Aringer Martin, Distler Oliver, Hoffmann-Vold Anna-Maria, Kuwana Masataka, Prosch Helmut, Volkmann Elizabeth R
University Medical Center and Faculty of Medicine, TU Dresden, Dresden, Germany
Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
RMD Open. 2024 Dec 23;10(4):e004704. doi: 10.1136/rmdopen-2024-004704.
Interstitial lung disease (ILD) associated with rheumatoid arthritis or with connective tissue diseases such as systemic sclerosis can be collectively named systemic autoimmune rheumatic disease-associated ILDs (SARD-ILDs) or rheumatic musculoskeletal disorder-associated ILDs. SARD-ILDs result in substantial morbidity and mortality, and there is a high medical need for effective therapies that target both fibrotic and inflammatory pathways in SARD-ILD. Phosphodiesterase 4 (PDE4) hydrolyses cyclic AMP, which regulates multiple pathways involved in inflammatory processes. PDE4 is overexpressed in peripheral blood monocytes from patients with inflammatory diseases. However, clinical data on pan-PDE4 inhibition in fibrotic conditions are lacking. The PDE4B subtype is highly expressed in the brain, lungs, heart, skeletal muscle and immune cells. As such, inhibition of PDE4B may be a novel approach for fibrosing ILDs such as idiopathic pulmonary fibrosis (IPF) and SARD-ILD. Preclinical data for PDE4B inhibition have provided initial evidence of both anti-inflammatory and antifibrotic activity, with reduced potential for gastrointestinal toxicity compared with pan-PDE4 inhibitors. In a proof-of-concept phase II trial in patients with IPF, nerandomilast (BI 1015550), the only PDE4B inhibitor currently in clinical development, prevented a decline in lung function over 12 weeks compared with placebo. The potential clinical benefit of PDE4B inhibition is now being investigated in the phase III setting, with two trials evaluating nerandomilast in patients with IPF (FIBRONEER-IPF) or with progressive pulmonary fibrosis other than IPF (FIBRONEER-ILD). Here, we review the preclinical and clinical data that provide rationale for PDE4B inhibition as a treatment strategy in patients with SARD-ILD.
与类风湿关节炎或系统性硬化症等结缔组织病相关的间质性肺病（ILD）可统称为系统性自身免疫性风湿病相关ILD（SARD - ILD）或风湿性肌肉骨骼疾病相关ILD。SARD - ILD会导致严重的发病和死亡，因此迫切需要针对SARD - ILD中纤维化和炎症途径的有效治疗方法。磷酸二酯酶4（PDE4）可水解环磷酸腺苷（cAMP），而环磷酸腺苷调节炎症过程中涉及的多种途径。PDE4在炎症性疾病患者的外周血单核细胞中过度表达。然而，关于在纤维化疾病中抑制泛PDE4的临床数据尚缺乏。PDE4B亚型在脑、肺、心脏、骨骼肌和免疫细胞中高度表达。因此，抑制PDE4B可能是治疗特发性肺纤维化（IPF）和SARD - ILD等纤维化ILD的新方法。抑制PDE4B的临床前数据已提供抗炎和抗纤维化活性的初步证据，与泛PDE4抑制剂相比，胃肠道毒性潜力降低。在一项针对IPF患者的概念验证II期试验中，目前唯一处于临床开发阶段的PDE4B抑制剂奈拉米司特（BI 1015550）与安慰剂相比，在12周内预防了肺功能下降。目前正在III期试验中研究抑制PDE4B的潜在临床益处，有两项试验在评估奈拉米司特治疗IPF患者（FIBRONEER - IPF）或非IPF的进行性肺纤维化患者（FIBRONEER - ILD）的疗效。在此，我们综述了临床前和临床数据，这些数据为抑制PDE4B作为SARD - ILD患者的治疗策略提供了理论依据。
