Department of Dermatology, Children's Hospital, Chongqing Medical University, Chongqing, China.
Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, China.
JAMA Dermatol. 2019 May 1;155(5):585-593. doi: 10.1001/jamadermatol.2019.0008.
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.
To evaluate the efficacy and safety of topical PDE4 inhibitors in mild to moderate AD.
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.
Only double-blind randomized clinical trials with topical PDE4 inhibitors vs topical vehicle treatment for patients with mild to moderate AD were included.
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.
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.
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.
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.
重要性：对于特应性皮炎（AD）患者，局部用药是主要治疗手段，但选择有限。磷酸二酯酶 4（PDE4）抑制剂是 AD 治疗的新候选药物。
目的：评估局部 PDE4 抑制剂在轻中度 AD 中的疗效和安全性。
数据来源：从 MEDLINE、Embase、Cochrane 对照试验注册库、中国医学数据库（万方、中国国家知识基础设施、中国生物医学文献数据库和中国科技期刊数据库）、ClinicalTrials.gov 和其他试验注册处检索到临床试验，检索时间截至 2018 年 8 月 15 日。未对语言进行限制。
研究选择：仅纳入了比较局部 PDE4 抑制剂与局部载体治疗轻中度 AD 患者的双盲随机临床试验。
数据提取和综合：两位审查员独立提取研究特征、干预措施细节和结局。使用随机效应模型进行荟萃分析。采用 Cochrane 协作偏倚风险评估工具评估偏倚风险。使用漏斗图和 Egger 检验评估发表偏倚。
主要结局和测量：目标病变评分的变化以标准化均数差（SMD）及其 95%置信区间（CI）表示。研究者评估的结局和安全性以 95%CI 的相对风险表示。
结果：共纳入 7 项研究，涉及 1869 例轻中度 AD 患者。总体而言，与局部载体对照相比，局部应用 PDE4 抑制剂可显著降低目标病变评分（SMD-0.40；95%CI，-0.61 至 -0.18；P<0.001），并显著提高研究者评估的皮肤清晰或几乎清晰的应答率（相对风险，1.50；95%CI，1.33-1.70；P<0.001）。治疗相关不良事件或因不良事件而需要停药的发生率无差异。亚组分析表明，在使用 PDE4 抑制剂治疗 14 天和 28 天后，目标病变评分显著降低。然而，这些有益效果仅在 PDE4 抑制剂克立硼罗和 AN2898 中显示（克立硼罗治疗 14 天：SMD-0.59；95%CI，-1.15 至 -0.02；P=0.04；AN2898 治疗 14 天：SMD-0.76；95%CI，-1.38 至 -0.13；P=0.02；克立硼罗治疗 28 天：SMD-0.86；95%CI，-1.44 至 -0.28；P=0.004；AN2898 治疗 28 天：SMD-0.68；95%CI，-1.30 至 -0.05；P=0.03）。各研究间异质性不显著。
结论：这项荟萃分析表明，局部 PDE4 抑制剂是治疗轻中度 AD 的安全有效方法。目前的证据支持将克立硼罗或 AN2898 作为轻中度 AD 维持或序贯治疗的选择。
