In vivo imaging of early stages of rheumatoid arthritis by α5β1-integrin-targeted positron emission tomography

Abstract

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 αvβ3 and α5β1 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 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. Conclusion α5β1-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).

RGD-Binding Integrins Revisited: How Recently Discovered Functions and Novel Synthetic Ligands (Re-)Shape an Ever-Evolving Field

“…In addition, monomeric and dimeric 99m Tc-labeled tracers based on the cyclic heptapeptide (cyclo[phg-isoDGRk], ligand 10 , Figure 7 ) for SPECT imaging [ 351 , 352 ] were reported. Encouraging early results in tracer development await further follow-up studies with a clear focus on defining the role and significance of α5β1 as a novel candidate for clinical nuclear imaging, especially in terms of imaging tumor angiogenesis but also for other indications, such as rheumatic diseases [ 424 ].…”

Insights Into Leukocyte Trafficking in Inflammatory Arthritis – Imaging the Joint

“…Thus, indicating an accumulation of activated immune cells in the arthritic joint, which could result from either increased leukocyte migration or enhanced proliferation of the cells within the tissue or a combination of both. Protein specific PET tracers, such as 68 Ga-Aquibeprin or 68 Ga-Avebetrin that bind specifically to α 5 β 1 -integrin or α V β 3 -integrin, respectively, can also be used to track the expression pattern of molecules involved in leukocyte trafficking ( Notni et al, 2019 ). Such tracers showed increased expression of α 5 β 1 - and α V β 3 -integrins in arthritic joints compared to non-arthritic joints in mice with CIA ( Notni et al, 2019 ), suggesting arthritis increases the expression of these integrins to facilitate leukocyte accumulation.…”

“…Protein specific PET tracers, such as 68 Ga-Aquibeprin or 68 Ga-Avebetrin that bind specifically to α 5 β 1 -integrin or α V β 3 -integrin, respectively, can also be used to track the expression pattern of molecules involved in leukocyte trafficking ( Notni et al, 2019 ). Such tracers showed increased expression of α 5 β 1 - and α V β 3 -integrins in arthritic joints compared to non-arthritic joints in mice with CIA ( Notni et al, 2019 ), suggesting arthritis increases the expression of these integrins to facilitate leukocyte accumulation. Tracer studies are currently limited to detecting global cellular activity (accumulation/proliferation) but are unable to identify individual cells or subsets or their movement.…”

Current Applications for Nuclear Medicine Imaging in Pulmonary Disease

“…FDG PET/CT can be used for early diagnosis of RPC and follow-up [ 54 , 55 ]. New specific PET tracers are being developed, for example, α5β1-integrin PET appears to be a promising tool for early diagnosis of RA and therapy monitoring [ 56 ].…”