Clinical Molecular Imaging of Pulmonary CXCR4 Expression to Predict Outcome of Pirfenidone Treatment in Idiopathic Pulmonary Fibrosis

Abstract

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive disease for which two antifibrotic drugs recently were approved. However, an unmet need exists to predict responses to antifibrotic treatment, such as pirfenidone. Recent data suggest that upregulated expression of CXCR4 is indicative of outcomes in IPF.Research QuestionCan quantitative, molecular imaging of pulmonary CXCR4 expression as a biomarker for disease activity predict response to the targeted treatment pirfenidone and prognosis in patients with IPF?Study Design and MethodsCXCR4 expression was analyzed by immunohistochemistry examination of lung tissues and reverse-transcriptase polymerase chain reaction analysis of BAL. PET-CT scanning with the specific CXCR4 ligand 68Ga-pentixafor was performed in 28 IPF patients and compared with baseline clinical characteristics. In 16 patients, a follow-up scan was obtained 6 to 12 weeks after initiation of treatment with pirfenidone. Patients were followed up in our outpatient clinic for ≥ 12 months.ResultsImmunohistochemistry analysis showed high CXCR4 staining of epithelial cells and macrophages in areas with vast fibrotic remodeling. Targeted PET scanning revealed CXCR4 upregulation in fibrotic areas of the lungs, particularly in zones with subpleural honeycombing. Baseline CXCR4 signal demonstrated a significant correlation with Gender Age Physiology stage (r = 0.44; P = .02) and with high-resolution CT scan score (r = 0.38; P = .04). Early changes in CXCR4 signal after initiation of pirfenidone treatment correlated with the long-term course of FVC after 12 months (r = −0.75; P = .0008). Moreover, patients with a high pulmonary CXCR4 signal on follow-up PET scan after 6 weeks into treatment demonstrated a statistically significant worse outcome at 12 months (P = .002). In multiple regression analysis, pulmonary CXCR4 signal on follow-up PET scan emerged as the only independent predictor of long-term outcome (P = .0226).InterpretationCXCR4-targeted PET imaging identified disease activity and predicted outcome of IPF patients treated with pirfenidone. It may serve as a future biomarker for personalized guidance of antifibrotic treatment. Idiopathic pulmonary fibrosis (IPF) is a progressive disease for which two antifibrotic drugs recently were approved. However, an unmet need exists to predict responses to antifibrotic treatment, such as pirfenidone. Recent data suggest that upregulated expression of CXCR4 is indicative of outcomes in IPF. Can quantitative, molecular imaging of pulmonary CXCR4 expression as a biomarker for disease activity predict response to the targeted treatment pirfenidone and prognosis in patients with IPF? CXCR4 expression was analyzed by immunohistochemistry examination of lung tissues and reverse-transcriptase polymerase chain reaction analysis of BAL. PET-CT scanning with the specific CXCR4 ligand 68Ga-pentixafor was performed in 28 IPF patients and compared with baseline clinical characteristics. In 16 patients, a follow-up scan was obtained 6 to 12 weeks after initiation of treatment with pirfenidone. Patients were followed up in our outpatient clinic for ≥ 12 months. Immunohistochemistry analysis showed high CXCR4 staining of epithelial cells and macrophages in areas with vast fibrotic remodeling. Targeted PET scanning revealed CXCR4 upregulation in fibrotic areas of the lungs, particularly in zones with subpleural honeycombing. Baseline CXCR4 signal demonstrated a significant correlation with Gender Age Physiology stage (r = 0.44; P = .02) and with high-resolution CT scan score (r = 0.38; P = .04). Early changes in CXCR4 signal after initiation of pirfenidone treatment correlated with the long-term course of FVC after 12 months (r = −0.75; P = .0008). Moreover, patients with a high pulmonary CXCR4 signal on follow-up PET scan after 6 weeks into treatment demonstrated a statistically significant worse outcome at 12 months (P = .002). In multiple regression analysis, pulmonary CXCR4 signal on follow-up PET scan emerged as the only independent predictor of long-term outcome (P = .0226). CXCR4-targeted PET imaging identified disease activity and predicted outcome of IPF patients treated with pirfenidone. It may serve as a future biomarker for personalized guidance of antifibrotic treatment. Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by progressive respiratory failure, resulting in a median survival of less than 3 years after diagnosis in untreated patients.1King Jr., T.E. Pardo A. Selman M. Idiopathic pulmonary fibrosis.Lancet. 