Background Tissue macrophage recruitment and osteoclastogenesis is dependent on the activation of colony stimulating factor-1 (CSF-1) receptor (R). To target macrophages and block osteoclastogenesis a JNJ compound was identified as a potent inhibitor of CSF-1R kinase that is effective in a streptococcal cell wall (SCW) model of rheumatoid arthritis (RA) in rats.
Objectives To demonstrate that functional and structural imaging can be used to monitor RA disease progression and efficacy of a CSF-1R kinase inhibitor in this aggressive model of rheumatoid arthritis.
Methods Female Lewis rats were inoculated with SCW proteoglycan polysaccharide. By day 18 rats developed a stable immune-mediated polyarthritis; rats were randomized into three study groups: SCW-vehicle, SCW-JNJ-CSF-1R inhibitor (10 mg/kg, po, BID) and a naïve, disease-free group (n=6/group); Treatment began on day 19 and continued daily for 14 days. Rats were scanned with [18F]fluorodeoxyglucose (18FDG) positron emission tomography (PET), MMPSense optical fluorescence imaging, and ultra-high resolution x-ray computed tomography (CT). 18FDG is a radioactive analogue of glucose that measures the increase in metabolic activity in inflamed tissues which is detected using PET. 18FDG-PET imaging was conducted at two time points, on day 18 prior to treatment, and again on day 31 after 13 days of treatment with compound. CT imaging was obtained at termination.
Results On day 19, 18FDG-PET signal was markedly elevated in SCW-inoculated rats as compared to the naïve disease-free group. By day 31, the 18FDG-PET signal was reduced to near control in the JNJ-CSF-1R inhibitor-treated rats, whereas signal intensity remained elevated in the SCW-vehicle group. Using an optical fluorescent imaging probe MMPSense that is activated by matrix metalloproteinases, key proteases involved in joint bone destruction, the degree of MMP activity in the joint was measured. On day 24, the optical intensity in the SCW-vehicle group was approximately twice the naïve group, whereas JNJ-CSF-1R inhibitor reduced the signal to that in the naïve group. These results for both 18FDG-PET and MMPSense suggest a very effective anti-inflammatory effect of JNJ-SCF-1R inhibitor after a relatively short duration of treatment. At termination excised paws were scanned in the CT imager and 3-D images revealed severe bone erosion in the tibia from the SCW-vehicle group. Histological analyses indicated that these erosions resulted from penetrating lesions of cortical and trabecular bone. Conversely, in the SCW-JNJ-CSF-1R inhibitor-treated group the bone erosion was reduced. These imaging results correlated with the reductions in clinical and histological scores seen in the CSF-1R kinase inhibitor-treated group.
Conclusions Multi-imaging modalities including optical, PET and CT provided a wide range of imaging capabilities to fully characterize the beneficial effects of the CSF-1R inhibitor. It is concluded, based on the imaging results that the JNJ-CSF-1 kinase inhibitor may be effective in treating RA in humans.
Disclosure of Interest None Declared