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Application of Topical Phosphodiesterase 4 Inhibitors in Mild to Moderate Atopic DermatitisA Systematic Review and Meta-analysis

Educational Objective
To recognize the efficacy and safety of topical phosphodiesterase 4 (PDE4) inhibitors in mild to moderate atopic dermatitis.
1 Credit CME
Key Points

Questions  Are topical phosphodiesterase 4 inhibitors safe and effective as treatment of mild to moderate atopic dermatitis?

Findings  In this meta-analysis, 7 double-blind randomized clinical trials of topical phosphodiesterase 4 inhibitors vs vehicle treatment for 1869 patients with mild to moderate atopic dermatitis were included. Topical application of phosphodiesterase 4 inhibitors was associated with a statistically significant improvement in both target lesion score and investigators’ assessment of atopic dermatitis compared with the control vehicles.

Meaning  Topical phosphodiesterase 4 inhibitors represent a new option for the management of atopic dermatitis.


Importance  Topical medication is the central treatment for patients with atopic dermatitis (AD), but the options are limited. Phosphodiesterase 4 (PDE4) inhibitors are a new candidate for AD therapy.

Objective  To evaluate the efficacy and safety of topical PDE4 inhibitors in mild to moderate AD.

Data Sources  Clinical trials were identified from MEDLINE, Embase, Cochrane Controlled Register of Trials, Chinese medical databases (Wanfang, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, and China Science and Technology Journal Database), ClinicalTrials.gov, and other trial registries from inception to August 15, 2018. No restrictions on languages were placed.

Study Selection  Only double-blind randomized clinical trials with topical PDE4 inhibitors vs topical vehicle treatment for patients with mild to moderate AD were included.

Data Extraction and Synthesis  Two reviewers independently extracted study features, intervention details, and outcomes. A meta-analysis was performed using the random-effects model. The Cochrane Collaboration’s risk of bias assessment tool was used to assess the risk of bias. Funnel plots and Egger tests were used to assess the publication bias.

Main Outcomes and Measures  Changes from baseline in target lesion score were expressed in terms of standardized mean differences (SMDs) with 95% CIs. Outcomes of investigators’ assessment and safety were expressed in terms of relative risk with 95% CIs.

Results  Seven studies were identified, which included 1869 patients with mild to moderate AD. Overall, compared with the topical vehicle control, topical application of PDE4 inhibitors was associated with a significant decrease in target lesion score (SMD −0.40; 95% CI, −0.61 to −0.18; P < .001) and a higher response rate in investigators’ assessment of clear or almost clear skin (relative risk, 1.50; 95% CI, 1.33-1.70; P < .001). There was no difference in treatment-related adverse events or in adverse events that required discontinuation of therapy. Subgroup analyses indicated that after 14 and 28 days of therapy with PDE4 inhibitors, target lesion score was significantly decreased. However, these beneficial effects were displayed only for the PDE4 inhibitors crisaborole and AN2898 (crisaborole at day 14: SMD, −0.59; 95% CI, −1.15 to −0.02; P = .04; AN2898 at day 14: SMD, −0.76; 95% CI, −1.38 to −0.13; P = .02; crisaborole at day 28: SMD, −0.86; 95% CI, −1.44 to −0.28; P = .004; AN2898 at day 28: SMD, −0.68; 95% CI, −1.30 to −0.05; P = .03). Heterogeneity was not significant across studies.

Conclusions and Relevance  This meta-analysis suggests that topical PDE4 inhibitors are a safe and effective treatment for mild to moderate AD. Current evidence supports the use of crisaborole or AN2898 as the choice of maintenance or sequential therapy for mild to moderate AD.

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Article Information

Accepted for Publication: December 31, 2018.

Published Online: March 27, 2019. doi:10.1001/jamadermatol.2019.0008

Correction: This article was corrected on May 22, 2019, to fix an error in the description of a study that was included in the meta-anlaysis.

Open Access: This article is published under the JN-OA license and is free to read on the day of publication.