2011; 378: 1949-1961Abstract Full Text Full Text PDF PubMed Scopus (1166) Google Scholar, 2Raghu G. Collard H.R. Egan J.J. et al.An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management.Am J Respir Crit Care Med. 2011; 183: 788-824Crossref PubMed Scopus (4813) Google Scholar, 3Lederer D.J. Martinez F.J. Idiopathic pulmonary fibrosis.N Engl J Med. 2018; 379: 797-798PubMed Google Scholar However, interindividual outcome shows great variability. Recently, two antifibrotic drugs, pirfenidone and nintedanib, have been approved for treatment of IPF.4King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2087) Google Scholar,5Richeldi L. du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (2304) Google Scholar For both drugs, it has been demonstrated clearly that they attenuate the mean rate of FVC decline over a 12-month period in patients with IPF.4King Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2087) Google Scholar,5Richeldi L. du Bois R.M. Raghu G. et al.Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2071-2082Crossref PubMed Scopus (2304) Google Scholar Some patients show stable or even improved FVC values after 12 months of treatment, whereas others deteriorate rapidly despite antifibrotic treatment.1King Jr., T.E. Pardo A. Selman M. Idiopathic pulmonary fibrosis.Lancet. 2011; 378: 1949-1961Abstract Full Text Full Text PDF PubMed Scopus (1166) Google Scholar,3Lederer D.J. Martinez F.J. Idiopathic pulmonary fibrosis.N Engl J Med. 2018; 379: 797-798PubMed Google Scholar Although FVC is a well-accepted primary end point in clinical trials, it needs to be monitored for a 12-month period to draw statistically significantly conclusions. Currently, no markers are available that allow the prediction of long-term response to any of the approved antifibrotic treatments as soon as treatment is started or as treatment progresses. Recently, the role of CXCR4 and its ligand CXCL12 (also known as SDF-1) in organ fibrosis has been highlighted.6Yuan A. Lee Y. Choi U. Moeckel G. Karihaloo A. Chemokine to fibrosis multiple J PubMed Scopus Google Scholar CXCR4 has a role in on such as and of cells as as A. and 2011; PubMed Scopus Google a in the cells and PubMed Scopus Google Scholar CXCR4 is in and a in the cells and PubMed Scopus Google Scholar have CXCR4 expression of macrophages and have the role of CXCR4 in of cells to L. et of in the of cells that have in response to the PubMed Scopus Google Scholar, et macrophages after PubMed Scopus Google Scholar, M. et CXCL12 into macrophages and cells of PubMed Scopus Google Scholar CXCR4 epithelial of epithelial of cells and a in the cells and PubMed Scopus Google A. et are of pulmonary disease a Full Text Full Text PDF PubMed Scopus Google Scholar have and of the and CXCR4 A. Lee Y. Choi U. Moeckel G. Karihaloo A. Chemokine to fibrosis multiple J PubMed Scopus Google L. et of in the of cells that have in response to the PubMed Scopus Google W.Z. and of cells by CXCR4 and 2014; PubMed Scopus Google et of the a and to PubMed Scopus Google Scholar In is to be the fibrosis and to be to disease Jr., T.E. Pardo A. Selman M. Idiopathic pulmonary fibrosis.Lancet. 2011; 378: 1949-1961Abstract Full Text Full Text PDF PubMed Scopus (1166) Google Scholar,3Lederer D.J. Martinez F.J. Idiopathic pulmonary fibrosis.N Engl J Med. 2018; 379: 797-798PubMed Google et of the of by of and expression of and in idiopathic pulmonary PubMed Scopus Google M. T.E. Pardo A. Idiopathic pulmonary fibrosis: and its and for Med. PubMed Scopus Google Scholar it has been to of pulmonary by data that CXCR4 expression of cells is indicative of in A. et expression is indicative of outcome and in idiopathic pulmonary J Respir Crit Care Med. PubMed Scopus Google Scholar molecular imaging of CXCR4 expression in IPF as a biomarker for disease activity and For a specific which recently was for clinical PET imaging of CXCR4 in and S. et molecular imaging of CXCR4 expression in patients with multiple Med. PubMed Scopus Google Scholar, A. et imaging of the CXCR4 after PubMed Scopus Google Scholar, et of CXCR4 expression in and J 2018; PubMed Scopus Google Scholar Immunohistochemistry analysis for CXCR4 was obtained the lung of IPF lung and as recently an CXCR4 A. et expression is indicative of outcome and in idiopathic pulmonary J Respir Crit Care Med. PubMed Scopus Google U. et and of 2011; PubMed Scopus Google Scholar data for CXCR4 expression of cells were obtained a recently of patients with IPF and A. et expression is indicative of outcome and in idiopathic pulmonary J Respir Crit Care Med. 