European Journal of Nuclear Medicine

, Volume 22, Issue 11, pp 1339–1346

New agents for scintigraphy in rheumatoid arthritis

  • Marjolein H. W. de Bois
  • Ernest K. J. Pauwels
  • Ferdinand C. Breedveld
Review Article


Radiopharmaceuticals have been used as investigative tools for the detection and treatment of arthritis activity in rheumatoid arthritis (RA) since the 1950s. Against the background of the pathophysiology of RA, the current status of joint scintigraphy and possible future developments are reviewed. Both non-specific (radiolabelled leucocytes and technetium-99m labelled human immunoglobulin) and specific targeting radiopharmaceuticals (including radiolabelled antibodies) are considered. The use of radiopharmaceuticals in the detection of arthritis activity has the advantages of allowing direct imaging of joints by means of whole-body scintigraphy and of joints that are difficult to assess clinically or radiographically. Promising results have been obtained with radiolabelled anti-CD4 and anti-E-selectin antibodies and with somatostatin receptor imaging, but more data are available regarding99mTc-IgG scintigraphy, which differentiates between the various degrees of arthritis activity and thus facilitates the choice of antirheumatic drug. Newer promising approaches to the imaging of RA include the use of radiolabelled J001 and cytokines, though studies on these are limited at present.

Key words

Rheumatoid arthritis Human immunoglobulin Radiolabelled antibodies Somatostatin receptors J001 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Cush JJ, Lipsky PE. Cellular basis for rheumatoid inflammation.Clin Orthop Rel Res 1991; 265: 9–22.Google Scholar
  2. 2.
    Lipsky PE, Davis LS, Cush JJ, Oppenheimer-Marks N. The role of cytokines in the pathogenesis of rheumatoid arthritis.Springer Semin Immunopathol 1990; 11: 123–162.Google Scholar
  3. 3.
    Chu CQ, Field M, Allard S, Abney E, Feldmann M, Maini RN. Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair.Br J Rheumatol 1992; 31: 653–661.Google Scholar
  4. 4.
    Feldmann M, Brennan FM, Chantry D, Haworth C, Turner M, Abney E, Buchan G, Barrett K, Barkley D, Chu A, Field M, Maini RN. Cytokine production in the rheumatoid joint; implications for treatment.Ann Rheum Dis 1990; 49: 480–486.Google Scholar
  5. 5.
    Gardner DL.Pathological basis of the connective tissue diseases, 1st edn. London: Edward Arnold, 1992.Google Scholar
  6. 6.
    Firestein GS. Rheumatoid synovitis and pannus. In. Klippel SH, Dieppe PA, eds.Rheumatology. Mosby Year Book: London, 1994.Google Scholar
  7. 7.
    Cotran RS, Kuman V Robbins SL. Inflammation and repair. In: Cotran RS, Kuman V, Robbins SL, eds.Pathologic basis of disease. Philadelphia: W.B. Saunders; 1989: 39–86.Google Scholar
  8. 8.
    Robinson DR. Lipid mediators of inflammation. In: Zvaifler N, ed.Rheumatic disease clinics of North America. Philadelphia: W.B. Saunders; 1987: 385–405.Google Scholar
  9. 9.
    Mapp PI, Grootveld MC, Blake DR. Hypoxia, oxidative stress and rheumatoid arthritis.Br Med Bull 1995; 151: 419–436.Google Scholar
  10. 10.
    FitzGerald O, Soden M, Yanni G, Robinson R, Bresnihan B. Morphometric analysis of blood vessels in synovial membranes obtained from clinically affected and unaffected joints of patients with rheumatoid arthritis.Ann Rheum Dis 1991; 50: 792–796.Google Scholar
  11. 11.
    Stevens CR, Blake DR, Merry P, Revell PA, Levick JR. A comparative study by morphometry of the microvasculature in normal and rheumatoid synovium.Arthritis Rheum 1991; 34: 1508–1513.Google Scholar
  12. 12.
    Rotschild BM, Masi AT. Pathogenesis of rheumatoid arthritis. A vascular hypothesis.Semin Arthritis Rheum 1982; 12: 11–31.Google Scholar
  13. 13.
    Springer TA. Adhesion receptors of the immune system.Nature 1990; 346: 425–434.Google Scholar
  14. 14.
    Panayi GS, Lanchbury JS, Kingsley GH. The importance of the T cell initiating and maintaining the chronic synovitis of rheumatoid arthritis.Arthritis Rheum 1992; 35: 729–735.Google Scholar
  15. 15.
