Psoriasis and psoriatic arthritis are common clinical conditions that negatively impact health-related quality of life and are linked to serious medical comorbidities. Disease mechanisms involve local and systemic chronic inflammatory processes. Available biologic therapies specifically target single inflammatory mediators, such as tumor necrosis factor-α (TNF-α), in the context of a larger inflammatory signaling cascade. To interrupt this pathological cascade earlier in the response or further upstream, and return pro-inflammatory and anti-inflammatory signaling to a homeostatic balance, the use of a phosphodiesterase4 (PDE4) inhibitor has been explored. PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messenger that controls a network of pro-inflammatory and anti-inflammatory mediators. With PDE4 inhibition, and the resulting increases in cAMP levels in immune and non-immune cell types, expression of a network of pro-inflammatory and anti-inflammatory mediators can be modulated. Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-α, and interleukin (IL)-23 and increases IL-10. In phase II studies of subjects with psoriasis and psoriatic arthritis, apremilast reversed features of the inflammatory pathophysiology in skin and joints and significantly reduces clinical symptoms. The use of an oral targeted PDE4 inhibitor for chronic inflammatory diseases, like psoriasis and psoriatic arthritis, represents a novel treatment approach that does not target any single mediator, but rather focuses on restoring a balance of pro-inflammatory and anti-inflammatory signals.

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Apremilast作用机理及其在牛皮癣和牛皮癣关节炎中的应用

牛皮癣和牛皮癣关节炎是对健康相关的生活质量产生负面影响的常见临床疾病，并与严重的合并症相关。疾病机制涉及局部和全身性慢性炎症过程。在较大的炎症信号级联反应中，可用的生物疗法专门针对单个炎症介质，例如肿瘤坏死因子-α（TNF-α）。为了在应答中或更早地中断该病理级联，并使促炎和抗炎信号恢复到体内平衡，已经研究了磷酸二酯酶4（PDE4）抑制剂的使用。PDE4是负责环磷酸一腺苷（cAMP）水解的主要酶类，控制促炎和抗炎介质网络的细胞内第二信使。有了PDE4抑制作用，免疫和非免疫细胞类型中cAMP的水平增加，可以调节促炎和抗炎介质的网络表达。普雷米司特是一种口服靶向性PDE4抑制剂，可调节多种与牛皮癣和牛皮癣关节炎有关的炎性介质，包括诱导型一氧化氮合酶，TNF-α和白介素（IL）-23的表达降低并增加IL-10 。在对牛皮癣和牛皮癣关节炎的受试者进行的II期研究中，前列地斯特逆转了皮肤和关节的炎症病理生理学特征，并显着减轻了临床症状。