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Emerging optical and nuclear medicine imaging methods in rheumatoid arthritis

Abstract

Molecular and multimodal imaging procedures that complement the use of existing anatomical modalities for the diagnosis and monitoring of rheumatoid arthritis (RA) have undergone substantial developmental advances. These techniques have the potential to greatly improve the management of patients with RA through early diagnosis and maximization of the newly available opportunities for early therapeutic intervention. Quantitative, noninvasive monitoring of biomarkers of the molecular events induced during the onset of RA could be used to guide the initial selection of therapy and for assessment of early therapeutic responses. Biomolecular imaging techniques that can reveal the pathophysiological features of RA—including infrared thermography, near-infrared molecular imaging, and PET—are being used to investigate the earliest cellular and biochemical inflammatory events in the development of the disease. Noninvasive imaging of abnormal specific molecular events in early RA could enable early targeted intervention that could be tailored to optimize patient responses before destructive anatomical changes occur. In this Review, we summarize new advances in biomolecular imaging techniques, with an emphasis on their current state of development in terms of the management of RA.

Key Points

  • Biomolecular imaging can detect specific molecular events that are associated with the onset and progression of RA

  • Thermography can be used to detect and quantitatively assess clinically meaningful changes in arthritic joints

  • Near-infrared imaging can detect a broad spectrum of specific enzymatic activities, including local levels of caspase or cathepsin activity

  • PET imaging is a highly specific and sensitive technique that can be used to assess biochemical processes, such as cell metabolism, angiogenesis and apoptosis

  • Noninvasive whole-body analysis of specific molecular events during the onset of RA could facilitate early intervention and the use of tailored therapies to optimize the responses of individual patients

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Figure 1: Biomolecular imaging techniques used to aid the early diagnosis of RA in research.
Figure 2: Thermal imaging of the left wrist skin surface in a 9-year-old girl with polyarticular juvenile idiopathic arthritis.
Figure 3: Assessment of RA pathophysiology using light scattering through finger joints.
Figure 4: NIR imaging of macrophages and protease activity in mice with CIA.
Figure 5: 18F-FDG-PET–CT imaging in arthritis.
Figure 6: PET quantitation of metabolic activity in RA joints using ROVER software.
Figure 7: Imaging cell death in a mouse model of RA using radiolabelled annexin V.

References

  1. Brennan, P. et al. A simple algorithm to predict the development of radiological erosions in patients with early rheumatoid arthritis: prospective cohort study. BMJ 313, 471–476 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. Klarlund, M. et al. Magnetic resonance imaging, radiography, and scintigraphy of the finger joints: one year follow up of patients with early arthritis. Ann. Rheum. Dis. 59, 521–528 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. McQueen, F. M. et al. Magnetic resonance imaging of the wrist in early rheumatoid arthritis reveals progression of erosions despite clinical improvement. Ann. Rheum. Dis. 58, 156–163 (1999).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. McQueen, F. M. et al. What is the fate of erosions in early rheumatoid arthritis? Tracking individual lesions using x rays and magnetic resonance imaging over the first two years of disease. Ann. Rheum. Dis. 60, 859–868 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Kokkonen, H. et al. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 62, 383–391 (2010).

    CAS  PubMed  Google Scholar 

  6. Davila, L. & Ranganathan, P. Pharmacogenetics: implications for therapy in rheumatic diseases. Nat. Rev. Rheumatol. 7, 537–550 (2011).

    CAS  Article  PubMed  Google Scholar 

  7. Devereaux, M. D., Parr, G. R., Thomas, D. P. & Hazleman, B. L. Disease activity indexes in rheumatoid arthritis; a prospective, comparative study with thermography. Ann. Rheum. Dis. 44, 434–437 (1985).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. Spadling, S. J. et al. Three-dimensional and thermal surface imaging produces reliable measures of joint shape and temperature: a potential tool for quantifying arthritis. Arthritis Res. Ther. 10, R10 (2008).