    Kitsis E, Weissmann G. The role of the neutrophil in rheumatoid arthritis.Clin Orthop Rel Res 1991; 265: 63–72.Google Scholar
  16. 16.
    Feldmann M, Brennan FM, Field M, Maini RN. Pathogenesis of rheumatoid arthritis. In: Smolen IS, Kalden JR, Maini RN, eds.Rheumatoid arthritis. Berlin Heidelberg New York: Springer; 1992: 41–54.Google Scholar
  17. 17.
    Dinarello CA. Growth factors. In: Kelley WN, Harris ED, Ruddy S, Sledge CB, eds.Textbook of rheumatology. Philadelphia: W.B. Saunders; 1989: 285–294.Google Scholar
  18. 18.
    Elliot MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen IS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H, Woody IN. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factorα (cA2) versus placebo in rheumatoid arthritis.Lancet 1994; 344: 1104.Google Scholar
  19. 19.
    Uno K, Matsui N, Nohira K, Suguro T, Kitakata Y, Uchiyama G, Miyoshi T, Uematsu S, Inoue S, Arimizu N. Indium-111 leukocyte imaging in patients with rheumatoid arthritis.J Nucl Med 1986; 27: 339–344.Google Scholar
  20. 20.
    Rydgren L, Wollmer P, Hultguist R, Gustafson T.111Indium-labelled leucocytes for measurement of inflammatory activity in arthritis.Scand J Rheumatol 1991; 20: 319–325.Google Scholar
  21. 21.
    Al-Janabi MA, Jones AKP, Solanki KK, Sobnack R, Bomanji J, Al-Nahhas AA, Doyle DV, Britton KE, Huskisson EC.99m-Tcm-labelled leucocyte imaging in active rheumatoid arthritis.Nucl Med Commun 1988; 9: 987–991.Google Scholar
  22. 22.
    Al-Janabi MA, Sobnack R, Solanki KK, Jones AK, Critchley M, Smith ML, Britton KE, Huskisson EC. The response of99mTcm-methylene disphosphonate and99mTcm-hexametazime-labelled neutrophils to intra-articular steroid injection in rheumatoid arthritis.Nucl Med Commun 1992; 13: 528–534.Google Scholar
  23. 23.
    Jones AKP, Al-Jabani MA, Solanski KK, Sobnack R, Greenwood A, Doyle DV Britton KE, Huskisson EC. In vivo leucocyte migration in arthritis.Arthritis Rheum 1991; 34: 270–275.Google Scholar
  24. 24.
    Fischman AJ, Rubin RH, Khaw BA, Callahan RJ, Wilkinson R, Keech F, Nedelman M, Dragotakes S, Kramer PB, LaMuraglia GM, Lind S, Strauss HW. Detection of acute inflammation with indium-111 labeled nonspecific polyclonal IgG.Semin Nucl Med 1988; 18: 355–344.Google Scholar
  25. 25.
    Rubin RH, Fischman AJ, Callahan RJ, Khaw BA, Keech F, Ahmad M, Wilkinson R, Strauss HW. In-111-labeled nonspecific immunoglobulin scanning in the detection of focal infection.N Engl J Med 1989; 321: 935–940.Google Scholar
  26. 26.
    Buscombe JR, Lui D, Ensing G, de Jong R, Ell PJ. Tc-99m-human immunoglobulin (HIG) — first results of a new agent for the localization of infection and inflammation.Eur J Nucl Med 1990; 16: 649–655.Google Scholar
  27. 27.
    Breedveld FC, van Kroonenburgh MJPG, Camps JAJ, Feitsma HIJ, Markusse HM, Pauwels EKJ. Imaging of inflammatory arthritis with technetium-99m-labeled IgG.J Nucl Med 1989; 30: 2017–2021.Google Scholar
  28. 28.
    Lubbe van der PAHM, Arndt JW, Calame W, Ferreira TC, Pauwels EKJ, Breedveld FC, Measurement of synovial inflammation in rheumatoid arthritis with technetium-99m labelled human polyclonal immunoglobulin G.Eur J Nucl Med 1991; 18: 119–123.Google Scholar
  29. 29.
    Berná L, Torres G, Diez C, Estorch M, Martinez-Duncher D, Carrio I. Technetium-99m human polyclonal immunoglobulin G studies and conventional bone scans to detect active joint inflammation in chronic rheumatoid arthritis.Eur J Nucl Med 1992; 19: 173–176.Google Scholar
  30. 30.