Corresponding Authors: Hua Wang, MD, PhD (huawang@hospital.cqmu.edu.cn), and Xiao-yan Luo, MD, PhD, Department of Dermatology, Children’s Hospital, Chongqing Medical University, Chongqing 400014, China (xyluo@hospital.cqmu.edu.cn).

Author Contributions: Drs Wang and Luo had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Yang and J. Wang contributed equally to this work.

Concept and design: X. Zhang, H. Wang, Luo.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Yang, H. Wang, Luo.

Critical revision of the manuscript for important intellectual content: J. Wang, X. Zhang, Y. Zhang, Qin, H. Wang, Luo.

Statistical analysis: Yang, J. Wang, X. Zhang, Y. Zhang, Qin, Luo.

Administrative, technical, or material support: Yang, J. Wang, X. Zhang, H. Wang, Luo.

Supervision: Yang, H. Wang, Luo.

Conflict of Interest Disclosures: None reported.

Nutten  S.  Atopic dermatitis: global epidemiology and risk factors.  Ann Nutr Metab. 2015;66(suppl 1):8-16. doi:10.1159/000370220PubMedGoogle ScholarCrossref
Karimkhani  C, Boyers  LN, Prescott  L,  et al.  Global burden of skin disease as reflected in Cochrane Database of Systematic Reviews.  JAMA Dermatol. 2014;150(9):945-951. doi:10.1001/jamadermatol.2014.709PubMedGoogle ScholarCrossref
Drucker  AM, Wang  AR, Li  WQ, Sevetson  E, Block  JK, Qureshi  AA.  The Burden of Atopic Dermatitis: summary of a report for the National Eczema Association.  J Invest Dermatol. 2017;137(1):26-30. doi:10.1016/j.jid.2016.07.012PubMedGoogle ScholarCrossref
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):116-132. doi:10.1016/j.jaad.2014.03.023PubMedGoogle ScholarCrossref
Nakahara  T, Koga  T, Fukagawa  S, Uchi  H, Furue  M.  Intermittent topical corticosteroid/tacrolimus sequential therapy improves lichenification and chronic papules more efficiently than intermittent topical corticosteroid/emollient sequential therapy in patients with atopic dermatitis.  J Dermatol. 2004;31(7):524-528. doi:10.1111/j.1346-8138.2004.tb00548.xPubMedGoogle ScholarCrossref
Breuer  K, Werfel  T, Kapp  A.  Safety and efficacy of topical calcineurin inhibitors in the treatment of childhood atopic dermatitis.  Am J Clin Dermatol. 2005;6(2):65-77. doi:10.2165/00128071-200506020-00001PubMedGoogle ScholarCrossref
Siegfried  EC, Jaworski  JC, Hebert  AA.  Topical calcineurin inhibitors and lymphoma risk: evidence update with implications for daily practice.  Am J Clin Dermatol. 2013;14(3):163-178. doi:10.1007/s40257-013-0020-1PubMedGoogle ScholarCrossref
Akama  T, Baker  SJ, Zhang  YK,  et al.  Discovery and structure-activity study of a novel benzoxaborole anti-inflammatory agent (AN2728) for the potential topical treatment of psoriasis and atopic dermatitis.  Bioorg Med Chem Lett. 2009;19(8):2129-2132. doi:10.1016/j.bmcl.2009.03.007PubMedGoogle ScholarCrossref
Hanifin  JM, Lloyd  R, Okubo  K, Guerin  LL, Fancher  L, Chan  SC.  Relationship between increased cyclic AMP-phosphodiesterase activity and abnormal adenylyl cyclase regulation in leukocytes from patients with atopic dermatitis.  J Invest Dermatol. 1992;98(6)(suppl):100S-105S. doi:10.1111/1523-1747.ep12462340PubMedGoogle ScholarCrossref
Gittler  JK, Shemer  A, Suárez-Fariñas  M,  et al.  Progressive activation of Th2/Th22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis.  J Allergy Clin Immunol. 2012;130(6):1344-1354. doi:10.1016/j.jaci.2012.07.012PubMedGoogle ScholarCrossref
Zebda  R, Paller  AS.  Phosphodiesterase 4 inhibitors.  J Am Acad Dermatol. 2018;78(3)(suppl 1):S43-S52. doi:10.1016/j.jaad.2017.11.056PubMedGoogle ScholarCrossref
