Pharmacy World and Science

, Volume 21, Issue 2, pp 49–59 | Cite as

New therapeutic targets for rheumatoid arthritis

  • H.J. Dinant
  • B.A.C. Dijkmans


New insights into the pathogenesis of rheumatoid arthritis (RA) and consequently new targets of therapy are covered in a broad overview fashion. Short‐term significant beneficial effect on RA disease activity has been established in a small but rapidly growing number of double‐blind placebo‐controlled trials now including recombinant human IL‐1 receptor antagonist, chimeric (mouse/human) monoclonal antibodies (mAb) against TNFa (cA2), humanised (human/mouse) anti‐TNFa mAb (CDP571) and recombinant human TNF‐receptor‐Fc fusion protein (TNFR : Fc). Placebo‐controlled trials of anti‐T cells agents such as chimeric anti‐CD4 mAb (cM‐T412) and anti‐CD5 immunoconjugate, did not demonstrate clinical benefit. A placebo‐controlled study of the anti‐T cell derived cytokine IL‐2 (DAB486IL‐2) showed only modes clinical improvement. Other anti‐T cell approaches such as autologous T cell vaccination and induction of tolerance by oral type II collagen have been unsuccessful. The one controlled trial with an anti‐inflammatory cytokine, recombinant human IFN‐g, showed modest clinical benefits. Controlled trials with IL‐4 and IL‐10 and with anti‐adhesion molecules are awaited.

Rheumatoid arthritis Pathogenesis Therapy Monoclonal antibodies Biologicals 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Waaler E. On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. Acta Pathol Microbiol Scand 1940;17:172-88.Google Scholar
  2. 2.
    Silman AJ, MacGregor AJ, Thomson W, Holligan S, Carthy D, Farhan A, Ollier WER. Twin concordance rates for rheumatoid arthritis: Results from a nation-wide study. Br J Rheumatol 1993;32:903-7.Google Scholar
  3. 3.
    Van Zeben D, Hazes JM, Zwinderman AH, Cats A, Schreuder GMTh, D'Amaro J, Breedveld FC. Association of HLA-DR4 with a more progressive disease course in patients with rheumatoid arthritis. Arthritis Rheum 1991;34:822-30.Google Scholar
  4. 4.
    Rasker JJ, Cosh JA, Cause and age at death in a prospective study of 100 patients with rheumatoid arthritis. Ann Rheum Dis 1981;40:115-20.Google Scholar
  5. 5.
    Pinals RS. Survival in rheumatoid arthritis. Arthritis Rheum 1987;30:473-475.Google Scholar
  6. 6.
    Fries JF. The assessment of disability: from first to future principles. Br J Rheumatol 1983;22(Suppl):48-58.Google Scholar
  7. 7.
    Scott DL, Symmons DP, Coulton BL, Popert AJ. Long-term outcome of treating rheumatoid arthritis: results after 20 years. Lancet 1987;1:1108-11.Google Scholar
  8. 8.
    Fries JF. Safety issues related to DMARD therapy. J Rheumatol 1990;25(Suppl):14-7.Google Scholar
  9. 9.
    van der Heide A, Jacobs JW, Bijlsma JW, Heurkens AH, van Booma-Frankfort C, van der Veen MJ, Haanen HC, Hofman DM, van Albada-Kuipers GA, ter Borg EJ, Brus HL, Dinant HJ, Kruize AA, Schenk Y. The effectiveness of early treatment with 'second-line antirheumatic drugs. A randomized, controlled trial. Ann Intern Med 1996;124:699-707.Google Scholar
  10. 10.
    Boers M, Verhoeven AC, Markusse HM, van der Laar MAFJ, Westhovens R, van Denderen C, van Zeben D, Dijkmans BAC, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJA, van der Heijde DMFM, Boonen A, van der Linden S. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:309-18.Google Scholar
  11. 11.
    van de Putte LBA. Chronic arthritis: Why the joint? Scand J Rheumatol 1995;24(Suppl 101):7-9.Google Scholar
  12. 12.
    Edwards JCW, Willoughby DA. Demonstration of bone marrow derived cells in synovial lining by means of giant intracellular granules as genetic markers. Ann Rheum Dis 1982;41:177-82.Google Scholar
  13. 13.
    Schumacher HR Jr, Bautista BB, Krauser RE, Mathur AK, Gall EP. Histological appearance of the synovium in early rheumatoid arthritis. Semin Arthritis Rheum 1994;23(Suppl 2):3-10.Google Scholar
  14. 14.
