Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York.
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, New York; Department of Dermatology, University of Magna Graecia, Catanzaro, Italy.
J Am Acad Dermatol. 2023 Aug;89(2):283-292. doi: 10.1016/j.jaad.2023.02.064. Epub 2023 Apr 11.
Safe and effective long-term topical treatments for atopic dermatitis (AD) remain limited.
In this phase 2a, single-center, intrapatient, and vehicle-controlled study, we examine the mechanism of action of crisaborole 2% ointment, a topical nonsteroidal PDE4 (phosphodiesterase-4) inhibitor, in a proteomic analysis of 40 adults with mild to moderate AD and 20 healthy subjects.
Within the AD cohort, 2 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.
Compared to the vehicle, crisaborole significantly reversed dysregulation of the overall lesional proteome and of key markers and pathways (eg, Th2, Th17/Th22, and T-cell activation) associated with AD pathogenesis toward both nonlesional and normal skin. Significant clinical correlations were observed with markers associated with nociception and Th2, Th17, and neutrophilic activation.
Study limitations include predominance of white patients in the cohort, relatively short treatment time, and regimented administration of crisaborole.
Our results demonstrate crisaborole-induced normalization of the AD proteome toward a nonlesional molecular phenotype and further support topical PDE4 inhibition in the treatment of mild to moderate AD.
安全有效的长期局部治疗特应性皮炎（AD）仍然有限。
在这项 2a 期、单中心、患者内和对照药物的研究中，我们通过对 40 名轻度至中度 AD 成人和 20 名健康受试者的蛋白质组学分析，研究了 2%考尼索罗软膏（一种局部非甾体 PDE4（磷酸二酯酶-4）抑制剂）的作用机制。
在 AD 队列中，2 个靶病变以患者内（1:1）的方式随机接受双盲考尼索罗/载体，每天应用 2 次，持续 14 天。所有参与者在基线时采集生物标志物分析用的活检标本，然后 AD 患者在第 8 天（可选）和第 15 天仅采集活检标本。
与载体相比，考尼索罗显著逆转了 AD 发病机制相关的整体病变蛋白质组以及关键标志物和途径（如 Th2、Th17/Th22 和 T 细胞激活）的失调，使非病变和正常皮肤向正常状态恢复。与与伤害感受和 Th2、Th17 和嗜中性粒细胞激活相关的标志物观察到显著的临床相关性。
研究的局限性包括队列中以白人患者为主、治疗时间相对较短以及考尼索罗的规定给药。
我们的结果表明，考尼索罗诱导 AD 蛋白质组向非病变的分子表型正常化，并进一步支持局部 PDE4 抑制用于治疗轻度至中度 AD。
