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Rheumatoid Arthritis: Preclinical Imaging

Therapeutic Potential

Rodent models of rheumatoid arthritis (RA) have been widely used in the preclinical evaluation of novel therapeutic agents, and efficacy in these models is usually based on the assessment of clinical signs and symptoms. However, inhibition of erythema and swelling does not necessarily translate into disease modification, and histopathologic endpoints are usually required to confirm this activity.

Recent developments in the use of various imaging modalities, including x-rays/μCT, MRI, PET and optical imaging, have demonstrated their utility for the evaluation of disease progression and therapeutic effects. Imaging applications can provide multiple, previously inaccessible, physiological or functional parameters, often earlier than non-imaging methods, and present a temporal view of the disease process. The endpoints obtained by imaging may be more predictive than traditional measures, and some are clinically translatable.This article aims to summarise the preclinical imaging approaches used in the evaluation of RA in small animal models.

Measuring Rheumatoid Arthritis

The drug discovery process is a long and expensive undertaking consisting of several stages; beginning with identification and validation of a drug target, followed by lead identification using high-throughput screening, lead optimisation and profiling in relevant disease models. Shortening this process is critical in managing the costs and time involved in bringing a drug to market. Improved characterisation of compounds and the assessment of their effects in early phases of testing offer one way to accomplish this goal. In the case of rheumatoid arthritis, traditional models used in preclinical research have focused on the induction of an arthritic response in various rodent models (1,2).These models rely on the administration of immunogenic or nonimmunogenic challenges to specific strains of mice or rats in order to produce joint inflammation. While the kinetics of disease development are agonist- and model-dependent, a very similar time course is common to all. An initial acute inflammatory response subsides and is replaced by a second, extensive wave of inflammation.This phase of the disease tends to persist for a while and then slowly resolves.The resolution phase is accompanied by extensive skeletal changes including anklyosis of the joints. The activity of therapeutic test agents is usually assessed by measuring inhibition of joint swelling, as estimated by calliper measurements or paw volume determinations, and the visual assessment of erythema.These estimates of disease burden and intensity are reflections of the inflammatory process and do not necessarily reflect changes at the structural level, which must be confirmed by standard histopathologic techniques.

The application of various imaging modalities has the potential to dramatically increase the efficiency of lead candidate selection by providing more predictive data at an earlier time point when compared to traditional methods. Imaging, in many instances, is also translatable to the clinical evaluation of candidate agents. The methods provide a richer dataset and might provide a measure of discrimination when deciding which potential candidate would be best suited for further development. Here we briefly describe various imaging approaches currently in use to probe different aspects of RA and its response to therapy.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) provides excellent soft tissue contrast and high resolution images, and is unparalleled in its flexibility and broad applicability. It is widely used in the clinic to obtain anatomical and functional information. MRI can be used to assess soft tissue changes surrounding the bone (see Figure 1). The cited studies were able to clearly visualise two distinct phases of disease activity in rat adjuvant induced arthritis (3-5). The first phase, occurring relatively early, exhibited periarticular inflammatory changes characterised by synovitis, synovial hyperplasia and distention of the joint capsule into the surrounding tissue. The second, later phase had features of continued soft tissue inflammation, and considerable bony changes such as periostitis and exostosis. The soft tissue swelling, joint effusion and bone erosion scores were highly correlated with histologic observations.


Figure 1: Multiple magnetic resonance images through a normal rat ankle. MRI enables assessment of soft tissue in joints

Nuclear Imaging

Positron emission tomography (PET) is also becoming an increasing area of focus for drug discovery and development because of its unique capabilities (6). New tracers such as 18Fsodium fluoride can be used to assess disease progression in RA models (see Figure 2). The skeletal uptake of 18F in NaF relies on the exchange of hydroxyl ions in the hydroxyapatite crystal which is an indicator of bone metabolic activity. While this approach has not been extensively applied to the study of arthritis animal models, it has been used as a tool for monitoring the increased bone turnover associated with certain malignancies prior to the advent of 99mTc-labelled bisphophonates. This ‘old school’ approach to the assessment of bone remodelling may hold a great deal of promise for the assessment of skeletal changes in animal models of arthritis.