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In multiple regression analysis, pulmonary CXCR4 signal at the follow-up PET scan emerged as the only independent predictor of long-term outcome P = of of PET to follow-up PET to at the follow-up PET to to at PET to at PET to the follow-up PET to to the follow-up PET to to in pulmonary to to in pulmonary to to values in = = mean in a P values in = = mean Recently, demonstrated that high expression of CXCR4 is upregulated in IPF and with A. et expression is indicative of outcome and in idiopathic pulmonary J Respir Crit Care Med. PubMed Scopus Google Scholar that CXCR4 is in and epithelial cells in IPF and is upregulated by clinical molecular imaging for the in of and CXCR4 expression in IPF. CXCR4 expression was in the areas of fibrotic at the subpleural and areas of which was by CXCR4 immunohistochemistry In a of 16 patients treated with demonstrated that both high CXCR4 expression on the follow-up PET scan and changes in CXCR4 signal predicted outcomes after 12 months. Immunohistochemistry for CXCR4 expression revealed CXCR4 expression in IPF tissues compared with data CXCR4 expression was high in and epithelial cells in the lung epithelial cells and It is of that our immunohistochemistry data clearly that macrophages high of CXCR4 in IPF have demonstrated that CXCR4 is by macrophages to and that an in of macrophages is by 68Ga-pentixafor PET L. et of in the of cells that have in response to the PubMed Scopus Google A. et imaging of the CXCR4 after PubMed Scopus Google M. 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PubMed Scopus Google Scholar it that 68Ga-pentixafor PET macrophages and epithelial cells in IPF lungs, both recently to be with disease M. et cells disease in idiopathic pulmonary Respir PubMed Scopus Google Scholar, Y. et with disease in idiopathic pulmonary Med. 2014; Scholar, S. J.J. of cells and in have in idiopathic pulmonary 2018; PubMed Scopus Google Scholar even that CXCR4 expression is to L. et of in the of cells that have in response to the PubMed Scopus Google W.Z. and of cells by CXCR4 and 2014; PubMed Scopus Google et of the a and to PubMed Scopus Google Scholar is to be the of fibrosis and particularly of Jr., T.E. Pardo A. Selman M. Idiopathic pulmonary fibrosis.Lancet. 2011; 378: 1949-1961Abstract Full Text Full Text PDF PubMed Scopus (1166) Google Scholar,3Lederer D.J. Martinez F.J. 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PubMed Scopus Google Scholar demonstrated that PET scanning is of of pulmonary and in patients with IPF. However, is a of and a of of have to specific in such as macrophages for et imaging of idiopathic pulmonary fibrosis PubMed Scopus Google Scholar However, imaging of CXCR4 expression as a of disease activity in IPF has been In obtained follow-up CXCR4 imaging in 16 patients after initiation of treatment with pirfenidone. 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Although its of is pirfenidone has antifibrotic and in in and of of the of fibrosis in by and and the J 2018; PubMed Scopus Google Scholar have a of pirfenidone on markers of disease such as decline in FVC and Jr., T.E. Bradford W.Z. Castro-Bernardini S. et al.A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis.N Engl J Med. 2014; 370: 2083-2092Crossref PubMed Scopus (2087) Google Bradford W.Z. et in patients with idiopathic pulmonary fibrosis two 2011; Full Text Full Text PDF PubMed Scopus Google Scholar that pirfenidone treatment is with treatment and that patients to of molecular response by of CXCR4-targeted scan to patients that However, are only to the of CXCR4-targeted scan for to that the in CXCR4 expression are with clinical In with our data a role of CXCR4 in which needs to be in G. et analysis of and in idiopathic pulmonary PubMed Scopus Google et of in of pulmonary 2018; PubMed Scopus Google Scholar the of the the However, the are and be obtained for both and that CXCR4 expression correlated with the CXCR4 PET role of CXCR4 in IPF is and the high of the has been demonstrated in A. et imaging of the CXCR4 after PubMed Scopus Google M. et of CXCR4 expression by a specific targeted Med. 2011; PubMed Scopus Google Scholar our of the CXCR4 for and Y. et al.A of CXCR4 and PubMed Scopus Google of CXCR4 expression in is in by a PubMed Scopus Google Scholar CXCR4 imaging may only of IPF by our in the imaging was on with 68Ga-pentixafor in clinical such as of the in of respiratory or may imaging data Targeted PET imaging with 68Ga-pentixafor the and CXCR4 expression in lung and In CXCR4 imaging may have a role in disease activity and treatment response and in outcomes in patients treated with pirfenidone.

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