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

Abstract

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.

Figure 1.. Flowchart of the Identification, Inclusion, and Exclusion of Studies

Figure 2.. Meta-analysis of the Association of Phosphodiesterase 4 (PDE4) Inhibitors vs Topical Control Vehicle With Change From Baseline in Target Lesion Score by Treatment Duration

Results based on inverse-variance random-effects meta-analyses. SMD indicates standardized mean difference.

Figure 3.. Meta-analysis of the Association of Phosphodiesterase 4 (PDE4) Inhibitors vs Topical Control Vehicle With Investigators’ Assessment of Clear or Almost Clear Skin by Treatment Duration

Results based on Mantel-Haenszel random-effects meta-analyses.