Figure 2: 18F sodium fluoride PET images of a rat with advanced adjuvant induced arthritis. Image on the left shows high uptake of the tracer in the ankles, indicating increased bone turnover. The image on the right shows the same rat, after two weeks of dexamethasone treatment

Computed Tomography

Computed tomography (CT) is well suited for anatomical imaging of the skeletal tissue in models of arthritis. For example, in a collagen-induced arthritis model, untreated animals undergo significant bone remodelling and deterioration in bone structure, while successfully treated animals (for example, methotrexate) show inhibition of this disease progression (see Figure 3). In a study conducted by Sims et al, the authors used μ-CT imaging to demonstrate that zoledronic acid preserved bone structure in rat collagen-induced arthritis in the absence of an effect on inflammation as measured by traditional end points (7). Some μ-CT systems can generate hard data regarding cortical and trabecular bone volumes and other measures of bone morphometry. These systems are high energy, high resolution instruments designed to scan samples, usually ex vivo. Lower energy systems are used routinely to perform in vivo studies, such as the one illustrated in Figure 3, for longitudinal studies. The resulting data are usually scored semi-quantitatively based on the overall appearance of the 3D surface area representation. Software algorithms can also be used to perform these measurements in a more objective manner by determining estimates of the bone surface roughness as a measure of the severity of disease (8,9).


Figure 3: Micro CT images of ankles obtained from rats in an adjuvant induced arthritis model. Image on the left is a limb from a vehicle treated animal. The roughness of the joint is an indication of the severity of disease. The image on the right is a limb from a methotrexate treated rat. Both semi and fully quantitative assessment of bone surface roughness is possible

Optical Imaging

A mechanistic understanding of various disease processes in RA is possible through the use of activatable optical imaging probes (10).These near-infrared (NIR) probes are quenched (that is optically silent) in their native state, but are activated in the presence of activating enzymes such as matrix metalloproteinases (MMPsense) or cathepsins (CatB FAST). Another series of probes have been conjugated to a bisphosphonate agent that binds to hydrxoyapatite.The use of these agents in combination with 3D fluorescence molecular tomography (3D-FMT) permits the interrogation of mechanistic effects of candidate therapeutic agents in models of RA.The use of this approach has been recently demonstrated by Peterson et al (11).These investigators used these probes to demonstrate their ability to differentiate between disease modifying anti-rheumatic drugs (DMARDs) and non-DMARD agents in mouse collagen antibody induced arthritis.They demonstrated that neither the traditional measures of paw thickness or clinical score, nor numerous plasma markers could differentiate between celecoxib (a non-DMARD agent) and a p38 MAPK inhibitor (DMARD). In contrast, the use of the NIR probes to detect cathepsin, matrix metalloproteinase or bone resorption clearly delineated between these two classes of agents.The optical imaging data were in good agreement with histopathologic examination of the affected limbs.The study demonstrates the utility of optical imaging in the rapid, non-invasive, longitudinal study of disease progression that is highly correlated with the underlying pathophysiology.


Figure 4: Fluorescence images of mice ankles at various stages of disease in a collagen-induced arthritis model. Mice were injected with an activatable probe with light emission dependant on upregulation of matrix metallopoteinase or cathepsin activity. This approach enables a quantitative and mechanistic assessment of disease progression or modification

Conclusion

This overview of the application of imaging technologies offers a glimpse of how the clever application of these methods can be used to accelerate and refine the drug discovery process for DMARDs.Different types of structural data can be obtained using classical techniques such as MRI, CT and PET scanning – technologies that are translatable to the clinic.The utility of a novel optical imaging modality provides mechanistic data, permitting the dissection of anti-inflammatory activity from disease modification. While this application is not yet clinically available, the development of suitable protocols for that translation is currently under investigation.

