;134(1):58–67.

    Article  CAS  Google Scholar 

  30. Schafer PH, Parton A, Gandhi AK, et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010;159(4):842–55. doi:10.1111/j.1476-5381.2009.00559.x.

    Article  CAS  PubMed  Google Scholar 

  31. Notaro ER, Sidbury R. Systemic agents for severe atopic dermatitis in children. Paediatr Drugs. 2015;17(6):449–57. doi:10.1007/s40272-015-0150-4.

    Article  PubMed  Google Scholar 

  32. Volf EM, Au SC, Dumont N, Scheinman P, Gottlieb AB. A phase 2, open-label, investigator-initiated study to evaluate the safety and efficacy of apremilast in subjects with recalcitrant allergic contact or atopic dermatitis. J Drugs Dermatol. 2012;11(3):341–6.

    CAS  PubMed  Google Scholar 

  33. Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs. 2007;8(5):364–72.

    CAS  PubMed  Google Scholar 

  34. Giembycz MA. Can the anti-inflammatory potential of PDE4 inhibitors be realized: guarded optimism or wishful thinking? Br J Pharmacol. 2008;155(3):288–90. doi:10.1038/bjp.2008.297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014;26(9):2016–29. doi:10.1016/j.cellsig.2014.05.014.

    Article  CAS  PubMed  Google Scholar 

  36. Sigurgeirsson B, Boznanski A, Todd G, et al. Safety and efficacy of pimecrolimus in atopic dermatitis: a 5-year randomized trial. Pediatrics. 2015;135(4):597–606. doi:10.1542/peds.2014-1990.

    Article  PubMed  Google Scholar 

  37. Eichenfield DZ, Eichenfield LF. Pimecrolimus is safe and effective in treating atopic dermatitis. J Pediatr. 2015;167(5):1171–2. doi:10.1016/j.jpeds.2015.08.060.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pediatric and Adolescent Dermatology, Rady Children’s Hospital, San Diego, 8010 Frost Street, Suite 602, San Diego, CA, 92123, USA

    Jusleen Ahluwalia, Jeremy Udkoff, Andrea Waldman, Jenna Borok & Lawrence F. Eichenfield

  2. Department of Pediatric and Adolescent Dermatology, San Diego School of Medicine, University of California, 9500 Gillman Drive, La Jolla, CA, 92093, USA

    Jusleen Ahluwalia, Jeremy Udkoff, Andrea Waldman, Jenna Borok & Lawrence F. Eichenfield

Authors
  1. Jusleen Ahluwalia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jeremy Udkoff
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrea Waldman
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jenna Borok
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lawrence F. Eichenfield
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jusleen Ahluwalia.

Ethics declarations

Funding

No funding was received for the preparation of this review.

Conflict of interest

Jusleen Ahluwalia, Jeremy Udkoff, Andrea Waldman, and Jenna Borok have no conflicts of interests. Lawrence Eichenfield has served as an investigator and consultant to Celgene, Anacor, Pfizer, Medimetriks, and Otsuka Pharmaceuticals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ahluwalia, J., Udkoff, J., Waldman, A. et al. Phosphodiesterase 4 Inhibitor Therapies for Atopic Dermatitis: Progress and Outlook. Drugs 77, 1389–1397 (2017). https://doi.org/10.1007/s40265-017-0784-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40265-017-0784-3

Search

Navigation