EULAR 2016 | Daily Highlights
EARLY DETECTION OF LUNG INVOLVEMENT IN SYSTEMIC SCLEROSIS USING MOLECULAR TARGETED IMAGINGAbstract: OP0045
Authors: J. Schniering1,*, S. Haller2, Z. Guo1, C. Feghali-Bostwick3, R. Schibli2, O. Distler1, C. Müller2, B. Maurer1
Co Authors: 1Division of Rheumatology, University Hospital Zurich, Zurich, 2Center for Radiopharmaceutical Sciences ETH-PSI-USZ, PSI-Villigen, Switzerland, 3Division of Rheumatology & Immunology, Medical University of South Carolina, Charleston, United States
Interstitial lung disease (ILD) is one of the leading causes of death in systemic sclerosis (SSc). Since routine diagnostics such as CT and pulmonary function tests only detect impaired organ function and/or damage, there is an unmet need for the non-invasive diagnosis of ILD at earliest, possibly still reversible disease stages.
To assess nuclear imaging for the detection of SSc-ILD by using radiotracers specifically targeting integrin ?v?3 as a pathophysiologic key molecule of early inflammation-dependent fibrosis in the murine model of bleomycin-induced pulmonary fibrosis and in the multisystemic Fra-2 transgenic (tg) mouse model of SSc.
Expression of integrin ?v?3 was analysed in lung sections from patients with SSc-ILD, idiopathic pulmonary fibrosis (IPF), healthy controls (n=5) as well as from bleomycin-treated mice, Fra-2 tg mice and respective controls (n=4) using immunohistochemistry. In vivo imaging was performed using 111In-DOTA-RGD radioconjugates specifically targeting integrin ?v?3. SPECT (single photon emission computed tomography) was performed using a small-animal SPECT/CT scanner (NanoSPECT/CT, Mediso). Animals were scanned at early disease time points to visualise inflammation-dependent pulmonary fibrosis. The pulmonary accumulation of the radiotracer was confirmed by ex vivo SPECT/CT, biodistribution, and autoradiography studies. Nonparametric non-related data were expressed as median(Q1,Q3). For statistical analysis, the Mann-Whitney U test was applied. P-values <0.05 were considered statistically significant.
In lung sections of patients with SSc-ILD and IPF, the expression of integrin ?v?3 was increased by 3.7-fold and 2.9-fold, respectively as compared to healthy controls (p<0.009, p<0.02). Lungs of bleomycin-treated and Fra-2 tg mice, but not of controls showed a significant increase in integrin ?v?3 expression (upregulation by 5.7-fold and 4.8-fold, respectively) as we have similarly observed in SSc-ILD and IPF patients (p<0.03 each, Fig. C). Integrin ?v?3 was primarily expressed on endothelial cells, inflammatory cells and myofibroblasts as indicated by sequential stainings with cell type-specific markers. Notably, at day 7 after intratracheal bleomycin installation, the peak of pulmonary inflammation, nuclear SPECT/CT with 111In-DOTA-RGD targeting integrin ?v?3, successfully visualised pulmonary inflammation and incipient fibrosis in the model of bleomycin-induced pulmonary fibrosis. Similarly, imaging of integrin ?v?3 in Fra-2 tg mice at 13 weeks of age, the starting point of pulmonary fibrosis, showed a higher pulmonary uptake of the radiotracer in Fra-2 tg mice than in controls (Fig. A). Ex vivo SPECT/CT of isolated lungs, biodistribution and autoradiography studies confirmed the in vivo results and validated the specific radiotracer uptake in lungs from bleomycin-challenged mice and Fra-2 tg mice as compared to controls (Fig. B).
Our data provide the first evidence that targeting pathophysiologic key molecules using nuclear imaging methods for the visualization of inflammation-dependent fibrosis is a promising non-invasive approach for the early detection of lung involvement in SSc.
Disclosure of Interest
J. Schniering Grant/research support from: Swiss National Science Foundation (S-85605-02-01), S. Haller Grant/research support from: Swiss National Science Foundation (S-85605-02-01), Z. Guo Grant/research support from: respective institution, C. Feghali-Bostwick Grant/research support from: respective institution, R. Schibli Grant/research support from: respective institution, O. Distler Grant/research support from: Bayer, Sanofi, Ergonex, Boehringer Ingelheim, Actelion, Pfizer, Consultant for: 4 D Science, Actelion, Active Biotec, Bayer, BiogenIdec, BMS, Boehringer Ingelheim, EpiPharm, Ergonex, espeRare foundation, Genentech/Roche, GSK, Inventiva, Lilly, medac, MedImmune, Pharmacyclics, Pfizer, Serodapharm, Sinoxa, C. Müller Grant/research support from: respective institution, B. Maurer Grant/research support from: respective institution
The diagnosis of interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) is currently mainly based on lung function testing and high-resolution computer tomography (HRCT). Lung function testing has recently been shown to have a remarkable low sensitivity when used for screening of SSc-ILD. HRCT is more sensitive, but still detects SSc-ILD at stages when fibrosis has already developed. Thus, there is a high unmet need for the development of screening and imaging techniques that are able to detect SSc-ILD at earlier stages, before damage to the lungs has occurred. The current study shows first promising pre-clinical results using molecular imaging to detect SSc-ILD at stages when key pathophysiological pathways are already activated, but damage (fibrosis) has not yet occurred. This novel concept needs further testing with additional targets, optimization of image detection methods and most importantly, testing in proof of concept studies before it can be applied to clinical practice.
Prof. Dr. Oliver Distler
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