Crisaborole reverses dysregulation of the mild to moderate atopic dermatitis proteome towards nonlesional and normal skin

Background: Safe and effective long-term topical treatments for atopic dermatitis (AD) remain limited.
Objective: In this phase 2a, single-center, intrapatient, vehicle-controlled study, we examine the mechanism of action of crisaborole 2% ointment, a topical nonsteroidal PDE4 inhibitor, in a proteomic analysis of 40 adults with mild-to-moderate AD and 20 healthy subjects.
Methods: Within the AD cohort, two target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Punch biopsy specimens were collected for biomarker analysis at baseline from all participants, then from AD patients only at day 8 (optional) and day 15.
Results: Compared to the vehicle, crisaborole significantly reversed dysregulation of the overall lesional proteome and of key markers and pathways (e.g. Th2, Th17/Th22, T-cell activation) associated with AD pathogenesis towards both nonlesional and normal skin. Significant clinical correlations were observed with markers associated with nociception and Th2, Th17, and neutrophilic activation.
Limitations: Study limitations include predominance of white patients in the cohort, relatively short treatment time, and regimented administration of crisaborole.
Conclusion: Our results demonstrate crisaborole-induced normalization of the AD proteome towards a non-lesional molecular phenotype and further support topical PDE4 inhibition in the treatment of mild-to-moderate AD.

背景：针对特应性皮炎（AD）的安全有效长期局部治疗方案仍显不足。目标：在本项2a期、单中心、受试者内比较研究之中，我们通过蛋白质组学分析，考察了2%克索布洛尔乳膏，一种局部非甾体PDE4抑制剂的作用机制，该分析针对40名患有轻度至中度AD的成年人和20名健康受试者进行。方法：在AD组别中，两个目标皮损以受试者内（1:1）随机方式接受每日两次双盲克索布洛尔/赋形剂治疗，持续14天。所有参与者均在基线时收集活检标本进行生物标志物分析，AD患者仅在第八天（可选）和第十五天进行。结果：与赋形剂相比，克索布洛尔显著逆转了AD整体皮损蛋白质组以及与AD发病机制相关的关键标记物和通路（例如Th2、Th17/Th22、T细胞活化）的失调，并趋向于非皮损和正常皮肤。观察到与痛觉、Th2、Th17和中性粒细胞活化相关的标记物与临床有显著相关性。局限性：本研究局限性包括队列中白人患者占多数、治疗时间相对较短以及克索布洛尔的规范化给药。结论：我们的结果表明，克索布洛尔导致AD蛋白质组向非皮损分子表型正常化，进一步支持了局部PDE4抑制剂在治疗轻度至中度AD中的应用。