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Multicenter Study
. 2023 Dec 27;13(1):22977.
doi: 10.1038/s41598-023-49180-4.

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib

Masaki Okamoto  1   2 , Kiminori Fujimoto  3 , Takeshi Johkoh  4 , Atsushi Kawaguchi  5 , Hiroshi Mukae  6 , Noriho Sakamoto  6 , Takashi Ogura  7 , Satoshi Ikeda  7 , Yasuhiro Kondoh  8 , Yasuhiko Yamano  8 , Kosaku Komiya  9 , Kenji Umeki  10 , Hirotaka Nishikiori  11 , Yoshinori Tanino  12 , Toru Tsuda  13 , Naoki Arai  14 , Masamichi Komatsu  15 , Susumu Sakamoto  16 , Kazuhiro Yatera  17 , Yoshikazu Inoue  18 , Yasunari Miyazaki  19 , Seishu Hashimoto  20 , Yasuo Shimizu  21 , Hironao Hozumi  22 , Hiroshi Ohnishi  23 , Tomohiro Handa  24 , Noboru Hattori  25 , Tomoo Kishaba  26 , Motoyasu Kato  27 , Minoru Inomata  28 , Hiroshi Ishii  29 , Naoki Hamada  30 , Satoshi Konno  31 , Yoshiaki Zaizen  32 , Arata Azuma  33 , Takafumi Suda  22 , Kenji Izuhara  34 , Tomoaki Hoshino  32
Affiliations
Multicenter Study

A prospective cohort study of periostin as a serum biomarker in patients with idiopathic pulmonary fibrosis treated with nintedanib

Masaki Okamoto et al. Sci Rep. .

Abstract

This study investigated the utility of periostin, a matricellular protein, as a prognostic biomarker in patients with idiopathic pulmonary fibrosis (IPF) who received nintedanib. Monomeric and total periostin levels were measured by enzyme-linked immunosorbent assay in 87 eligible patients who participated in a multicenter prospective study. Forty-three antifibrotic drug-naive patients with IPF described in previous studies were set as historical controls. Monomeric and total periostin levels were not significantly associated with the change in forced vital capacity (FVC) or diffusing capacity of the lungs for carbon monoxide (DLCO) during any follow-up period. Higher monomeric and total periostin levels were independent risk factors for overall survival in the Cox proportional hazard model. In the analysis of nintedanib effectiveness, higher binarized monomeric periostin levels were associated with more favorable suppressive effects on decreased vital capacity (VC) and DLCO in the treatment group compared with historical controls. Higher binarized levels of total periostin were associated with more favorable suppressive effects on decreased DLCO but not VC. In conclusion, higher periostin levels were independently associated with survival and better therapeutic effectiveness in patients with IPF treated with nintedanib. Periostin assessments may contribute to determining therapeutic strategies for patients with IPF.

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Conflict of interest statement