    Bois de MHW, Arndt JW, Velde van der EA, Lubbe van der PAHM, Westedt ML, Pauwels EKJ, Breedveld FC.99mTc human immunoglobulin scintigraphy — a reliable method to detect joint activity in rheumatoid arthritis.J. Rheumatol 1992; 13: 1371–1376.Google Scholar
  31. 31.
    Liberatore M, Clemente M, Iurilli AP, Zorzin L, Marini M, Di Rocco E, Cotella AC. Scintigraphic evaluation of disease activity in rheumatoid arthritis: a comparison of technetium-99m human non-specific immunoglobulins, leucocytes and albumin nanocolloids.Eur J Nucl Med 1992; 19: 853–857.Google Scholar
  32. 32.
    Pons F, Moyá F, Herranz R, Solá M, Del Olmo JA, Piera C, Muñoz-Gomez J, Setoain J. Detection and quantitative analysis of joint activity inflammation with99m-Tem-polyclonal human immunoglobulin G.Nucl Med Commun 1993; 14: 225–231.Google Scholar
  33. 33.
    Bois de MHW, Arndt JW, Velde van der EA, Pauwels EKJ, Breedveld FC. Joint scintigraphy for quantification of synovitis with99mTc-labelled human immunoglobulin G compared to late phase scintigraphy with99mTc-labelled disphosphonate.Br J Rheumatol 1994; 33: 67–73.Google Scholar
  34. 34.
    Bois de MHW, Arndt JW, Tak PP, Kluin PM, van der Velde EA, Pauwels EKJ, Breedveld FC.99mTcm-labelled polyclonal human immunoglobulin G scintigraphy before and after intraarticular knee injection of triamcinolone hexacetonide in patients with rheumatoid arthritis.Nucl Med Commun 1993; 14: 883–887.Google Scholar
  35. 35.
    Bois de MHW, Westedt M-L, Arndt JW Wiarda KS, Velde van der EA, Pauwels EKJ, Breedveld FC. Technetium-99m labelled polyclonal human immunoglobulin G scintigraphy before and 26 weeks after initiation of parenteral gold treatment in patients with rheumatoid arthritis.J Rheumatol 1995; 22: 1461–1465.Google Scholar
  36. 36.
    Bois de MHW, Tak PP, Arndt JW, Kluin PM, Pauwels EKJ, Breedveld FC. Joint scintigraphy for quantification of synovitis with99mTc-labelled human immunoglobulin G compared to histological examination.Clin Exp Rheumatol 1995; 13: 155–159.Google Scholar
  37. 37.
    Jamar F, Manicourt DH, Leners N, van den Berghe M, Beckers C. Evaluation of disease activity in rheumatoid arthritis and other arthritides using technetium-99m labelled nonspecific human immunoglobulin.J Rheumatol 1995; 22: 850–854.Google Scholar
  38. 38.
    Morrel EM, Tompkins RG, Fischman AJ, Wilkinson RA, Burke JF, Rubin RH, Strauss HW, Yarmush ML. Autoradiographic method for quantitation of radiolabelled proteins in tissues using indium-111.J Nucl Med 1989; 30: 1538–1545.Google Scholar
  39. 39.
    Juweid M, Strauss HW, Yaoita H, Rubin RH, Fischman AJ. Accumulation of immunoglobulin G at focal sites of inflammation.Eur J Nucl Med 1992; 19: 159–165.Google Scholar
  40. 40.
    Oyen WJG, Claessens RAMJ, van der Meer JWM, Corstens FHM. Biodistribution and kinetics of radiolabelled proteins in rats with focal infection.J Nucl Med 1992; 33: 388–394.Google Scholar
  41. 41.
    Claessens RAMJ, Koenders EB, Boerman OC, Oyen WJG, Borm GF, van der Meer JWM, Corstens FHM. Dissociation of indium from indium-111-labelled diethylene triamine pentaacetic acid conjugated non-specific polyclonal human immunoglobulin G in inflammatory foci.Eur J Nucl Med 1995; 22: 212–219.Google Scholar
  42. 42.
    Calame W, Feitsma HIJ, Ensing GJ, Arndt J-W, van Furt R, Pauwels EKJ. Binding of99mTc-labelled polyclonal human immunoglobulin to bacteria as a mechanism for scintigraphic detection of infection.Eur J Nucl Med 1991; 18: 396–400.Google Scholar
  43. 43.
    Fischman AJ, Rubin RH, White JA, Locke E, Wilkinson RA, Nedelman M, Callahan RJ, Khaw BA, Strauss HW. Localization of Fc and Fab fragments of nonspecific polyclonal IgG at focal sites of inflammation.J Nucl Med 1990; 31: 1199–1205.Google Scholar
  44. 44.
