Monocytes play a critical role in the inflammation associated with psoriasis, and their abnormalities have been reported as biomarkers of cardiovascular event risk, a psoriasis comorbidity. Monocytic cells in chronic inflammatory disorders express elevated levels of cAMP phosphodiesterase. Restoring cAMP levels using the oral cAMP phosphodiesterase-4 inhibitor, apremilast, improves clinical outcomes for a subset of patients with psoriasis. We asked whether aberrant monocyte subsets or transcriptomic pathways can function as biomarkers of psoriasis endotypes that can predict enhanced clinical responses to cAMP phosphodiesterase inhibition. A 16-week open-label study of 22 patients with monocyte flow cytometric and transcriptomic analysis was performed. Subjects with elevated hyperadhesive monocyte doublets at baseline were more likely to be responders to apremilast ( < .0001); 82% of subjects with elevated hyperadhesive monocyte doublets achieved 50% reduction in PASI compared with 46% in those without elevated doublets. We observed a significant reduction in hyperadhesive monocyte-containing doublets and monocyte–platelet aggregates, suggesting an effect of apremilast on the adhesiveness of blood monocytes during chronic inflammation. Monocyte differentially expressed gene transcripts predictive of clinical response uncovered pharmacoendotypes with distinct patterns of nucleotide metabolism, energetics, and differentiation. Further study to understand the basis of drug responsiveness and to develop an apremilast psoriasis treatment algorithm using monocyte-refined gene expression is required to validate and become practical in clinical use, offering patients a test that personalizes their likelihood of clinical response.

中文翻译：

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循环单核细胞对接受阿普斯特治疗的中重度斑块型银屑病受试者具有预测性和反应性

单核细胞在与银屑病相关的炎症中发挥着关键作用，其异常已被报道为心血管事件风险（一种银屑病合并症）的生物标志物。慢性炎症性疾病中的单核细胞表达 cAMP 磷酸二酯酶水平升高。使用口服 cAMP 磷酸二酯酶 4 抑制剂阿普斯特恢复 cAMP 水平可改善部分银屑病患者的临床结果。我们询问异常的单核细胞亚群或转录组通路是否可以作为银屑病内型的生物标志物，从而预测对 cAMP 磷酸二酯酶抑制的临床反应增强。对 22 名患者进行了为期 16 周的开放标签研究，进行了单核细胞流式细胞术和转录组分析。基线时单核细胞过度粘附升高的受试者更有可能对阿普斯特有反应（<.0001）； 82% 具有升高的高粘附性单核细胞双联体的受试者的 PASI 降低了 50%，而没有升高的双联体的受试者的 PASI 降低了 46%。我们观察到含有高粘附性单核细胞的双联体和单核细胞-血小板聚集体显着减少，表明阿普斯特对慢性炎症期间血液单核细胞的粘附性有影响。预测临床反应的单核细胞差异表达基因转录本揭示了具有不同核苷酸代谢、能量学和分化模式的药物内型。需要进一步研究以了解药物反应性的基础并开发使用单核细胞精炼基因表达的阿普斯特银屑病治疗算法，以验证并在临床使用中实用，为患者提供个性化临床反应可能性的测试。