    Article  Google Scholar 

  9. Fischer, T. et al. Detection of rheumatoid arthritis using non-specific contrast enhanced fluorescence imaging. Acad. Radiol. 17, 375–381 (2010).

    Article  PubMed  Google Scholar 

  10. Prapavat, V. et al. The development of a finger joint phantom for the optical stimulation of early inflammatory rheumatic changes [German]. Biomed. Tech. (Berl.) 42, 319–326 (1997).

    CAS  Article  Google Scholar 

  11. Scheel, A. K. et al. Assessment of proximal finger joint inflammation in patients with rheumatoid arthritis, using a novel laser-based imaging technique. Arthritis Rheum. 46, 1177–1184 (2002).

    Article  PubMed  Google Scholar 

  12. Hielscher, A. H. et al. Sagittal laser optical tomography for imaging of rheumatoid finger joints. Phys. Med. Biol. 49, 1147–1163 (2004).

    Article  PubMed  Google Scholar 

  13. Scheel, A. K. et al. First clinical evaluation of sagittal laser optical tomography for detection of synovitis in arthritic finger joints. Ann. Rheum. Dis. 64, 239–245 (2005).

    CAS  Article  PubMed  Google Scholar 

  14. Klose, C. D., Klose, A. D., Netz, U., Beuthan, J. & Hielscher, A. H. Multiparameter classifications of optical tomographic images. J. Biomed. Opt. 13, 050503 (2008).

    Article  PubMed  Google Scholar 

  15. Aswathy, R. G., Yoshida, Y., Maekawa, T. & Kumar, D. S. Near-infrared quantum dots for deep tissue imaging. Anal. Bioanal. Chem. 397, 1417–1435 (2010).

    CAS  Article  PubMed  Google Scholar 

  16. Canvin, J. M. et al. Infrared spectroscopy: shedding light on synovitis in patients with rheumatoid arthritis. Rheumatology (Oxford) 42, 76–82 (2003).

    CAS  Article  Google Scholar 

  17. Fischer, T. et al. Assessment of unspecific near-infrared dyes in laser-induced fluorescence imaging of experimental arthritis. Acad. Radiol. 13, 4–13 (2006).

    Article  PubMed  Google Scholar 

  18. Hansch, A. et al. In vivo imaging of experimental arthritis with near-infrared fluorescence. Arthritis Rheum. 50, 961–967 (2004).

    Article  PubMed  Google Scholar 

  19. Hansch, A. et al. Diagnosis of arthritis using near-infrared fluorochrome Cy5.5. Invest. Radiol. 39, 626–632 (2004).

    CAS  Article  PubMed  Google Scholar 

  20. Chen, W. T., Mahmood, U., Weissleder, R. & Tung, C. H. Arthritis imaging using a near-infrared fluorescence folate-targeted probe. Arthritis Res. Ther. 7, R310–R317 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. Simon, G. H. et al. Optical imaging of experimental arthritis using allogeneic leukocytes labeled with a near-infrared fluorescent probe. Eur. J. Nucl. Med. Mol. Imaging 33, 998–1006 (2006).

    CAS  Article  PubMed  Google Scholar 

  22. Pogue, B. W. Near-infrared characterization of disease via vascular permeability probes. Acad. Radiol. 13, 1–3 (2006).

    Article  PubMed  Google Scholar 

  23. Rengel, Y., Ospelt, C. & Gay, S. Proteinases in the joint: clinical relevance of proteinases in joint destruction. Arthritis Res. Ther. 9, 221 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Ntziachristos, V., Tung, C. H., Bremer, C. & Weissleder, R. Fluorescence molecular tomography resolves protease activity in vivo. Nat. Med. 8, 757–760 (2002).

    CAS  Article  PubMed  Google Scholar 

  25. Wunder, A., Tung, C. H., Müller-Ladner, U., Weissleder, R. & Mahmood, U. In vivo imaging of protease activity in arthritis: a novel approach for monitoring treatment response. Arthritis Rheum. 50, 2459–2465 (2004).