    Harris ED Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Eng J Med 1990;322:1277-1289.Google Scholar
  15. 15.
    Firestein GS. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum 1996;39:1781-90.Google Scholar
  16. 16.
    Kriegsmann J, Keyszer GM, Geiler T, Brauer R, Gay RE, Gay S. Expression of vascular cell adhesion molecule-1 mRNA and protein in rheumatoid synovium demonstrated by in situ hybridization and immunochemistry. Lab Invest 1995;72:209-14.Google Scholar
  17. 17.
    Van Dinther-Janssen ACHM, Kraal G, van Soesbergen RM, Scheper RJ, Meijer CJLM. Immunohistological and functional analysis of adhesion molecule expression in the rheumatoid synovial lining layer: implications for synovial lining cell destruction. J Rheumatol 1994;21:1998-2004.Google Scholar
  18. 18.
    Müller-Ladner U. Molecular and cellular interactions in rheumatoid synovium. Curr Opin Rheumatol 1996;8:210-20.Google Scholar
  19. 19.
    Shiozawa S, Shiozawa K, Fujita T. Presence of HLA-DR antigen on synovial type A and B cells: An immunoelectron microscopic study in rheumatoid arthritis, osteoarthritis and normal traumatic joints. Immunology 1983;50:587-94.Google Scholar
  20. 20.
    Schumacher HR Jr. Fate of particular material arriving at the synovium via the circulation. An ultrastructural study. Ann Rheum Dis 1973;32:212-8.Google Scholar
  21. 21.
    Zvaifler NJ, Firestein GS. Pannus and pannocytes: alternative models of joint destruction in rheumatoid arthritis. Arthritis Rheum 1994;37:783-9.Google Scholar
  22. 22.
    Ritchtlin C, Dwyer E, Bucala R, Winchester R. Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole synovial tissue obtained from inflammatory synovitis. Scand J Immunol 1994;40:292-8.Google Scholar
  23. 23.
    Roivainen A, Isomaki P, Nikkari S, Saario R, Vuori K, Toivanen P. Oncogene expression in synovial fluid cells in reactive and early rheumatoid arthritis: a brief report. Br J Rheumatol 1995;34:805-8.Google Scholar
  24. 24.
    Firestein GS, Yeo M, Zvaifler NJ. Apoptosis in rheumatoid arthritis synovium. J Clin Invest 1995:96:1631-8.Google Scholar
  25. 25.
    Firestein GS, Zvaifler NJ. How important are T cells in chronic rheumatoid synovitis? Arthritis Rheum 1990;33:768-73.Google Scholar
  26. 26.
    Alvaro-Garcia JM, Zvaifler NJ, Brown CB, Kaushansky K, Firestein GS. Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and TNFα. J Immunol 1991;146:3365-71.Google Scholar
  27. 27.
    Bathon JM, Hwang JJ, Shin LH, Precht PA, Towns MC, Horton WE Jr. Type VI collagen-specific messenger RNA is expressed constitutively by cultured human synovial fibroblasts and is suppressed by interleukin-1. Arthritis Rheum 1994;37:1350-6.Google Scholar
  28. 28.
    van den Hoff H, de Koning M, van Kampen J, van der Korst JK. Interleukin-1 reversibly inhibits the synthesis of biglycan and decorin in intact articular cartilage in culture. J Rheumatol 1995;22:1520-6.Google Scholar
  29. 29.
    van Leeuwen MA, Westra J, Limburg PC, van Riel PLCM, van Rijswijk MH. Clinical significance of interleukin-6 measurement in early rheumatoid arthritis: relation with laboratory and clinical variables and radiological progression in a threeyear prospective study. Ann Rheum Dis 1995;54:674-7.Google Scholar
  30. 30.
    Lipsky PE. The control of antibody production by immunomodulatory molecules. Arthritis Rheum 1989;32:1345-5.Google Scholar
  31. 31.
    Mihara M, Moriya Y, Kishimoto T, Ohsugi Y. Interleukin-6 (IL-6) induces the proliferation of synovial fibroblastic cells in the presence of soluble IL-6 receptor. Br J Rheumatol 1995;34:321-5.Google Scholar
  32. 32.