    Oyen WJG, Claessens RAMJ, Rademakers JMM, Pauw de BE, Meer van der JWM, Corstens FHM. Diagnosing infections in febrile granulocytopenic patients with indium-111 labeled human IgG.J Clin Oncol 1992; 10: 61–68.Google Scholar
  45. 45.
    De Sousa M. Basics AL, Dynesius-Trentham R, Kerr S, Bernardo A, Duarte JG, Trentham DE. Potential of indium-111 to measure inflammatory arthritis.J Rheumatol 1986; 13: 1108–1116.Google Scholar
  46. 46.
    Goldenberg DM. Immunodiagnosis and immunodetection of colorectal cancer.Cancer Bull 1978; 30: 213–218.Google Scholar
  47. 47.
    Goldenberg DM, Larson SM. Radioimmunodetection in cancer identification.J Nucl Med 1992; 33: 803–814.Google Scholar
  48. 48.
    Serafini AN. From monoclonal antibodies to peptides and molecular recognition units: an overview.J Nucl Med 1993; 34: 533–536.Google Scholar
  49. 49.
    Horneff G, Winkler T. Kalden JR, Emmrich F, Burmester GR. Human anti-mouse antibody response induced by anti-CD4 monoclonal antibody therapy in patients with rheumatoid arthritis. Clin Immunol Immunopathol 1991; 59: 89–103.Google Scholar
  50. 50.
    Marcus C, Thakur ML, Huynh TV, Louie IS, Leibling M, Minami C, Diggles L. Imaging rheumatic joint diseases with anti-T lymphocyte antibody OKT-3.Nucl Med Commun 1994; 15: 824–830.Google Scholar
  51. 51.
    Becker W Emmrich F, Horneff G, Burmester G, Seiler F, Schwarz A, Kalden J, Wolf F. Imaging rheumatoid arthritis specifically with technetium 99m CD4-specific (T-helper lymphocytes) antibodies.Eur J Nucl Med 1990; 17: 156–159.Google Scholar
  52. 52.
    Kinne RW, Becker W, Schwab J, Horneff G, Schwarz A, Kalden JR, Emmrich F, Burmester GR, Wolf F. Comparison on99mTcm-labelled specific murine anti-CD4 monoclonal antibodies and nonspecific human immunoglobulin for imaging inflamed joints in rheumatoid arthritis.Nucl Med Commun 1993; 14: 667–675.Google Scholar
  53. 53.
    Kinne RW, Becker W, Simon G, Paganelli G, Palombo-Kinne E, Wolski A, Bloch S, Schwarz A, Wolf F, Emmrich F. Joint uptake and body distribution of a technetium-99m-labeled anti-rat-CD4 monoclonal antibody in rat adjuvant arthritis.J Nucl Med 1993; 34: 92–98.Google Scholar
  54. 54.
    Keelan ETM, Licence ST, Peters AM, Binns RM, Haskard DO. Characterization of E-selectin expression in vivo with use of a radiolabeled monoclonal antibody.Am J Physiol 1994; 266: 14279–14290.Google Scholar
  55. 55.
    Keelan ETM, Harrison AA, Chapman PT, Binns RM, Peters M, Haskard DO. Imaging vascular endothelial activation: an approach using radiolabeled monoclonal antibodies against the endothelial cell adhesion molecule E-selectin.J Nucl Med 1994; 35: 276–281.Google Scholar
  56. 56.
    Chapman PT, Jamar F, Keelan ETM, Peters AM, Haskard DO. Targeting endothelial activation in inflammation using111In-labelled anti-E-selectin monoclonal antibody.Br J Rheumatol 1995; 34 Suppl 1: 81.Google Scholar
  57. 57.
    Hagen van PM, Krenning EP, Kwekkeboom DJ, Reubi JC, Anker-Lugtenburg van der PJ, Löwenberg B, Lamberts SWJ. Somatostatin and the immune and haematopoetic system: a review.Eur J Clin Invest 1994; 24: 91–99.Google Scholar
  58. 58.
    Hagen van PM, Markusse HM, Lamberts SWJ, Kwekkeboom DJ, Reubi JC, Krenning ESP. Somatostatin receptor imaging. The presence of somatostatin receptors in rheumatoid arthritis.Arthritis Rheum 1994; 10: 1521–1527.Google Scholar
  59. 59.