    CAS  Article  PubMed  Google Scholar 

  26. Li, J. et al. Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model. Arthritis Rheum. 64, 1098–1109 (2012).

    CAS  Article  PubMed  Google Scholar 

  27. Post, A. M. et al. Imaging cell death with radiolabeled annexin V in an experimental model of rheumatoid arthritis. J. Nucl. Med. 43, 1359–1365 (2002).

    CAS  PubMed  Google Scholar 

  28. Blankenberg, F. G. In vivo detection of apoptosis. J. Nucl. Med. 49 (Suppl. 2), 81S–95S (2008).

    CAS  Article  PubMed  Google Scholar 

  29. Edgington, L. E. et al. Noninvasive optical imaging of apoptosis by caspase-targeted activity-based probes. Nat. Med. 15, 967–973 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. McBride, H. J. Nuclear imaging of autoimmunity: focus on IBD and RA. Autoimmunity 43, 539–549 (2010).

    Article  PubMed  Google Scholar 

  31. Gotthardt, M., Bleeker-Rovers, C. P., Boerman, O. C. & Oyen, W. J. Imaging of inflammation by PET, conventional scintigraphy, and other imaging techniques. J. Nucl. Med. 51, 1937–1949 (2010).

    PubMed  Google Scholar 

  32. Sokoloff, L. et al. The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J. Neurochem. 28, 897–916 (1977).

    CAS  Article  PubMed  Google Scholar 

  33. Hawkins, R. A. et al. PET cancer evaluations with FDG. J. Nucl. Med. 32, 1555–1558 (1991).

    CAS  PubMed  Google Scholar 

  34. Ju, J. H. et al. Visualization and localization of rheumatoid knee synovitis with FDG-PET/CT images. Clin. Rheumatol. 27 (Suppl. 2), S39–S41 (2008).

    Article  PubMed  Google Scholar 

  35. Matsui, T. et al. Inflammatory cytokines and hypoxia contribute to 18F-FDG uptake by cells involved in pannus formation in rheumatoid arthritis. J. Nucl. Med. 50, 920–926 (2009).

    CAS  Article  PubMed  Google Scholar 

  36. Basu, S. et al. Novel quantitative techniques for assessing regional and global function and structure based on modern imaging modalities: implications for normal variation, aging and diseased states. Semin. Nucl. Med. 37, 223–239 (2007).

    Article  PubMed  Google Scholar 

  37. Torigian, D. A. et al. Feasibility and performance of novel software to quantify metabolically active volumes and 3D partial volume corrected SUV and metabolic volumetric products of spinal bone marrow metastases on 18F-FDG-PET/CT. Hell. J. Nucl. Med. 14, 8–14 (2011).

    PubMed  Google Scholar 

  38. Basu, S. & Alavi, A. Unparalleled contribution of 18F-FDG PET to medicine over 3 decades. J. Nucl. Med. 49, 17N–21N, 37N (2008).

    Article  PubMed  Google Scholar 

  39. Basu, S. et al. Functional imaging of inflammatory diseases using nuclear medicine techniques. Semin. Nucl. Med. 39, 124–145 (2009).

    Article  PubMed  Google Scholar 

  40. Vogel, W. V., van Riel, P. L. & Oyen, W. J. FDG-PET/CT can visualise the extent of inflammation in rheumatoid arthritis of the tarsus. Eur. J. Nucl. Med. Mol. Imaging 34, 439 (2007).

    Article  PubMed  Google Scholar 

  41. Brenner, W. 18F-FDG PET in rheumatoid arthritis: there still is a long way to go. J. Nucl. Med. 45, 927–929 (2004).

    CAS  PubMed  Google Scholar 

  42. Fonseca, A. et al. 18F-FDG PET imaging of rheumatoid articular and extraarticular synovitis. J. Clin. Rheumatol. 14, 307 (2008).

    Article  PubMed  Google Scholar 

  43. Kubota, K. et al. Whole-body FDG-PET/CT on rheumatoid arthritis of large joints. Ann. Nucl. Med. 23, 783–791 (2009).

    Article  PubMed  Google Scholar 

  44. Lin, P. W., Liu, R. S., Liou, T. H., Pan, L. C. & Chen, C. H. Correlation between joint [F-18] FDG PET uptake and synovial TNF-α concentration: a study with two rabbit models of acute inflammatory arthritis. Appl. Radiat. Isot. 65, 1221–1226 (2007).