    Chikanza IC, Roux-Lombard P, Dayer JM, Panayi GS. Dysregulation of the in vivo production of interleukin-1 receptor antagonist in patients with rheumatoid arthritis: pathogenetic implications. Arthritis Rheum 1995;38:642-8.Google Scholar
  33. 33.
    Brennan FM, Gibbons DL, Cope AP, Katsikis P, Maini RN, Feldmann M. TNF inhibitors are produced spontaneously by rheumatoid and osteoarthritic synovial joint cell cultures: evidence of feedback control of TNF action. Scand J Immunol 1995;42:158-65.Google Scholar
  34. 34.
    Cush JJ, Splawski JB, Thomas R, McFarlin JE, Schulze-Koops H, Davis LS, Fujita K, Lipsky PE. Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 1995;38:96-104.Google Scholar
  35. 35.
    Hart PH, Ahern MJ, Smith MD, Finlay-Jones JJ. Comparison of the suppressive effects of interleukin-10 and interleukin-4 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis. Immunology 1995;84:536-42.Google Scholar
  36. 36.
    Miossec P, Chomarat P, Dechanet J, Moreau JF, Roux JP, Delmas P, Bnachereau J. Interleukin-4 inhibits bone resorption through an effect on osteoclasts and proinflammatory cytokines in an ex vivo model of bone resorption in rheumatoid arthritis. Arthritis Rheum 1994;37:1715-122.Google Scholar
  37. 37.
    Paulus HE, Machleder HI, Levine S, Yu DTY, MacDonald NS. Lymphocyte involvement in rheumatoid arthritis: Studies during thoracic duct drainage. Arthritis Rheum 1977;20:1249-62.Google Scholar
  38. 38.
    Trentham DE, Belli JA, Anderson RJ, Buckley JA, Goetzle EJ, David JR, Austen KF. Clinical and immunological effects of total lymphoid irradiation in refractory rheumatoid arthritis. N Engl J Med 1981;305:976-82.Google Scholar
  39. 39.
    Karsh J, Klippel JH, Plotz PH, Decker JL, Wright DG, Flye MW. Lymphapheresis in rheumatoid arthritis. Arthritis Rheum 1981;24:867-73.Google Scholar
  40. 40.
    van Rijthoven AWAM, Dijkmans BAC, Goei The HS, Hermans J, Montnor-Beckers LMB, Jacobs PCJ, Cats A. Cyclosporin treatment for rheumatoid arthritis: a placebo controlled, double blind, multicenter study. Ann Rheum Dis 1986;45:726-31.Google Scholar
  41. 41.
    Weyand CM, Hicok K, Conn D, Goranzy JJ. The influence of HLA-DRB1 genes on disease severity in rheumatoid arthritis. Ann Intern Med 1992;117:801-6.Google Scholar
  42. 42.
    Calabres LH, Wilke WS, Perkins AD, Tubbs RR. Rheumatoid arthritis complicated by infection with human immunodeficiency virus and the development of Sjögren's syndrome. Arthritis Rheum 1989;32:1453-7.Google Scholar
  43. 43.
    Ranges GE, Sriram S, Cooper SM. Prevention of type II collagen-induced arthritis by in vivo treatment with anti-L3T4. J Exp Med 1985;162:1105-6.Google Scholar
  44. 44.
    Moreland LW, Pratt PW, Mayes MD, Potlethwaite A, Weisman MH, Schnitzer T, Lightfoot R, Calabrese L, Zelinger DJ, Woody JN, et al. Double-blind placebo-controlled multicenter trial using chimeric monoclonal anti-CD4 antibody, cM-T412, in rheumatoid arthritis patients receiving concomitant methotrexate. Arthritis Rheum 1995;38:1581-8.Google Scholar
  45. 45.
    van der Lubbe PA, Dijkmans BAC, Markusse HM, Nässander U, Breedveld FC. A randomized double-blind placebo-controlled study of CD4 monoclonal antibody therapy in early rheumatoid arthritis. Arthritis Rheum 1995;38:1097-106.Google Scholar
  46. 46.
    van der Lubbe PA, Breedveld FC, Tak PP, Schantz A, Woody J, Miltenburg AM. Treatment with a chimeric CD4 monoclonal antibody is associated with a relative loss of CD4+/CD45RA+ cells in patients with rheumatoid arthritis. J Autoimmun 1997;10:87-97.Google Scholar
  47. 47.
