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Biological Agents for Rheumatoid Arthritis

Targeting Both Physical Function and Structural Damage

Drugs volume 64, pages 1267–1283 (2004)Cite this article

Abstract

Rheumatoid arthritis (RA) is a chronic progressive inflammatory disease of multifactorial aetiology. The pivotal role of proinflammatory cytokines in the pathogenesis and perpetuation of synovitis has been demonstrated in basic research since the late 1980s and in clinical research since the early 1990s. Biological agents are monoclonal antibodies or recombinant forms of natural inhibitory molecules which selectively interact with molecules or cell receptors affecting immune or inflammatory processes. In RA, etanercept, infliximab and adalimumab are currently available to target tumour necrosis factor (TNF) and an interleukin (IL)-l receptor antagonist is available to target IL-1 activity. Trials have shown benefits as monotherapy, although the best results for disease control are seen when biological agents are coadministered with methotrexate.

The use of these agents in clinical trials and in practice has resulted in dramatic improvements in RA disease control, and delay and prevention of radiographic damage. The remarkable benefits to patients in well-being, quality of life and function, and the speed of onset of action are reminiscent of the early days of corticosteroid use. Ten years after the first clinical trials of anti-TNF therapies, the adverse effect profile is evolving and includes, for anti-TNF therapy, an increased risk of infections associated with immune suppression, injection and infusion reactions, and a risk of drug induced autoimmune syndromes such as systemic lupus erythematosus. Where these drugs are affordable, the prognosis of individuals for control of severe RA is better than ever before. This manuscript summarises the clinical trial results and post-marketing information regarding the biological agents currently in use for RA.

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References

  1. Kaldin JR. How do the biologics fit into the current DMARD armamentarium? J Rheumatol 2001 Jun 28; 62: 27–35

    Google Scholar 

  2. van der Heijde DM. Joint erosions and the patient with early rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl. 2: 74–8

    PubMed  Google Scholar 

  3. Dougados D, Suurmeiher T, Krol B, et al. Work disability in early rheumatoid arthritis. Ann Rheum Dis 1995; 54: 445–60

    Google Scholar 

  4. Mitchell DM, Spitz PW, Young DY, et al. Survival, prognosis and causes of death in rheumatoid arthritis. Arthritis Rheum 1986; 29: 706–14

    Article  PubMed  CAS  Google Scholar 

  5. Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol 1990; 17: 994–1002

    PubMed  CAS  Google Scholar 

  6. Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 1995 Jul 20; 333(3): 137–41

    Article  PubMed  CAS  Google Scholar 

  7. O’Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydrox-ychloroquine, or a combination of all three medications. N Engl J Med 1996; 334 C20: 1287–91

    Article  Google Scholar 

  8. Boers M, Verhoeven AC, Markusse HM, et al. Randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350: 309–18

    Article  PubMed  CAS  Google Scholar 

  9. Verhoeven AS, Boers M, Tugwell P. Combination therapy in rheumatoid arthritis: updated systematic review. Br J Rheumatol 1998; 37(6): 612–9

    Article  PubMed  CAS  Google Scholar 

  10. The HERA Study Group. A randomized trial of hydroxychloro-quine in early rheumatoid arthritis: the HERA Study. Am J Med 1995; 98: 156–68

    Article  Google Scholar 

  11. Kirwan J. The effect of glucocorticoids on joint destruction. N Engl J Med 1995; 333(3): 142–6

    Article  PubMed  CAS  Google Scholar 

  12. Hughes LB, Moreland LW. New therapeutic approaches to the management of rheumatoid arthritis. Biodrugs 2001; 15(6): 379–93

    Article  PubMed  CAS  Google Scholar 

  13. Arend WP, Malyak M, Guthridge CJ, et al. Interleukin-1 receptor antagonist: role in biology. Annu Rev Immunol 1998; 16: 27–55

    Article  PubMed  CAS  Google Scholar 

  14. Cvetkovic RS, Keating G. Anakinra. Biodrugs 2002; 16(4): 303–11

    Article  PubMed  CAS  Google Scholar 

  15. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344: 907–16

    Article  PubMed  CAS  Google Scholar 

  16. Brennan FM, Chantry D, Jackson A, et al. Inhibitory effect of TNFα antibodies on synovial cell IL1 production in rheumatoid arthritis. Lancet 1989; II: 244–7