Masaki Okamoto, Hiroshi Mukae, Yasunari Miyazaki, Tomohiro Handa, Naoki Hamada, and Tomoaki Hoshino received more than 1,000,000 JPY as research funding from Nippon Boehringer-Ingelheim, co., ltd. Kiminori Fujimoto received more than 1,000,000 JPY as research funding from Micron KK. Satoshi Ikeda received more than 1,000,000 JPY as research funding from Chugai pharmaceutical co., ltd. and AstraZeneca pharmaceuticals co., ltd. Kazuhiro Yatera received more than 1,000,000 JPY as research funding from FUJIFILM, co., ltd., Taiho pharmaceuticals co., ltd., GlaxoSmithKline K.K., Insmed Inc., Bayer pharmaceuticals co., ltd. Hirotaka Nishikiori received more than 1,000,000 JPY as research funding from Nippon Nippon Boehringer-Ingelheim, co., ltd. and M3, Inc., Tokyo. Yoshinori Tanino received more than 1,000,000 JPY as research funding from Nippon Boehringer-Ingelheim, co., ltd. and StemRIM Inc. Hironao Hozumi received more than 1,000,000 JPY as research funding from TERUMO LIFE SCIENCE FOUNDATION. Tomohiro Handa received more than 1,000,000 JPY as research funding from FUJIFILM, co., ltd. Hiroshi Ishii received more than 1,000,000 JPY as research funding from Shionogi pharmaceuticals co., ltd. Kenji Izuhara received more than 1,000,000 JPY as research funding from Shino test co., ltd., AstraZeneca pharmaceuticals co., ltd., and Torii Pharmaceutical co., ltd. Masaki Okamoto, Hiroshi Mukae, Noriho Sakamoto, Takashi Ogura, Yoshikazu Inoue, Yasunari Miyazaki, Motoyasu Kato, Hiroshi Ishii, Satoshi Konno, Arata Azuma and Takafumi Suda received more than 500,000 JPY as honoraria from Nippon Boehringer-Ingelheim, co., ltd. Takeshi Johkoh received more than 500,000 JPY as honoraria from Nippon Boehringer-Ingelheim, co., ltd., Kyorin Pharmaceutical co., ltd., and AstraZeneca pharmaceuticals co., ltd. Satoshi Ikeda received more than 500,000 JPY as honoraria from Ono Pharmaceutical co., ltd., Chugai pharmaceutical co., ltd., Pfizer Japan inc., AstraZeneca pharmaceuticals co., ltd., Bristol-Myers Squibb Company. Yasuhiro Kondoh and Yasuhiko Yamano received more than 500,000 JPY as honoraria from Nippon Boehringer-Ingelheim, co., ltd. and Bristol-Myers Squibb, co., ltd. Kosaku Komiya received more than 500,000 JPY as honoraria from Nippon Boehringer-Ingelheim, co., ltd. and Kyorin Pharmaceutical, co., ltd. Kazuhiro Yatera received more than 500,000 JPY as honoraria from Nippon Boehringer-Ingelheim, co., ltd., AstraZeneca pharmaceuticals co., ltd., GlaxoSmithKline K.K., Novartis Pharma, co., ltd., Kyorin Pharmaceutical, co., ltd. Toru Tsuda received more than 500,000 JPY as honoraria from AstraZeneca pharmaceuticals co., ltd. Hiroshi Ohnishi received more than 500,000 JPY as honoraria from Novartis Pharma, co., ltd. Noboru Hattori received more than 500,000 JPY as honoraria from Nippon Boehringer-Ingelheim, co., ltd., and AstraZeneca pharmaceuticals co., ltd. Takafumi Suda received more than 500,000 JPY as honoraria from Nippon Boehringer-Ingelheim, co., ltd. and AstraZeneca pharmaceuticals co., ltd. Takashi Ogura and Toru Tsuda received more than 500,000 JPY as manuscript fees from Nippon Boehringer-Ingelheim, co., ltd. Noriho Sakamoto, Yasunari Miyazaki, and Satoshi Konno received more than 1,000,000 JPY as donations from Nippon Boehringer-Ingelheim m, co., ltd. Kazuhiro Yatera received more than 1,000,000 JPY as donations from TEIJIN PHARMA co., ltd. and Taiho pharmaceuticals co., ltd. Kenji Izuhara received more than 1,000,000 JPY as donations from Shino test co., ltd. Tomohiro Handa belongs to an endowed department sponsored by TEIJIN PHARMA., co., ltd. Satoshi Konno belongs to an endowed department sponsored by Nippon Boehringer-Ingelheim m, co., ltd. Yoshikazu Inoue is a clinical trial advisor of Boehringer Ingelheim, Inc, Taiho Pharma, Kyorin Pharmaceutical co.ltd., Roche/Promedior co.ltd., Galapagos, CSL Behring, Vicore Pharma AB, Savara Inc. The enzyme-linked immunosorbent assay of periostin in the present study was performed free of charge by Shino-Test Co., Ltd. Other co-authors have no potential conflict of interest.