    CAS  Article  PubMed  Google Scholar 

  45. Mountz, J. D. et al. Molecular imaging: new applications for biochemistry. J. Cell. Biochem. Suppl. 39, 162–171 (2002).

    Article  PubMed  Google Scholar 

  46. Roivainen, A. et al. Use of positron emission tomography with methyl-11C-choline and 2-18F-fluoro-2-deoxy-D-glucose in comparison with magnetic resonance imaging for the assessment of inflammatory proliferation of synovium. Arthritis Rheum. 48, 3077–3084 (2003).

    CAS  Article  PubMed  Google Scholar 

  47. Polisson, R. P. et al. Use of magnetic resonance imaging and positron emission tomography in the assessment of synovial volume and glucose metabolism in patients with rheumatoid arthritis. Arthritis Rheum. 38, 819–825 (1995).

    CAS  Article  PubMed  Google Scholar 

  48. Carey, K. et al. Evolving role of FDG PET imaging in assessing joint disorders: a systematic review. Eur. J. Nucl. Med. Mol. Imaging 38, 1939–1955 (2011).

    Article  PubMed  Google Scholar 

  49. Beckers, C. et al. Assessment of disease activity in rheumatoid arthritis with 18F-FDG PET. J. Nucl. Med. 45, 956–964 (2004).

    CAS  PubMed  Google Scholar 

  50. Beckers, C. et al. 18F-FDG PET imaging of rheumatoid knee synovitis correlates with dynamic magnetic resonance and sonographic assessments as well as with the serum level of metalloproteinase-3. Eur. J Nucl. Med. Mol. Imaging 33, 275–280 (2006).

    Article  PubMed  Google Scholar 

  51. Palmer, W. E. et al. Quantification of inflammation in the wrist with gadolinium-enhanced MR imaging and PET with 2-[F-18]-fluoro-2-deoxy-D-glucose. Radiology 196, 647–655 (1995).

    CAS  Article  PubMed  Google Scholar 

  52. Goerres, G. W. et al. F-18 FDG whole-body PET for the assessment of disease activity in patients with rheumatoid arthritis. Clin. Nucl. Med. 31, 386–390 (2006).

    Article  PubMed  Google Scholar 

  53. Szekanecz, Z., Besenyei, T., Paragh, G. & Koch, A. E. New insights in synovial angiogenesis. Joint Bone Spine 77, 13–19 (2010).

    CAS  Article  PubMed  Google Scholar 

  54. Friedlander, M. et al. Involvement of integrins αvβ3 and αvβ5 in ocular neovascular diseases. Proc. Natl Acad. Sci. USA 93, 9764–9769 (1996).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. Sipkins, D. A. et al. Detection of tumor angiogenesis in vivo by αvβ3-targeted magnetic resonance imaging. Nat. Med. 4, 623–626 (1998).

    CAS  Article  PubMed  Google Scholar 

  56. Nakamura, I., Duong le, T., Rodan, S. B. & Rodan, G. A. Involvement of αvβ3 integrins in osteoclast function. J. Bone Miner. Metab. 25, 337–344 (2007).

    CAS  Article  PubMed  Google Scholar 

  57. Wilder, R. L. Integrin αvβ3 as a target for treatment of rheumatoid arthritis and related rheumatic diseases. Ann. Rheum. Dis. 61 (Suppl. 2), ii96–ii99 (2002).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. Beer, A. J. et al. PET-based human dosimetry of 18F-galacto-RGD, a new radiotracer for imaging αvβ3 expression. J. Nucl. Med. 47, 763–769 (2006).

    CAS  PubMed  Google Scholar 

  59. Niu, G. & Chen, X. PET Imaging of Angiogenesis. PET Clin. 4, 17–38 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Leung, K. 4-[18F]Fluorobenzoyl-Phe-Ala-Leu-Gly-Glu-Ala-NH2. Molecular Imaging and Contrast Agent Database [online], (2011).