    Article  Google Scholar 

  17. Arend WP, Dayer J-M. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor α in rheumatoid arthritis. Arthritis Rheum 1995 Feb; 38(2): 151–60

    Article  PubMed  CAS  Google Scholar 

  18. Felson DT, Anderson JJ, Boers M, et al. The American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727–35

    Article  PubMed  CAS  Google Scholar 

  19. Fries JF, Spitz PW, Young DY, et al. The dimensions of health outcomes: the Health Assessment Questionnaire, Disability and Pain scales. J Rheumatol 1982; 9: 789–93

    PubMed  CAS  Google Scholar 

  20. Wells GA, Tugwell P, Kraag G, et al. Minimum important differences between patients with rheumatoid arthritis: the patient’s perspective. J Rheumatol 1993; 20: 557–60

    PubMed  CAS  Google Scholar 

  21. Wolfe F, Michaud K. Work disability in a national sample of RA patients [abstract]. Arthritis Rheum 2002 Sep; 46(9): S90

    Google Scholar 

  22. van Gestel AM, Prevoo M, Van’t Hof MA, et al. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum 1996; 39: 34–40

    Article  PubMed  Google Scholar 

  23. Boers M, Tugwell P, Brooks PM. Progress towards optimal trial endpoints in rheumatoid arthritis. Biodrugs 1997 Jan; 7(1): 40–50

    Article  PubMed  CAS  Google Scholar 

  24. Boers M. Validity of radiography as outcome measure in rheumatoid arthritis. J Rheumatol 1995; 22: 1783–6

    PubMed  CAS  Google Scholar 

  25. Boers M, van der Heijde DMFM. Prevention or retardation of damage in rheumatoid arthritis: issues of definition, evaluation and interpretation of plain radiographs. Drugs 2002; 62(12): 1717–24

    Article  PubMed  Google Scholar 

  26. Sharp TJ, Lidsky MD, Collins LC, et al. Methods of scoring the progression of radiologic changes in rheumatoid arthritis: correlation of radiologic, clinical and laboratory abnormalities. Arthritis Rheum 1971; 14: 706–20

    Article  PubMed  CAS  Google Scholar 

  27. Larsen A, Dale K, Eek M. Radiographie evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn (Stockh) 1977; 18: 481–91

    CAS  Google Scholar 

  28. Strand V, Sharp JT. Radiographie data from recent randomized controlled trials in rheumatoid arthritis: what have we learned? Arthritis Rheum 2003 Jan; 48(1): 21–34

    Article  PubMed  Google Scholar 

  29. van der Heijde DM, van Leeuwen MA, van Riel PL, et al. Biannual radiographie assessments of hands and feet in a three-year prospective followup of patients with early rheumatoid arthritis. Arthritis Rheum 1992 Jan; 35(1): 26–34

    Article  PubMed  Google Scholar 

  30. Genant HK, Jiang Y, Peterfy C, et al. Assessment of rheumatoid arthritis using a modified scoring method on digitized and original radiographs. Arthritis Rheum 1998; 41: 1583–90

    Article  PubMed  CAS  Google Scholar 

  31. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p 75)-Fc fusion protein. N Engl J Med 1997 Jul 17; 337: 141–7

    Article  PubMed  CAS  Google Scholar 

  32. Moreland LW, Margolies G, Heck LW Jr, et al. Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol 1996 Nov; 23(11): 1849–55

    PubMed  CAS  Google Scholar 

  33. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized controlled trial. Ann Intern Med 1999 Mar 16; 130(6): 478–86

    PubMed  CAS  Google Scholar 

  34. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000 Nov 30; 343(22): 1586–93

    Article  PubMed  CAS  Google Scholar 

  35. Weinblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med 1999 Jan 28; 340(4): 253–9

    Article  PubMed  CAS  Google Scholar 

  36. Maini R, St Clair EW, Breedveld F. Infliximab (chimeric anti-tumour necrosis factor a monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase 111 trial. Lancet 1999; 354: 1932–9

    Article  PubMed  CAS  Google Scholar 

  37. Weinblatt ME, Keystone EC, Furst DE. Adalimumab, a fully human anti-tumor necrosis factor-a monoclonal antibody for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003 Jan; 48(1): 35–45

    Article  PubMed  CAS  Google Scholar 

  38. Cohen S, Hurd E, Cush J, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of twenty-four week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002 Mar; 46(3): 614–24