    Tak PP, van der Lubbe PA, Cauli A, Daha MR, Smeets TJM, Kluin PM, Meinders AE, Yanni G, Panayi GS, Breedveld FC. Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis. Arthritis Rheum 1995;38:1457-65.Google Scholar
  48. 48.
    Isaacs JD, Watts RA, Hazleman BL, Hale G, Keogan MT, Cobbold SP, Waldmann H. Humanised monoclonal antibody therapy for rheumatoid arthritis. Lancet 1992;340:748-52.Google Scholar
  49. 49.
    Matteson EL, Yocum DE, St. Clair EW, Achkar AA, Thakor MS, Jacobs MR, Hays AE, Heitman CK, Johnston JM. Treatment of active refractory rheumatoid arthritis with humanized monoclonal antibody CAMPATH-1H administered by daily subcutaneous injection. Arthritis Rheum 1995;38:1187-93.Google Scholar
  50. 50.
    Weinblatt ME, Maddison PJ, Bulpitt KJ, Hazleman BL, Urowitz MB, Sturrock RD, Coblyn JS, Maier AL, Spreen WR, Manna VK, Johnston JM. CAMPATH-H1, a humanized monoclonal antibody, in refractory rheumatoid arthritis: an intravenous dose-escalation study. Arthritis Rheum 1995;38:1589-94.Google Scholar
  51. 51.
    Ruderman EM, Weinblatt ME, Thurmond LM, Pincus GS, Gravallese EM. Synovial tissue response to treatment with CAMPATH-1H. Arthritis Rheum 1995;38:254-8.Google Scholar
  52. 52.
    Olsen J, Brooks RH, Cush JJ, Lipsky PE, St. Clair EW, Matteson EL, Gold KN, Cannon GW, Jackson CG, McCune WJ, Fox DA, the Xoma RA investigator group, Nelson B, Lorenz T, Strans V. A double-blind, placebo-controlled study of anti-CD5 immunoconjugate in patients with rheumatoid arthritis. Arthritis Rheum 1996;39:1102-8.Google Scholar
  53. 53.
    Kirkham BW, Thien F, Pelton BK, Pitzalis C, Amlot P, Denman AM. Chimeric CD7 monoclonal antibody therapy in rheumatoid arthritis. J Rheumatol 1992;19:1348-52.Google Scholar
  54. 54.
    Waldmann TA, The IL-2/IL-2 receptor system: a target for rational immune intervention. Immunol Today 1993;14:264-70.Google Scholar
  55. 55.
    Firestein GS, Xu WD, Townsend K, et al. Cytokines in chronic inflammatory arthritis. I Failure to detect T cell lymphokines (interleukin 2 and interleukin 3) and presence of macrophage colony stimulating factor (CSF-1) and a novel mast cell growth factor in rheumatoid synovitis. J Exp Med 1988;168:1573-86.Google Scholar
  56. 56.
    Kyle V, Coughlan RJ, Tighe H, Waldmann H, Hazleman BL. Beneficial effects of monoclonal antibody to interleukin-2 receptor on activated T cells in rheumatoid arthritis. Ann Rheum Dis 1989;48:428-9.Google Scholar
  57. 57.
    Sewell KL, Parker KC, Woodworth TG, Reuben J, Swartz W, Trentham DE. DAB486IL-2 fusion toxin in refractory arthritis. Arthritis Rheum 1993;36:1223-33.Google Scholar
  58. 58.
    Moreland LW, Sewell KL, Trentham DE, Bucy RP, Sullivan WF, Schrohenloher RE, Shmerling RH, Parker KC, Swartz WG, Woodworth TG, Koopman WJ. Interleukin-2 diphtheria fusion protein (DAB486IL-2) in refractory rheumatoid arthritis: a double-blind placebo-controlled trial with openlabel extension. Arthritis Rheum 1995;38:1177-86.Google Scholar
  59. 59.
    Goronzy JJ, Bartz-Bazzanella P, Hu W, Jendro MC, Walser-Kuntz DR, Weyand CM. Dominant clonotypes in the repertoire of peripheral CD4+ T-cells in rheumatoid arthritis. J Clin Invest 1994;94:2068-76.Google Scholar
  60. 60.
    Howell MD, Diveley JP, Lundeen KA, Esty A, Winters ST, Carlo DJ, Brostoff SW. Limited T-cell receptor B-chain heterogeneity among interleukin-2 receptor-positive synovial T cells suggest a role for superantigen in rheumatoid arthritis. Proc Natl Acad Sci USA 1991;88:10921-5.Google Scholar
  61. 61.