    Google Scholar 

  61. Zheleznyak, A. et al. Integrin αvβ3 as a PET imaging biomarker for osteoclast number in mouse models of negative and positive osteoclast regulation. Mol. Imaging Biol. http://dx.doi.org/10.1007/s11307-011-0512-4.

  62. Martens, C. L. et al. Peptides which bind to E-selectin and block neutrophil adhesion. J. Biol. Chem. 270, 21129–21136 (1995).

    CAS  Article  PubMed  Google Scholar 

  63. Gaál, J. et al. 99mTc-HMPAO labelled leukocyte scintigraphy in patients with rheumatoid arthritis: a comparison with disease activity. Nucl. Med. Commun. 23, 39–46 (2002).

    Article  PubMed  Google Scholar 

  64. Barrera, P. et al. Radiolabelled interleukin-1 receptor antagonist for detection of synovitis in patients with rheumatoid arthritis. Rheumatology (Oxford) 39, 870–874 (2000).

    CAS  Article  Google Scholar 

  65. Roimicher, L. et al. 99mTc-anti-TNF-α scintigraphy in RA: a comparison pilot study with MRI and clinical examination. Rheumatology (Oxford) 50, 2044–2050 (2011).

    Article  Google Scholar 

  66. Gent, Y. Y. et al. Macrophage positron emission tomography imaging as a biomarker for preclinical rheumatoid arthritis: findings of a prospective pilot study. Arthritis Rheum. 64, 62–66 (2012).

    Article  PubMed  Google Scholar 

  67. van der Laken, C. J. et al. Noninvasive imaging of macrophages in rheumatoid synovitis using 11C-(R)-PK11195 and positron emission tomography. Arthritis Rheum. 58, 3350–3355 (2008).

    Article  PubMed  Google Scholar 

  68. Schrigten, D. et al. A new generation of radiofluorinated pyrimidine-2, 4, 6-triones as MMP-targeted radiotracers for positron emission tomography. J. Med. Chem. 55, 223–232 (2012).

    CAS  Article  PubMed  Google Scholar 

  69. Beyer, T. et al. A combined PET/CT scanner for clinical oncology. J. Nucl. Med. 41, 1369–1379 (2000).

    CAS  PubMed  Google Scholar 

  70. Tran, L. et al. CD20 antigen imaging with 124I–rituximab PET/CT in patients with rheumatoid arthritis. Hum. Antibodies 20, 29–35 (2011).

    CAS  Article  PubMed  Google Scholar 

  71. Delso, G. et al. Performance measurements of the Siemens mMR integrated whole-body PET/MR scanner. J. Nucl. Med. 52, 1914–1922 (2011).

    Article  PubMed  Google Scholar 

  72. Borrero, C. G., Mountz, J. M. & Mountz, J. D. Emerging MRI methods in rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 85–95 (2011).

    Article  PubMed  Google Scholar 

  73. Kropholler, M. A. et al. Quantification of (R)-[11C]PK11195 binding in rheumatoid arthritis. Eur. J. Nucl. Med. Mol. Imaging 36, 624–631 (2009).

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

J. D. Mountz's research work is funded by grants from the American College of Rheumatology Research and Education Foundation—Within Our Reach: Finding a Cure for Rheumatoid Arthritis campaign, the Alliance for Lupus Research—Target Identification in Lupus program, Veterans Administration Merit Review Grants (1I01BX000600-01), and NIH grants (1AI 071110 and ARRA 3RO1AI71110). The authors thank H. Hsu and J. Li for critical reading of this manuscript, F. Hunter for editorial suggestions and C. Humber and D. M. Frasher for assistance with manuscript preparation.

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Mountz, J., Alavi, A. & Mountz, J. Emerging optical and nuclear medicine imaging methods in rheumatoid arthritis. Nat Rev Rheumatol 8, 719–728 (2012). https://doi.org/10.1038/nrrheum.2012.148

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