    Hmama Z, Normier G, Kouassi E, Flacher M, Binz H, Revillard JP. Binding of a membrane proteoglycan from klebsiella pneumonia and its derivatives to human leukocytes.Immunobiology 1992; 186: 183–198.Google Scholar
  60. 60.
    Hmama Z, Kouassi E, Panaye G, Delassan S, Normier G, Binz H, Revillard JP. Binding of a bacterial acylpoly (1,3) galactoside to human blood leucocytes.Scand J Immunol 1992; 36: 11–20.Google Scholar
  61. 61.
    Diot P, Le Pape A, Nolibe D, Normier G, Revillard JP, Lasfargues G, Lavandier M, Lemarié E. Scintigraphy with JOOIX, a klebsiella membrane glycolipid, for the early diagnosis of chronic berylliosis: results from an experimental model.Br J Ind Med 1992; 49: 359–364.Google Scholar
  62. 62.
    Perin F, Pittet J-C, Hoffschir D, Normier G, Binz H, Le Pape A. Scintigraphic potentials of J001X acylated polygalactoside for imaging inflammatory lesions in pigs.Nucl Med Biol 1993; 20: 963–971.Google Scholar
  63. 63.
    Diot P, Lemarié E, Baulieu JL, Pascal S, Vaillant L, Revillard JR, Binz H, Normier G, Le Pape A. Scintigraphy with J001 macrophage targeting glycolipopeptide. A new approach for sarcoidosis imaging.Chest 1992; 102: 670–676.Google Scholar
  64. 64.
    Goupille P, Valat J-P, Le Pape A. Imaging of synovitis in rheumatoid arthritis with radionuclide tracers.J Rheumatol 1994; 21: 1975–1976.Google Scholar
  65. 65.
    Budinger TF, Taylor SE. New approaches to targeting arthritis with radiopharmaceuticals.R Rheumatol 1995; 22 Suppl 43: 62–67.Google Scholar
  66. 66.
    Thedrez P, Painuau J, Jacques Y, Chatal JP, Pelegrin A, Bouchaud C, Soulillou JP. Biodistribution of an anti-interleukin 2 receptor monoclonal antibody in rat recipients of a heart allograft, and its use as a rejection marker in gamma scintigraphy.Transplantation 1989; 48: 367–371.Google Scholar
  67. 67.
    Takahashi H, Herlyn D, Atkinson B, Powe J, Rodeck U, Alavi A, Bruce DA, Koprowski H. Radioimmunodetection of human glioma xenografts by monoclonal antibody to epidermal growth factor receptor.Cancer Res 1987; 3847–3850.Google Scholar
  68. 68.
    Abbs IC, Pratt JR, Dallman MJ, Sacks SH. Analysis of activated T cell infiltrates in rat renal allografts by gamma camera imaging after injection of123iodine-interleukin 2.Transplant Immunol 1993; 1: 45–51.Google Scholar
  69. 69.
    Signore A, Parman A, Pozilli P, Andreani D, Beverley PCL. Detection of activated lymphocytes in endocrine pancreas of BB/W rats by injection of123I-interleukin-2; an early sign of type 1 diabetes.Lancet 1987; I: 537–539.Google Scholar
  70. 70.
    Signore A, Chianelli M, Ferretti E, Toscano A, Britton KE, Andreani D, Gale EAM, Pozilli P. New approach for in vivo detection of insulitis in type 1 diabetes: activated lymphocyte targeting with123I-labelled interleukin 2.Eur J Endocrinol 1994; 131: 431–437.Google Scholar
  71. 71.
    Lövgvist A, Lindström A, Carlsson J. Binding, internalization and excretion of TNFα-dextran associated radioactivity in cultured human glioma cells.Cancer Biother 1993; 8: 345–356.Google Scholar
  72. 72.
    Andersson A, Holmberg A, Carlsson J, Carlsson J, Pontén J, Westermark B. Binding of epidermal growth factor-dextran conjugates to cultured glioma cells.Int J Cancer 1991; 47: 439–444.Google Scholar
  73. 73.
    Schatten C, Pateisky N, Vavra N, Ehrenbock P, Angelberger P, Sivolapenko G, Epenetos A. Lymphoscintigraphy with123I-labelled epidermal growth factor.Lancet 1991; 337: 395–396.Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Marjolein H. W. de Bois
    • 1
  • Ernest K. J. Pauwels
    • 2
  • Ferdinand C. Breedveld
    • 1
  1. 1.Department of RheumatologyUniversity Hospital LeidenLeidenThe Netherlands
  2. 2.Department of Diagnostic Radiology and Nuclear MedicineUniversity HospitalLeidenThe Netherlands

Personalised recommendations