    Williams WV, Kieber-Emmons T, Fang Q, Von Feldt J, Wang B, Ramnujam T, Weiner DB. Conserved motifs in rheumatoid arthritis synovial tissue T-cell receptor beta chains. DNA Cell Biol 1993;12:425-34.Google Scholar
  62. 62.
    Moreland LW, Heck LW, Koopman WJ, Saway PA, Adamson TC, Fronek Z, O'Connor RD, Morgan EE, Diveley JD, Richieri SP, Carlo DJ, Brostoff SW. Vβ17 T-cell receptor peptide vaccine in rheumatoid arthritis: results of phase I dose escalation study. J Rheumatol 1996;23:1353-62.Google Scholar
  63. 63.
    van Laar JM, Miltenburg AMM, Verdonk MJA, Leow A, Elferink BG, Daha MR, Cohen IR, de Vries RR, Breedveld FC. Effects of inoculation with attenuated autologous T cells in patients with rheumatoid arthritis. J Autoimmun 1993;6:159-67.Google Scholar
  64. 64.
    Kingsley GH, Verwilghen J: T-cell vaccinations in humans. Clin Exp Rheumatol 1993;11:S63-S64.Google Scholar
  65. 65.
    Lohse AW, Bakker NPM, Hermann E, Poralla T, Jonker M, Meyer ZUM, Buschenfelde KH. Induction of an anti-vaccine response by T-cell vaccination in non-human primates and humans. J Autoimmun 1993;1:121-30.Google Scholar
  66. 66.
    Combe B, Cosso B, Clot J, Bonneau M, Sany J. Human placenta-eluted gammaglobulins in immunomodulating treatment of rheumatoid arthritis. Am J Med 1985;78:920-8.Google Scholar
  67. 67.
    Fiocco U, Cozzi L, Cozzi E. Treatment of rheumatoid arthritis by murine antiidiotypic monoclonal antibodies to a syngeneic anti-HLA class II monoclonal antibody. Br J Rheumatol 1991;30:90-4.Google Scholar
  68. 68.
    Smith JB, Fort FG. Treatment of rheumatoid arthritis by immunization with mononuclear white blood cells: results of preliminary trial. J Rheumatol 1996;23:220-5.Google Scholar
  69. 69.
    Pratt W, Heck L, Moreland L, Koopman W, Parkhill T, Pratt G, Hanavan S, Wehner N, Holcenberg J, Winkelhake J. Safety and immunogenicity of a single intramuscular injection of a synthetic HLA-DR4/1-peptide vaccine with alum adjuvant in rheumatoid arthritis patients (abstract). Arthritis Rheum 1995;38(Suppl 9):S281.Google Scholar
  70. 70.
    Nalger-Anderson C, Bober LA, Robinson ME, Siskind GW, Thorbecke GJ. Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci USA 1986;83:7443-6.Google Scholar
  71. 71.
    Zhang ZJ, Lee CSY, Lider O, Weiner HL. Suppression of adjuvant arthritis in Lewis rats by oral administration of type II collagen. J Immunol 1990; 145:2489-93.Google Scholar
  72. 72.
    Trentham DE, Dynesius-Trentham RA, Orav JE, Combitchi D, Lorenzo C, Sewell KL, Hafler DA, Weiner HL. Effects of oral administration of type II collagen on rheumatoid arthritis. Science 1993;261:1727-30.Google Scholar
  73. 73.
    Sieper J, Kary S, Sörensen H, Alten R, Eggens U, Hüge W, Hiepe F, Kühne A, Listing J, Ulbrich N, Braun J, Zink A, Mitchison NA. Oral type II collagen treatment in early rheumatoid arthritis: a double-blind, placebo-controlled, randomized trial. Arthritis Rheum 1996;39:41-51.Google Scholar
  74. 74.
    Moreland LW, Heck LW, Koopman WJ. Biologic agents for treating rheumatoid arthritis. Arthritis Rheum 1997;40:397-409.Google Scholar
  75. 75.
    Campion GV, Lebsack ME, Lookabaugh J, Gordon G, Catalano M and the IL-Ra Arthritis Study Group. Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 1996;39:1092-101.Google Scholar
  76. 76.
