Rheumatoid arthritis is a chronic and progressive inflammatory condition estimated to affect between 0.5% and 1% of the world’s population, with more women being affected than men. RA is a systemic disease manifesting mainly as a disabling destruction of the synovial joints of the hands and feet. In addition to the disability and decreased quality of life caused by RA, patients are at increased risk of developing cardiovascular disease. Joint destruction is induced by dysregulated immune activation of both the innate and adaptive immune responses resulting in alterations in the synovium, cartilage and bone. The normal joint has a thin synovial lining (intimal lining layer), 1-3 cells thick. Beneath this is a sub-lining layer of connective tissue scattered with immune cells, blood vessels and nerve cells. Together these layers form the synovium, which produces the synovial fluid that serves to lubricate the joint. Disease initiation results in profound changes in the structure and composition of the synovium and synovial fluid; with the infiltration of inflammatory cells, synovial cell hyperplasia, increased angiogenesis, fibroblast proliferation and extracellular matrix production. This increase in synovial cell proliferation can result in the lining increasing up to five times its original size and can result in pannus formation. The culmination of these events is bone and cartilage erosion and loss of joint function.
Extensive research spanning five decades has failed to elucidate the precise aetiology of RA. However, it is clear that the disease is complex, heterogenous and can probably be initiated by several mechanisms. The strongest association is with HLA II, although both genetic and environmental factors have been implicated in disease. Several animal models have been developed to study the mechanisms of disease and to screen potentially therapeutic agents. There are several commonly used induced models including Collagen-Induced Arthritis (CIA), Collagen-Antibody Induced Arthritis (CAIA), and Zymosan-induced arthritis. As well as several spontaneously arthritic mouse models: TNFa over-expressing transgenic (Tg) mice, K/BxN mice, SKG mice, Human DR4-CD4 mice, IL-1Ra-/- mice. However, it is recent advances in imaging technology that has allowed these models to provide significantly better information about disease and potential therapies. Here, we discuss state of the art imaging modalities paying particular attention to the advantages and disadvantages of using these new technologies in RA models.
Magnetic Resonance Imaging (MRI)
MRI employs powerful magnets and radiowaves to create excellent 3D images with superb spatial resolution. Furthermore, information about metabolic processes, physiology and tissue status can be obtained with MRI scanning. The magnetic field created by the scanner causes the body’s hydrogen atoms to line up in a specific orientation. Radiowaves are then sent towards these atoms and a computer records the signals that return. Bone erosion, synovitis, tendonopathy, and bone oedema can all be detected using this technique. In contrast to CT, MRI has improved soft tissue contrast and does not expose animal to low dose radiation. In addition, MRI does not always require contrast enhancing agents, minimising side effects on subjects. However, contrast enhancing agents such as gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) and ultra-small super paramagnetic iron oxide (USPIO) particles can be used to maximise the information retrieved by MRI. Gd-DTPA can generate information about vascular flow and permeability as well as information about intra-articular extracellular space, whereas, USPIO particles can generate information about articular content. Several studies that used this technique have shown that MRI technology can follow disease progression using synovial inflammation and draining lymph node volume as biomarkers. Importantly, these biomarkers respond to therapy and thus can be used to screen new potential therapies1-4. IV injection of USPIO particles leads to their accumulation within macrophages of the endoreticular system. These macrophages can be tracked and are recruited to the joint during disease5. MR technology has also been used to follow T cell fate in vivo. In these studies T cells are loaded ex vivo and reintroduced into the mouse which is then scanned to detect where the T cell localise 6, 7. MR scanning can detect disease before irreversible damage occurs. This in conjunction with the ability to image the same animal repeatedly results in MR scanning being an extremely powerful technique allowing longitudinal studies in the same animal where early disease can be followed and the response to therapy assessed.
- Dardzinski BJ et al., Magn Reson Imaging. 2001 (9):1209-16.
- Proulx ST, et al., Arthritis Rheum. 2007 56(12):4024-37.
- Guo R, et al., Arthritis Rheum. 2009 60(9):2666-76.
- Lee SI et al., J Radiol. 2009 10(6):651.
- Beckmann N et al., Magn Reson Med. 2003 49(6):1047-55.
- Dodd SJ et al., Biophys J. 1999 76(1 Pt 1):103-9.
- Josephson L et al., Bioconjug Chem. 2002 13(3):554-60.