, Volume 77, Issue 13, pp 1389–1397 | Cite as

Phosphodiesterase 4 Inhibitor Therapies for Atopic Dermatitis: Progress and Outlook

  • Jusleen AhluwaliaEmail author
  • Jeremy Udkoff
  • Andrea Waldman
  • Jenna Borok
  • Lawrence F. Eichenfield
Leading Article


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.


Compliance with Ethical Standards


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.


  1. 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 .CrossRefPubMedPubMedCentralGoogle Scholar
  2. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefGoogle Scholar
  6. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 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.CrossRefGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefGoogle Scholar
  10. 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.CrossRefGoogle Scholar
  11. 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.CrossRefGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 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.CrossRefPubMedGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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.Google Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.CrossRefGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 33.
    Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs. 2007;8(5):364–72.PubMedGoogle Scholar
  34. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.CrossRefPubMedGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Jusleen Ahluwalia
    • 1
    • 2
    Email author
  • Jeremy Udkoff
    • 1
    • 2
  • Andrea Waldman
    • 1
    • 2
  • Jenna Borok
    • 1
    • 2
  • Lawrence F. Eichenfield
    • 1
    • 2
  1. 1.Department of Pediatric and Adolescent DermatologyRady Children’s Hospital, San DiegoSan DiegoUSA
  2. 2.Department of Pediatric and Adolescent Dermatology, San Diego School of MedicineUniversity of CaliforniaLa JollaUSA

Personalised recommendations