    Drevlow B, Capezio J, Lovis R, Jacobs C, Landay A, Pope RM. Phase I study of recombinant human interleukin-1 receptor (RHUIL-1R) administered intra-articularly in active rheumatoid arthritis. (abstract) Arthritis Rheum 1993;36:S39.Google Scholar
  77. 77.
    Drevlow B, Lovis R, Haag MA, Sinacore J, Jacobs C, Blosch C, Beck C, Landay A, Moreland L, Pope RM. Phase I study of recombinant human interleukin-1 receptor (RHUIL-1R) administered subcutaneously in patients with active rheumatoid arthritis. (abstract) Arthritis Rheum 1994;37:S339.Google Scholar
  78. 78.
    Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, Brennan FM, Walker J, Bijl H, Ghrayeb J, Woody JN. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor a. Arthritis Rheum 1993;36:1681-90.Google Scholar
  79. 79.
    Elliott MJ, Maini RN, Feldmann M, Kalden JR, Antoni C, Smolen JS, Leeb B, Breedveld FC, Macfarlane JD, Bijl H. Randomised double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994;344:1105-10.Google Scholar
  80. 80.
    Paulus HE, Egger MJ, Ward JR, Williams HJ, and the Cooperative Systematic Studies of Rheumatic Diseases Group. Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. Arthritis Rheum 1990;33:477-84.Google Scholar
  81. 81.
    Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Bijl H, Woody JN. Repeated therapy with monoclonal antibody to tumor necrosis factor alpha (cA2) in patients with rheumatoid arthritis. Lancet 1994;344:1125-7.Google Scholar
  82. 82.
    Elliott MJ, Maini RN. Anti-cytokine therapy in rheumatoid arthritis. Baillière's Clin Rheumatol 1995;9:633-52.Google Scholar
  83. 83.
    Tak PP, Taylor PC, Breedveld FC, Smeets TJM, Daha MR, Kluin PM, Meinders AE, Maini RN. Decrease in cellularity and expression of adhesion molecules by anti-tumor necrosis factor a monoclonal antibody treatment in patients with rheumatoid arthritis. Arthritis Rheum 1996;39:1077-81.Google Scholar
  84. 84.
    Rankin ECC, Choy EHS, Kassimos D, Kingsley GH, Sopwith AM, Isenberg DA, Panayi GS. The therapeutic effects of an engineered human anti-tumor necrosis factor alpha antibody (CDP571) in rheumatoid arthritis. Br J Rheumatol 1995;34:334-42.Google Scholar
  85. 85.
    Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB, Blosch CM. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. New Engl J Med 1997;337:141-7.Google Scholar
  86. 86.
    Wendling D, Racadot E, Wijdenes J. Treatment of severe rheumatoid arthritis by anti-interleukin-6 monoclonal antibody. J Rheumatol 1993;20:259-62.Google Scholar
  87. 87.
    Veys EM, Mielants H, Verbruggen G, Grosclaude JP, Meyer W, Galazka A, Schindler J. Interferon gamma in RA: a double-blind study comparing human recombinant interferon gamma with placebo. J Rheumatol 1988;15:570-4.Google Scholar
  88. 88.
    Cannon GW, Pincus SH, Emkey RD, Denes A, Cohen SA, Wolfe F, Saway PA, Jaffer AM, Weaver AL, Cogen L, Schindler JD. Double-blind trial of recombinant γ-interferon versus placebo in the treatment of rheumatoid arthritis. Arthritis Rheum 1989;32:964-73.Google Scholar
  89. 89.
    Lemmel EM, Gaus W, Hofschneider PH. Multicenter doubleblind trial of interferon-γversus placebo in the treatment of rheumatoid arthritis. Arthritis Rheum 1991;34:1621-2.Google Scholar
  90. 90.
    Machold KP, Neumann K, Smolen JS. Recombinant human interferon gamma in the treatment of rheumatoid arthritis: double-blind placebo-controlled study. Ann Rheum Dis 1992;51:1039-43.Google Scholar
  91. 91.
    Alvaro-Garcia JM, Zvaifler NJ, Firestein GS. Cytokines in chronic inflammatory arthritis. V. Mutual angatonism between IFN-gamma and TNF-alpha on HLA-DR expression, proliferation, collagenase production and GM-CSF production by rheumatoid arthritis synoviocytes. J Clin Invest 1990;86:1790-8.Google Scholar
  92. 92.
