Abstract
BackgroundRheumatoid 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 αvβ3 and α5β1 for early detection of RA foci in collagen-induced arthritis (CIA) mouse models.ResultsDevelopment of RA in CIA mice was monitored by paw scoring, and αvβ3- and α5β1-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 β3/α5 immunohistochemistry (IHC), respectively. β3- and α5-IHC revealed elevated levels of both αvβ3- and α5β1-integrin in arthritic joints. Unlike αvβ3, α5β1 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 α5β1-integrin were substantially stronger (> 300% of baseline) than that of αvβ3-integrin (< 200%). A longitudinal PET follow-up revealed that the manifestation of clinical symptoms of RA is preceded by upregulation of α5β1- but not of αvβ3-integrin.Conclusionα5β1-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 α5β1-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).
Highlights
Rheumatoid arthritis (RA) is one of the most common rheumatic diseases
positron emission tomography (PET) imaging of RA-associated expression of αvβ3- and α5β1-integrin Figure 1 shows that the increase of the average clinical and magnetic resonance imaging (MRI) scores over time is accompanied with overall increasing integrin PET signals, which indicates that the integrin expression levels rise as the RA progresses
The consistently higher 68Ga-Aquibeprin uptakes suggest that the expression density of α5β1integrin is higher, while a similar baseline uptake of both tracers indicates that the stronger α5β1 signal is not related to a higher unspecific retention in the tissue
Summary
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. The established long-term therapies rely on the systemic application of disease-modifying anti-rheumatic drugs (DMARDs), above all, the immunosuppressive agent methotrexate (a folate receptor inhibitor) [2], or biologicals, such as tumor necrosis factor α (TNF-α) inhibitors [3,4,5]. Such therapies are most successful when the treatment is started early and aggressively [6], which in consequence, highlights the paramount importance of an early diagnosis. Since RSO requires the identification of affected joints, planning of RSO treatment could be enhanced by the sensitive and selective functional imaging of biomarkers that are associated with the early development stages of RA in joints
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