优先抑制磷酸二酯酶作为调节系统性硬化关键通路的新策略。
完整摘要 · 中文译文
系统性硬化症（SSc）是一种复杂的自身免疫性疾病，以血管病变、免疫失调以及皮肤和内脏器官的进行性纤维化为特征。其高疾病负担和对生活质量的影响凸显了针对潜在致病机制而非仅仅治疗器官特异性症状的疗法需求。磷酸二酯酶，包括磷酸二酯酶4B（PDE4B），是对SSc发病机制至关重要的多种细胞类型的细胞功能和炎症反应的关键调节因子。鉴于PDE4B的广泛作用，靶向它可能带来超越器官特异性表现的获益并改善现有治疗。选择性PDE4B抑制代表了一种针对SSc的新颖治疗方法，与早期的泛PDE4抑制剂相比具有更好的亚型选择性。Nerandomilast优先抑制PDE4B（对PDE4B的选择性是对PDE4D的9倍），通过避免胃肠道不耐受等不良事件，可能较口服泛PDE4抑制剂改善耐受性。在SSc相关小鼠和细胞模型中的临床前研究结果表明，PDE4B抑制可调节炎症细胞因子分泌、平滑肌细胞张力、内皮和上皮屏障完整性以及氧化应激下的细胞外基质合成；这提示nerandomilast可能减轻免疫失调、纤维化，并可能影响血管病变。两项关键性III期试验评价了nerandomilast在特发性肺纤维化（FIBRONEER™-IPF；NCT05321069）和进行性肺纤维化（FIBRONEER™-ILD；NCT05321082）患者中的疗效，后者纳入了 d 系统性硬化症相关间质性肺病（SSc-ILD）患者。正在进行的 CONQUEST 试验（NCT06195072）正在研究包括 nerandomilast 在内的多种药物在早期活动性 SSc-ILD 患者中的疗效和安全性。本文观点强调了在 SSc 治疗中靶向 PDE4B 的依据，并探讨了迄今在 SSc 中的临床前发现以及 SSc-ILD 中的临床发现。
完整摘要 · 英文原文
Systemic sclerosis (SSc) is a complex autoimmune disease marked by vasculopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. The high disease burden and impact on quality of life highlight the need for therapies that target underlying pathogenic mechanisms rather than merely treating organ-specific symptoms. Phosphodiesterases, including phosphodiesterase 4B (PDE4B), are key regulators of cellular function and inflammatory responses of several cell types central to SSc pathogenesis. Given PDE4B's broad effects, targeting it may provide benefits beyond organ-specific manifestations and improve current care. Selective PDE4B inhibition represents a novel therapeutic approach for SSc, with improved subtype selectivity compared with earlier pan-PDE4 inhibitors. Nerandomilast preferentially inhibits PDE4B (ninefold over PDE4D), potentially improving tolerability versus oral pan-PDE4 inhibitors by avoiding adverse events such as gastrointestinal intolerance. Preclinical findings in SSc-relevant mouse and cell models show that PDE4B inhibition modulates inflammatory cytokine secretion, smooth muscle cell tension, endothelial and epithelial barrier integrity, and extracellular matrix synthesis under oxidative stress; this suggests nerandomilast could attenuate immune dysregulation, fibrosis, and potentially impact vasculopathy. Two pivotal Phase III trials evaluated nerandomilast in patients with idiopathic pulmonary fibrosis (FIBRONEER™-IPF; NCT05321069) and progressive pulmonary fibrosis (FIBRONEER™-ILD; NCT05321082), the latter of which included patients with SSc-associated interstitial lung disease (SSc-ILD). The ongoing CONQUEST trial (NCT06195072) is investigating the efficacy and safety of various drugs, including nerandomilast, in patients with early active SSc-ILD. This perspective highlights the rationale for targeting PDE4B in SSc therapy and explores preclinical findings in SSc and clinical findings in SSc-ILD to date.