Kuronuma Koji, Susai Natsumi, Kuroita Tomohiro, Yamamoto Hiroki, Yoshioka Takeshi, Kaneko Shuji, Chiba Hirofumi
Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan.
These authors contributed equally to first authorship.
ERJ Open Res. 2022 Oct 24;8(4). doi: 10.1183/23120541.00245-2022. eCollection 2022 Oct.
Pirfenidone (PFD) is widely used in patients with idiopathic pulmonary fibrosis (IPF) and its adverse effects, such as nausea and photosensitivity, are well known. Many patients with IPF have reduced doses or even cessation of PFD because of its side-effects. No solutions have been found for these side-effects because the current mechanistic insights are insufficient.
Using the results of real-world data analysis from the US Food and Drug Administration Adverse Events Reporting System, we hypothesised that PFD-related symptoms may be similar to pellagra. Reverse translational experiments using female BALB/c mice were performed to validate and estimate this hypothesis. Niacin and its metabolite responses were compared between patients with IPF treated with PFD and those treated without PFD.
The pellagra hypothesis was translated from real-world data analysis. Pharmacological and comprehensive genetic investigations showed that PFD caused pellagra-related nausea and photosensitivity in a mouse model, which may have been mediated by the actions of nicotinamide methyltransferase (NNMT). Higher NNMT substrate responses were observed in urine from patients and mice with PFD than in those without PFD.
PFD may cause pellagra or pellagra-like symptoms such as photosensitivity. Further studies are required to investigate whether niacin prevents pellagra-like symptoms caused by PFD in patients with IPF.
吡非尼酮（PFD）广泛应用于特发性肺纤维化（IPF）患者，其不良反应如恶心和光敏反应广为人知。许多IPF患者因副作用而减少PFD剂量甚至停药。由于目前对其作用机制的认识不足，尚未找到解决这些副作用的方法。
利用美国食品药品监督管理局不良事件报告系统的真实世界数据分析结果，我们推测PFD相关症状可能与糙皮病相似。使用雌性BALB/c小鼠进行反向转化实验以验证和评估这一假设。比较了接受PFD治疗的IPF患者和未接受PFD治疗的患者的烟酸及其代谢物反应。
糙皮病假说源自真实世界数据分析。药理学和综合基因研究表明，PFD在小鼠模型中引起糙皮病相关的恶心和光敏反应，这可能是由烟酰胺甲基转移酶（NNMT）的作用介导的。与未使用PFD的患者和小鼠相比，使用PFD的患者和小鼠尿液中观察到更高的NNMT底物反应。
PFD可能导致糙皮病或类似糙皮病的症状，如光敏反应。需要进一步研究来调查烟酸是否能预防IPF患者中由PFD引起的类似糙皮病的症状。
