Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial
Crisaborole and atopic dermatitis skin biomarkers: An intrapatient randomized trial
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DOI：
10.1016/j.jaci.2019.06.047
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发表时间：
2019-11-01
影响因子：
14.2
通讯作者：
Guttman-Yassky, Emma
中科院分区：
文献类型：
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作者：
Bissonnette, Robert;Pavel, Ana B.;Guttman-Yassky, Emma
背景：2%克立沙硼软膏是一种非甾体类磷酸二酯酶4抑制剂，用于治疗轻中度特应性皮炎（AD）。阿沙硼洛的作用机制及其对疾病严重程度的损伤测量的影响尚未明确。目的：本项2a期、单中心、载体对照、患者内研究旨在通过评价轻度至中度AD成人（n = 40）的临床疗效和皮肤生物标志物的变化来进一步表征阿沙硼洛的作用机制。以患者内（14）方式将两个靶病灶随机分配至双盲阿托硼/溶媒组，每日两次给药，持续14天。然后，患者在所有受影响的区域应用阿托硼洛（开放标签）28天。在基线、第8天（可选）和第15天收集穿刺活检标本用于生物标志物分析。结果：与赋形剂相比，克瑞沙硼治疗导致损伤体征/症状的早期改善，早在第一次应用后24小时观察到瘙痒（瘙痒数字评定量表）的改善。在第8天，与媒介物相比，克瑞沙硼治疗的病灶显示病灶转录组谱从基线的显著百分比改善（91.15%对36.02%，P < 10（-15）），并持续至第15天（92.90%对49.59%，P < 10（-15））。与媒介物相比，克瑞沙硼显著调节关键AD生物标志物，包括T（H）2和T（H）17/T（H）22途径和表皮增生/增殖。分子配置文件和表皮病理正常化对nonlesional皮肤和相关的临床变化病变的严重程度和barrier function.Conclusion：Crisaborole逆转皮肤炎症和屏障功能的生物标志物配置文件，与相关的改善临床疗效的措施，突出了治疗效用的目标磷酸二酯酶4在AD患者。
Background: Crisaborole ointment 2% is a nonsteroidal phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate atopic dermatitis (AD). The mechanism of action of crisaborole and its effects on lesional measures of disease severity are not yet well defined.Objective: This phase 2a, single-center, vehicle-controlled, intrapatient study was designed to further characterize the mechanism of action of crisaborole through evaluation of clinical efficacy and changes in skin biomarkers in adults (n = 40) with mild-to-moderate AD.Methods: Two target lesions were randomized in an intrapatient (14) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Patients then applied crisaborole (open-label) to all affected areas for 28 days. Punch biopsy specimens were collected for biomarker analysis at baseline, day 8 (optional), and day 15.Results: Crisaborole treatment resulted in early improvement in lesional signs/symptoms versus vehicle, with improvement in pruritus (pruritus numeric rating scale) observed as early as 24 hours after the first application. Crisaborole-treated lesions showed significant percentage improvement from baseline in lesional transcriptomic profile compared with vehicle at day 8 (91.15% vs 36.02%, P < 10(-15)) that was sustained until day 15 (92.90% vs 49.59%, P < 10(-15)). Crisaborole significantly modulated key AD biomarkers versus vehicle, including T(H)2 and T(H)17/T(H)22 pathways and epidermal hyperplasia/proliferation. Molecular profiles and epidermal pathology normalized toward nonlesional skin and correlated with clinical changes in lesion severity and barrier function.Conclusion: Crisaborole reversed biomarker profiles of skin inflammation and barrier function, with associated improvements in clinical efficacy measures, highlighting the therapeutic utility of targeting phosphodiesterase 4 in patients with AD.