Clinical Molecular Imaging of Pulmonary CXCR4 Expression to Predict Outcome of Pirfenidone Treatment in IPF.

IPF is a progressive disease for which two antifibrotic drugs have recently been approved, however there is an unmet need to predict responses to antifibrotic treatment, such as pirfenidone. Recent data suggested that up-regulated expression of the C-X-C chemokine-receptor type 4 (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 of lung tissues and RT-PCR of BAL. PET-CT with the specific CXCR4 ligand, gallium-68 (68Ga)-pentixafor, was performed in 28 IPF patients (PET1) and compared with baseline clinical characteristics. In 16 patients, a follow-up scan (PET2) was obtained 6-12 weeks after initiation of treatment with pirfenidone. Patients were followed in our outpatient clinic for ≥12 months.Immunohistochemistry showed high CXCR4 staining of epithelial cells and macrophages in areas with vast fibrotic remodeling. Targeted PET revealed CXCR4 upregulation in fibrotic areas of the lungs, particularly in zones with subpleural honeycombing. Baseline CXCR4 signal demonstrated a significant correlation with GAP stage (r=0.44, P=0.02) and with HRCT score (r=0.38, P=0.04). Early changes in CXCR4 signal after initiation of pirfenidone treatment correlated with the long-term course of forced vital capacity (FVC) after 12 months (r=-0.75, P=0.0008). Moreover, patients with a high PET2 pulmonary CXCR4 signal after six weeks into treatment had a statistically significant worse outcome at 12 months (P=0.002). In multiple regression analysis, PET2 pulmonary CXCR4 signal emerged as the only independent predictor of long-term outcome (P=0.0226).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.

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