Figures

Figure 1
Figure 1
Study enrollment. IPF, idiopathic pulmonary fibrosis; MDD, multidisciplinary discussion; HRCT, high resolution computed tomography.
Figure 2
Figure 2
Comparisons of periostin levels between progressive and non-progressive patients after start of nintedanib. Serum monomeric and total periostin levels were compared between progressive and non-progressive participants after start of nintedanib. Monomeric (A) and total (B) periostin levels were compared between participants with and without a decrease in FVC by more than 5% over a 6 months period. Moreover, monomeric (C) and total (D) periostin levels were compared between participants with and without a decrease in FVC by more than 5% over a 12 months period. FVC, forced vital capacity. *P < 0.05 was considered to represent statistical significance.
Figure 3
Figure 3
Kaplan–Meier curves for overall survival. Survival curves for overall survival using the Kaplan–Meier Method. Variables significantly associated or tended to be associated with overall survival in univariate analysis of the Cox proportional hazards model including monomeric periostin (A), total periostin (B), DLCO (C), decreases in FVC (D) and DLCO (E) over 6 months period, and decreases in FVC (F) and DLCO (G) over 12 months period were analyzed using log-rank test. FVC, forced vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide. *P < 0.05 was considered to represent statistical significance.
Figure 4
Figure 4
Analysis of the associations between biomarker levels and nintedanib efficacy. As the historical control data, we used serum biomarker levels measured in 43 antifibrotic drug-naive patients with IPF who were selected from 60 patients who participated in previously published studies,. For evaluating the association between biomarker levels and efficacy of nintedanib, relative changes in VC and DLCO from baseline over 6 months were compared between the study participants (treatment group) and historical controls according to biomarker-high and -low groups. The median of each biomarker in the present study was set as the cut-off level. Statistical analysis for comparing two groups was performed by multiple regression analysis adjusted for age, VC, and DLCO at baseline. Changes in VC, and DLCO in the treatment group are shown by white spots on the black background bar, and those in the historical control group are shown by black spots on the white background bar. Comparisons of VC (A) and DLCO (B) in all patients in the treatment group and in historical controls are shown. The results of the comparison of decrease in VC are shown in (C) (monomeric periostin), (E) (total periostin), (G) (KL-6), (I) (SP-D), and (K) (LDH), and those of decrease in DLCO are shown in (D) (monomeric periostin), (F) (total periostin), (H) (KL-6), (J) (SP-D), and L (LDH). Data are expressed as the least squares mean ± standard error unless otherwise stated. LDH, lactate dehydrogenase; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein D; VC, vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide. *P < 0.05 was considered to represent statistical significance.
Figure 4
Figure 4
Analysis of the associations between biomarker levels and nintedanib efficacy. As the historical control data, we used serum biomarker levels measured in 43 antifibrotic drug-naive patients with IPF who were selected from 60 patients who participated in previously published studies,. For evaluating the association between biomarker levels and efficacy of nintedanib, relative changes in VC and DLCO from baseline over 6 months were compared between the study participants (treatment group) and historical controls according to biomarker-high and -low groups. The median of each biomarker in the present study was set as the cut-off level. Statistical analysis for comparing two groups was performed by multiple regression analysis adjusted for age, VC, and DLCO at baseline. Changes in VC, and DLCO in the treatment group are shown by white spots on the black background bar, and those in the historical control group are shown by black spots on the white background bar. Comparisons of VC (A) and DLCO (B) in all patients in the treatment group and in historical controls are shown. The results of the comparison of decrease in VC are shown in (C) (monomeric periostin), (E) (total periostin), (G) (KL-6), (I) (SP-D), and (K) (LDH), and those of decrease in DLCO are shown in (D) (monomeric periostin), (F) (total periostin), (H) (KL-6), (J) (SP-D), and L (LDH). Data are expressed as the least squares mean ± standard error unless otherwise stated. LDH, lactate dehydrogenase; KL-6, Krebs von den Lungen-6; SP-D, surfactant protein D; VC, vital capacity; DLCO, diffusing capacity of the lung for carbon monoxide. *P < 0.05 was considered to represent statistical significance.
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