    Allen JB, Wong HL, Costa GL, Bienkowski MJ, Wahl SM. Suppression of monocyte function and differential regulation of IL-1 and IL-1RA by IL-4 contribute to resolution of experimental arthritis. J Immunol 1993;151:4344-51.Google Scholar
  93. 93.
    Katsikis PD, Chu CQ, Brennan FM, Maini RN, Feldmann M. Immunoregulatory role of interleukin 10 in rheumatoid arthritis. J Exp Med 1994;179:1517-27.Google Scholar
  94. 94.
    Mojcik CF, Shevach EM. Adhesion molecules. A rheumatologic perspective. Arthritis Rheum 1997;40:991-1004.Google Scholar
  95. 95.
    Kavanaugh AF, Davis LS, Nichols LA, Norris SH, Rothlein R, Scharschmidt LA, Lipsky PE. Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum 1994;37:992-9.Google Scholar
  96. 96.
    Kavanaugh AF, Davis LS, Nichols SA, Lipsky PE. Retreatment of rheumatoid arthritis patients with an anti-ICAM-1 monoclonal antibody (abstract). Arthritis Rheum 1995;(Suppl 9)38:S280.Google Scholar
  97. 97.
    Kavanaugh AF, Davis LS, Jain LA, Nichols SA, Lipsky E. A phase I/II open label study of the safety and efficacy of an anti-ICAM-1 (intercellular adhesion molecule-1; CD54) monoclonal antibody in early rheumatoid arthritis. J Rheumatol 1996;23:1338-44.Google Scholar
  98. 98.
    Evans CE, Robbins PD. Prospects for treating arthritis by gene therapy. J Rheumatol 1994;21:779-82.Google Scholar
  99. 99.
    Doherty PJ. Gene therapy and arthritis. J Rheumatol 1995;22:1220-3.Google Scholar
  100. 100.
    Bandara G, Robbins PD, Georgescu HI, Mueller GM, Glorioso JC, Evans CH. Gene transfer to synoviocytes: prospects for gene treatment of arthritis. DNA Cell Biol 1992;11:227-31.Google Scholar
  101. 101.
    Bandara G, Mueller GM, Galea-Lauri J Tindal MH, Georgescu HI, Suchanek MK, Hung GL, Glorioso JC, Robbins PD, Evans CH. Intraarticular expression of biologically active interleukin-1 receptor antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci USA 1993;90:1-764-8.Google Scholar
  102. 102.
    Roessler BJ, Allen ED, Wilson JM, Hartman JW, Davidson BL. Adenoviral-mediated gene transfer to rabbit synovium in vivo. J Clin Invest 1993;92:1085-92.Google Scholar
  103. 103.
    Hung GL, Galea-Lauri J, Mueller GM, Georgescu HI, Larkin LA, Suchanek MK, Tindal MH, Robbins PD, Evans CH. Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Ther 1994;1:64-9.Google Scholar
  104. 104.
    Strand V. Issues in clinical trials of biologic agents. Baillière's Clin Rheumatol 1995;9:825-35.Google Scholar
  105. 105.
    Van der Lubbe P, Reiter C, Breedveld FC, Krüger K, Schattenkirchner M, Sanders ME, Rithmüller G. Chimeric CD4 monoclonal antibody cM-T412 as a therapeutic approach to rheumatoid arthritis. Arthritis Rheum 1993;36:1375-9.Google Scholar
  106. 106.
    Moreland LW, Pratt P, Iw RP, Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long term follow up of CD4+ cell counts. Arthritis Rheum 1994;37:834-8.Google Scholar
  107. 107.
    Watts RA, Isaacs JD, Hale G, Peripheral blood lymphocytes subsets after CAMPATH 1H therapy for RA — 3 year follow up. (abstract) Arthritis Rheum 1994;37:S338.Google Scholar
  108. 108.
    Weinblatt ME, Coblyn J, Maier A. Continued lymphocyte suppression following single dose MAB therapy with CAMPATH 1H: a 20 month follow up. (abstract) Arthritis Rheum 1994;37:S420.Google Scholar
  109. 109.
    Weinblatt ME. The experience with CAMPATH 1H. In Strand V, Johnson K, Simon L (eds). Proceedings: Biologic Agents in Autoimmune Disease IV. Atlanta: Arthritis Foundation 1995.Google Scholar

Copyright information

© Kluwer Academic Publishers 1999

Authors and Affiliations

  • H.J. Dinant
  • B.A.C. Dijkmans

There are no affiliations available

Personalised recommendations