References

  1. Hegen M, Keith JC Jr, Collins M and Nickerson-Nutter CL, Utility of animal models for identification of potential therapeutics for rheumatoid arthritis, Ann Rheum Dis 67: pp1,505-1,515, 2008
  2. Holmdahl R, The use of animal models for rheumatoid arthritis, Methods Mol Med 136: pp185-189, 2007
  3. Faure P, Doan BT and Beloeil JC, In vivo high resolution three-dimensional MRI studies of rat joints at 7 T, NMR Biomed 16: pp484-493, 2003
  4. Jacobson PB, Morgan SJ, Wilcox DM, Nguyen P, Ratajczak CA, Carlson RP, Harris RR and Nuss M, A new spin on an old model: in vivo evaluation of disease progression by magnetic resonance imaging with respect to standard inflammatory parameters and histopathology in the adjuvant arthritic rat, Arthritis Rheum 42: pp2,060-2,073, 1999
  5. Lee SW, Greve JM, Leaffer D, Lollini L, Bailey P, Gold GE and Biswal S, Early findings of small-animal MRI and small-animal computed tomography correlate with histological changes in a rat model of rheumatoid arthritis, NMR Biomed 21: pp527-536, 2008
  6. Blau M, Nagler W and Bender MA, Fluorine-18: a new isotope for bone scanning, J Nucl Med 3: pp332-334, 1962
  7. Sims NA, Green JR, Glatt M, Schlict S, Martin TJ, Gillespie MT and Romas E, Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen-induced arthritis, Arthritis Rheum 50: pp2,338-2,346, 2004
  8. Silva MD, Ruan J, Siebert E, Savinainen A, Jaffee B, Schopf L and Chandra S, Application of surface roughness analysis on micro-computed tomographic images of bone erosion: examples using a rodent model of rheumatoid arthritis, Mol Imaging 5: pp475-484, 2006
  9. Silva MD, Savinainen A, Kapadia R, Ruan J, Siebert E, Avitahl N, Mosher R, Anderson K, Jaffee B, Schopf L et al, Quantitative analysis of micro-CT imaging and histopathological signatures of experimental arthritis in rats, Mol Imaging 3: pp312-318, 2004
  10. Bremer C, Tung CH and Weissleder R, In vivo molecular target assessment of matrix metalloproteinase inhibition, Nat Med 7: pp743-748, 2001
  11. Peterson JD, Labranche TP, Vasquez KO, Kossodo S, Melton M, Rader R, Listello JT, Abrams MA and Misko TP, Optical tomographic imaging discriminates between diseasemodifying anti-rheumatic drug (DMARD) and non-DMARD efficacy in collagen antibody-induced arthritis, Arthritis Res Ther 12: R105, 2010

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Joseph A Cornicelli is the Director of Inflammation and Cardiovascular Pharmacology Services for Charles River Laboratories, and has over 22 years of experience in drug discovery and development. Trained at the University of Cincinnati, Joe completed post-doctoral fellowships at the Mayo Clinic Foundation and Columbia University, where he was part of the research faculty in the Department of Medicine. He joined Warner- Lambert in 1985 where he served as a Research Fellow in the inflammation and cardiovascular therapeutic areas. In 2007, he joined MIR Preclinical Services. He is responsible for directing discovery efforts for the assessment of potential therapeutics for inflammatory and cardiovascular disorders. Joe is a Fellow of the American Heart Association.

Vinod Kaimal is an imaging scientist with expertise in the application of multiple imaging modalities such as MRI, PET, CT and optical imaging to small animal models of disease. Trained as an electrical and biomedical engineer at the University of Cincinnati, Vinod has over five years of imaging experience, three of those at Charles River (formerly MIR preclinical services). At Charles River, he is responsible for the design, planning and execution of imaging studies, as well as associated data interpretation.

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