Early detection of rheumatoid arthritis in rats and humans with 99mTc-3PRGD2 scintigraphy: imaging synovial neoangiogenesis

Objectives: To validate (99m)Tc-labeled arginylglycylaspartic acid ((99m)Tc-3PRGD2) scintigraphy as a means to image synovial neoangiogenesis in joints afflicted by rheumatoid arthritis and to investigate its potential in the early detection and management of rheumatoid arthritis. Methods: Rheumatoid arthritis and osteoarthritis were generated in Sprague Dawley rats by type II collagen immunization and papain injection, respectively. Rats were imaged with (99m)Tc-3PRGD2 and (99m)Tc- methyl diphosphonate ((99m)Tc MDP). X-ray images were also obtained and assessed by a radiologist. Immunohistochemistry of α(v)β(3) and CD31confirmed the onset of synovial neoangiogenesis. The effect of bevacizumab on rheumatoid arthritis was followed with (99m)Tc-3PRGD2 scintigraphy. A patient with rheumatoid arthritis and a healthy volunteer were scanned with (99m)Tc-3PRGD2. Results: Two weeks after immunization, a significant increase in (99m)Tc-3PRGD2 was observed in the joints of the rheumatoid arthritis model though uptake in osteoarthritis model and untreated controls was low. (99m)Tc-MDP whole body scans failed to distinguish early rheumatoid arthritis joints from healthy controls. The expression of α(v)β(3) and CD31was significantly higher in the joints of rheumatoid arthritis rats compared to normal controls. In serial (99m)Tc-3PRGD2 scintigraphy studies, (99m)Tc-3PRGD2 uptake increased in parallel with disease progression. Bevacizumab anti-angiogenetic therapy both improved the symptoms of the rheumatoid arthritis rats and significantly decreased (99m)Tc-3PRGD2 uptake. Significantly higher (99m)Tc-3PRGD2 accumulation was also observed in rheumatoid arthritis joints in the patient. Conclusions: Our findings indicate that (99m)Tc-3PRGD2 scintigraphy could detect early rheumatoid arthritis by imaging the associated synovial neoangiogenesis, and may be useful in disease management.