TY - JOUR T1 - Analysis of real-world data and a mouse model indicates that pirfenidone causes pellagra JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00245-2022 SP - 00245-2022 AU - Koji Kuronuma AU - Natsumi Susai AU - Tomohiro Kuroita AU - Hiroki Yamamoto AU - Takeshi Yoshioka AU - Shuji Kaneko AU - Hirofumi Chiba Y1 - 2022/01/01 UR - http://openres.ersjournals.com/content/early/2022/07/22/23120541.00245-2022.abstract N2 - Background 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.Methods Using the results of real-world data analysis from the 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 by PFD and those treated without PFD.Results 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 N-methyltransferase. Higher nicotinamide N-methyltransferase substrate responses were observed in urine from patients and mice with PFD than in those without PFD.Conclusions 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.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.Conflict of interest: Tomohiro Kuroita, Natsumi Susai, and Takeshi Yoshioka are employees of Shionogi & Co., Ltd. Other authors declare no competing interests. ER -