Nemoto  O, Hayashi  N, Kitahara  Y,  et al; Japanese E6005 Study Investigators.  Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: results from a randomized, vehicle-controlled exploratory trial.  J Dermatol. 2016;43(8):881-887. doi:10.1111/1346-8138.13231PubMedGoogle ScholarCrossref
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. doi:10.1016/j.jaad.2016.05.046PubMedGoogle ScholarCrossref
Higgins  JPT, Green  S, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration. http://handbook-5-1.cochrane.org/. Updated March 2011. Accessed February 14, 2019.
Moher  D, Liberati  A, Tetzlaff  J, Altman  DG; PRISMA Group.  Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.  Int J Surg. 2010;8(5):336-341. doi:10.1016/j.ijsu.2010.02.007PubMedGoogle ScholarCrossref
Duval  S, Tweedie  R.  A nonparametric ‘trim and fill’ method of accounting for publication bias in meta-analysis.  J Am Stat Assoc. 2000;95:89-98. doi:10.1080/01621459.2000.10473905Google Scholar
Clinicaltrials.gov. Efficacy and safety of AN2898 and AN2728 topical ointments to treat mild-to-moderate atopic dermatitis. NCT01301508. https://clinicaltrials.gov/ct2/show/NCT01301508. Accessed February 14, 2019.
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):1108-1112.PubMedGoogle Scholar
Furue  M, Kitahara  Y, Akama  H, Hojo  S, Hayashi  N, Nakagawa  H; Japanese E6005 Study Investigators.  Safety and efficacy of topical E6005, 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):577-585. doi:10.1111/1346-8138.12534PubMedGoogle ScholarCrossref
Saeki  H, Furue  M, Furukawa  F,  et al; Committee for Guidelines for the Management of Atopic Dermatitis of Japanese Dermatological Association.  Guidelines for management of atopic dermatitis.  J Dermatol. 2009;36(10):563-577. doi:10.1111/j.1346-8138.2009.00706.xPubMedGoogle ScholarCrossref
Hanifin  JM, Rajka  G.  Diagnostic features of atopic dermatitis.  Acta Derm Venereol. 1980;(suppl 92):44-47. doi:10.2340/00015555924447Google Scholar
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.2016.04.001PubMedGoogle ScholarCrossref
Clinicaltrials.gov. Topical roflumilast in adults with atopic dermatitis. NCT01856764. https://clinicaltrials.gov/ct2/show/NCT01856764. Accessed February 14, 2019.
Feldman  SR, Krueger  GG.  Psoriasis assessment tools in clinical trials.  Ann Rheum Dis. 2005;64(suppl 2):ii65-ii68. doi:10.1136/ard.2004.031237PubMedGoogle ScholarCrossref
Chopra  R, Vakharia  PP, Sacotte  R,  et al.  Severity strata for Eczema Area and Severity Index (EASI), modified EASI, Scoring Atopic Dermatitis (SCORAD), objective SCORAD, Atopic Dermatitis Severity Index and body surface area in adolescents and adults with atopic dermatitis.  Br J Dermatol. 2017;177(5):1316-1321. doi:10.1111/bjd.15641PubMedGoogle ScholarCrossref
Yosipovitch  G, Gold  LF, Lebwohl  MG, Silverberg  JI, Tallman  AM, Zane  LT.  Early relief of pruritus in atopic dermatitis with crisaborole ointment, a non-steroidal, phosphodiesterase 4 inhibitor.  Acta Derm Venereol. 2018;98(5):484-489. doi:10.2340/00015555-2893PubMedGoogle ScholarCrossref
Ständer  S, Augustin  M, Reich  A,  et al; International Forum for the Study of Itch Special Interest Group Scoring Itch in Clinical Trials.  Pruritus assessment in clinical trials: consensus recommendations from the International Forum for the Study of Itch (IFSI) Special Interest Group Scoring Itch in Clinical Trials.  Acta Derm Venereol. 2013;93(5):509-514. doi:10.2340/00015555-1620PubMedGoogle ScholarCrossref
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