In vivo imaging of early stages of rheumatoid arthritis by α5ß1-integrin-targeted positron emission tomography.

BACKGROUND: Rheumatoid arthritis (RA) is one of the most common rheumatic diseases. Joint inflammation and pathological growth of joint cartilage cause swollen and painful joints, which severely diminishes the patients' life quality. There is no causal treatment. Symptomatic therapies should start as early as possible to take maximal effect. Hence, diagnostic procedures capable of detecting affected joints before the onset of clinical symptoms are highly desirable. We explored the value of PET imaging of integrin subtypes αvß3 and α5ß1 for early detection of RA foci in collagen-induced arthritis (CIA) mouse models. RESULTS: Development of RA in CIA mice was monitored by paw scoring, and αvß3- and α5ß1-integrin expression was quantified by µPET using 68Ga-Avebetrin and 68Ga-Aquibeprin. For consecutive sections of selected decalcified joints (knee, ankle), arthritic degeneration and integrin expression were assessed by MOVAT staining and ß3/α5 immunohistochemistry (IHC), respectively. ß3- and α5-IHC revealed elevated levels of both αvß3- and α5ß1-integrin in arthritic joints. Unlike αvß3, α5ß1 is strongly expressed in the proliferating synovial lining layer, which suggests that its presence is directly related to RA development. For mice with advanced RA (6 weeks after CIA), PET signals for α5ß1-integrin were substantially stronger (> 300% of baseline) than that of αvß3-integrin (< 200%). A longitudinal PET follow-up revealed that the manifestation of clinical symptoms of RA is preceded by upregulation of α5ß1- but not of αvß3-integrin. CONCLUSION: α5ß1-integrin PET could add a new functional imaging aspect to the portfolio of RA diagnostics because it appears to be a sensitive biomarker for early RA development. We suggest α5ß1-integrin PET as a valuable tool to achieve a higher precision for early diagnosis of RA, including initial staging, monitoring of the disease course, and drug treatment, and for planning of radiosynoviorthesis (RSO).