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Abstract
IntroductionStandard measurements used to assess murine models of rheumatoid arthritis, notably paw thickness and clinical score, do not align well with certain aspects of disease severity as assessed by histopathology. We tested the hypothesis that non-invasive optical tomographic imaging of molecular biomarkers of inflammation and bone turnover would provide a superior quantitative readout and would discriminate between a disease-modifying anti-rheumatic drug (DMARD) and a non-DMARD treatment.MethodsUsing two protease-activated near-infrared fluorescence imaging agents to detect inflammation-associated cathepsin and matrix metalloprotease activity, and a third agent to detect bone turnover, we quantified fluorescence in paws of mice with collagen antibody-induced arthritis. Fluorescence molecular tomographic (FMT) imaging results, which provided deep tissue detection and quantitative readouts in absolute picomoles of agent fluorescence per paw, were compared with paw swelling, clinical scores, a panel of plasma biomarkers, and histopathology to discriminate between steroid (prednisolone), DMARD (p38 mitogen-activated protein kinase (MAPK) inhibitor) and non-DMARD (celecoxib, cyclooxygenase-2 (COX-2) inhibitor) treatments.ResultsPaw thickness, clinical score, and plasma biomarkers failed to discriminate well between a p38 MAPK inhibitor and a COX-2 inhibitor. In contrast, FMT quantification using near-infrared agents to detect protease activity or bone resorption yielded a clear discrimination between the different classes of therapeutics. FMT results agreed well with inflammation scores, and both imaging and histopathology provided clearer discrimination between treatments as compared with paw swelling, clinical score, and serum biomarker readouts.ConclusionsNon-invasive optical tomographic imaging offers a unique approach to monitoring disease pathogenesis and correlates with histopathology assessment of joint inflammation and bone resorption. The specific use of optical tomography allowed accurate three-dimensional imaging, quantitation in picomoles rather than intensity or relative fluorescence, and, for the first time, showed that non-invasive imaging assessment can predict the pathologist's histology inflammation scoring and discriminate DMARD from non-DMARD activity.
Highlights
Standard measurements used to assess murine models of rheumatoid arthritis, notably paw thickness and clinical score, do not align well with certain aspects of disease severity as assessed by histopathology
Of current importance in the development of antiarthritic drugs is the ability to discriminate between disease-modifying anti-rheumatic drugs (DMARDs), which affect arthritis pathogenesis and progression, and nonDMARDs, which may show palliative effects and symptom relief in the absence of affecting disease progression
Inhibitors of p38 mitogen-activated protein kinase (MAPK) have been shown to reduce tumor necrosis factor (TNF) levels and affect disease pathogenesis in animal models of Rheumatoid arthritis (RA) [4,5,6,7,8], with some more modest effects in patients showing DMARD efficacy [4,9] limited by dosedependent toxicity
Summary
Standard measurements used to assess murine models of rheumatoid arthritis, notably paw thickness and clinical score, do not align well with certain aspects of disease severity as assessed by histopathology. We tested the hypothesis that non-invasive optical tomographic imaging of molecular biomarkers of inflammation and bone turnover would provide a superior quantitative readout and would discriminate between a disease-modifying antirheumatic drug (DMARD) and a non-DMARD treatment. Rheumatoid arthritis (RA) is a chronic destructive inflammatory disease of the joints. Of current importance in the development of antiarthritic drugs is the ability to discriminate between disease-modifying anti-rheumatic drugs (DMARDs), which affect arthritis pathogenesis and progression, and nonDMARDs, which may show palliative effects and symptom relief in the absence of affecting disease progression. Whereas p38 MAPK inhibitors significantly decrease underlying inflammation and bone destruction, cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib, and other nonsteroidal anti-inflammatory drugs (NSAIDs) are better at providing symptom relief than at altering disease progression [10,11]
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