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. 2019 Jan 15;20(1):10.
doi: 10.1186/s12931-019-0974-5.

Absence of early metabolic response assessed by 18F-FDG PET/CT after initiation of antifibrotic drugs in IPF patients

Benjamin Bondue  1 , Amélie Castiaux  2 , Gaetan Van Simaeys  2   3 , Céline Mathey  2 , Félicie Sherer  2   3 , Dominique Egrise  2   3 , Simon Lacroix  2   3 , François Huaux  4 , Gilles Doumont  3 , Serge Goldman  2   3
Affiliations

Absence of early metabolic response assessed by 18F-FDG PET/CT after initiation of antifibrotic drugs in IPF patients

Benjamin Bondue et al. Respir Res. .

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a progressive and irreversible respiratory failure. Non-invasive markers of disease activity are essential for prognosis and evaluation of early response to anti-fibrotic treatments.

Objectives: The aims of this study were to determine whether fluorodeoxyglucose ([18F]-FDG) lung uptake is reduced after initiation of pirfenidone or nintedanib and to assess its possible use as a prognostic factor.

Methods: [18F]-FDG PET/CT was performed in IPF patients and in a murine model of pulmonary fibrosis. PET/CTs were performed at day 8 and day 15 post-instillation of bleomycin in pirfenidone- or vehicule-treated mice. In IPF patients, PET-CT was performed before and 3 months after the initiation of pirfenidone or nintedanib.

Results: In bleomycin-treated mice, pirfenidone significantly reduced the [18F]-FDG uptake compared to vehicule-treated mice at day 15 (p < 0.001), whereas no difference was observed at day 8 after bleomycin administration. In IPF patients, [18F]-FDG lung uptake before and after 3 months of treatment by nintedanib (n = 11) or pirfenidone (n = 14) showed no significant difference regardless the antifibrotic treatment. Moreover, no difference was noticed between patients with progressive or non-progressive disease at one year of follow up.

Conclusions: Pirfenidone significantly reduces the lung [18F]-FDG uptake during the fibrotic phase in a mouse model of IPF. However, these preclinical data were not confirmed in IPF patients 3 months after the initiation of antifibrotic therapy. [18F]-FDG seems therefore not useful in clinical practice to assess the early response of IPF patients to nintedanib or pirfenidone.

Keywords: Biomarker; ILD; IPF; Idiopathic pulmonary fibrosis; Interstitial lung disease; Nintedanib; PET/CT; Pirfenidone.

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Conflict of interest statement

Ethics approval and consent to participate

Experiments in mice were approved by the local committee for animal welfare (CMMI).

For the human study, the protocol has been approved by the Erasme hospital Ethics Committee (ref. P2016/427). Written informed consent for participation in the study was obtained from all the patients.

Consent for publication

Not applicable.

Competing interests

B.B. received grants, consultancies and lecture fees from La Roche-Hoffmann and Boehringer Ingelheim. Other authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Pirfenidone reduces bleomycin-induced pulmonary fibrosis in mice. Groups of minimum five mice were used throughout these experiments. Mice were treated with either a saline sterile solution (control) or bleomycin (0.02 U) (Bleo). Bleomycin-treated mice orally received twice daily either 200 mg/kg/dose of pirfenidone resuspended in carboxymethylcellulose (Bleo + Pirf) or carboxymethylcellulose alone (Bleo + CMC). Saline-treated mice received carboxymethylcellulose (control). Mice were sacrificed at day 15 post-bleomycin administration for lymphocyte count in the BAL (a) and hydroxyproline measurement in the lungs (lung HPO) (b). Data are the mean ± SEM. Statistical analyses were performed by an ANOVA one-way test with Tukey’s test for comparisons between groups. **, p < 0.01; ***, p < 0.001
Fig. 2
Fig. 2
Pirfenidone reduces lung [18F]-FDG uptake during the fibrotic phase of the bleomycin-induced pulmonary fibrosis model. a Bleomycin (0.02 U)- and saline-treated mice orally treated with pirfenidone resuspended in carboxymethylcellulose (CMC) or CMC alone were used for in vivo imaging by [18F]-FDG PET/CT scan at day 8 and 15 after bleomycin instillation. Data shown corresponds to the lung SUVmean ± SEM and resulted from pooling of three Independent experiments. b Representative coronal sections obtained in bleomycin mice treated or not with pirfenidone at day 8 or 15 post instillation of bleomycin. Statistical analyses were performed by an ANOVA one-way test with Tukey’s test for comparisons between groups. *, p < 0.05; ***, p < 0.001
Fig. 3
Fig. 3
[18F]-FDG uptake changes before and 3 months after the initiation of antifibrotic drugs. a Different PET parameters were calculated (SUVmean, SUVmean corrected for the lung density - SUVmean-corr, SUVmax, metabolic lung volume -MLV, total lung glycolysis -TLG, target-to-background ratio -TBR) before and three months after the initiation of a treatment by pirfenidone or nintedanib. Data on graph correspond to the pooled results obtained with both antifibrotic drugs and consist of the median with whiskers corresponding to the percentile 10–90. b Individual changes in SUVmean-corr detailed for patients on pirfenidone (white boxes) and nintedanib (black squares). c The detailed changes in SUVmean-corr for patients on pirfenidone and nintedanib. Data on graph correspond to the median with whiskers corresponding to the percentile 10–90
Fig. 4
Fig. 4
Prognostic value of baseline [18F]-FDG and Δ[18F]-FDG lung uptake. a Baseline SUVmean corrected for the lung density (SUVmean-corr) and change in SUVmean-corr three months after the initiation of the antifibrotic drug between patients having a progressive or a non-progressive disease after one year of follow-up. b Correlation between the decline in FVC (absolute value or using the slope of the overall evolution at one year obtained by linear regression using least-squares method) and baseline SUVmean-corr or change in SUVmean-corr three months after the initiation of the antifibrotic drug
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