    Article  PubMed  CAS  Google Scholar 

  39. Kremer JM, Weinblatt ME, Fleischmann RM, et al. Etanercept added to background methotrexate in rheumatoid arthritis: continued observations [abstract]. Arthritis Rheum2002 Oct; 46(9S): S531

    Google Scholar 

  40. Genovese MC, Martin RW, Fleischmann RM, et al. Etanercept in early erosive rheumatoid arthritis (ERA trial): observations at 4 years [abstract]. Arthritis Rheum 2002 Oct; 46(9S): S530

    Google Scholar 

  41. Feldmann M, Elliott MJ, Woody NJ, et al. Anti-tumor necrosis factor-a therapy of rheumatoid arthritis. Adv Immunol 1997; 64: 283–350

    Article  PubMed  CAS  Google Scholar 

  42. Markham A, Lamb HM. Infliximab: a review of its use in the management of rheumatoid arthritis. Drugs 2000 Jun; 59: 1341–59

    Article  PubMed  CAS  Google Scholar 

  43. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor-a. Arthritis Rheum 1993 Dec; 36: 1681–90

    Article  PubMed  CAS  Google Scholar 

  44. Elliott MJ, Maini RN, Feldmann M, et al. Randomized double blind comparison of chimeric monoclonal antibody to tumour necrosis factor-a (cA2) versus placebo in rheumatoid arthritis. Lancet 1994 Oct 22; 344: 1105–10

    Article  PubMed  CAS  Google Scholar 

  45. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor a monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum 1998 Sep; 41(9): 1552–63

    Article  PubMed  CAS  Google Scholar 

  46. Lipsky PE, van der Heijde DMFM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000 Nov 30; 343: 1594–602

    Article  PubMed  CAS  Google Scholar 

  47. St Clair EW, Wagner CL, Fasanmade AA, et al. The relationship between infliximab concentrations to clinical improvement in rheumatoid arthritis: results from ATTRACT, a multi-center randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002 Jun; 46(6): 1451–9

    Article  Google Scholar 

  48. den Breeder A, van de Putte KBA, Rau R, et al. A single dose, placebo controlled study of the fully human anti-tumor necrosis factor-a antibody, Adalimumab, (D2E7) in patients with rheumatoid arthritis. J Rheumatol 2002 Nov; 29(11): 2288–98

    Google Scholar 

  49. Rau R. Adalimumab (a fully human anti-tumour necrosis factor alpha monoclonal antibody) in the treatment of active rheumatoid arthritis: the initial results of five trials. Ann Rheum Dis 2002 Nov; 61 Suppl. 2: ii70–3

    PubMed  CAS  Google Scholar 

  50. Rau R, Herborn G, Sander O, et al. Long term treatment with the fully human anti-TNF antibody D2E7 slows radiographic disease progression in rheumatoid arthritis [abstract]. Arthritis Rheum 1999; 42: S400

    Google Scholar 

  51. den Breeder AA, Joosten CA, Saxne T, et al. Long term anti-tumour necrosis factor alpha monotherapy in rheumatoid arthritis: effect on radiologic course and prognostic value of markers of cartilage turnover and endothelial activation. Ann Rheum Dis 2002 Apr; 61(4): 311–8

    Article  Google Scholar 

  52. FDA briefing document —March 4, 2003 meeting of Arthritis Advisory Committee. Safety update on TNFα blocking agents [online]. Available from URL: http://www.fda.gov/ohrms/dockets/ac/03/briefing/3930Bl_01_B-TNF.Briefing.pdf [Accessed 2004 Mar 15]

  53. MorelandL W, Cohen SB, Klareskog L, et al. Global safety and efficacy of more than five years of etanercept therapy in rheumatoid arthritis [abstract]. Arthritis Rheum 2002 Oct; 46(9S): S532

    Google Scholar 

  54. Phillips K, Husni ME, Karlson EW, et al. Experience with etanercept in an academic medical center: are the infection rates increased? Arthritis Care Res 2002 Jan; 47(1): 17–21

    Article  CAS  Google Scholar 

  55. Kavanaugh A, Keenan S, De Woody K, et al. Long term follow up of patients with Remicade (infliximab) in clinical trials [abstract]. Arthritis Rheum 2001; 44S: S108

    Google Scholar 

  56. Durez P, Van den Bosch F, Corluy L, et al. Safety of combination methotrexate and infliximab in a large Belgian observational cohort with refractory rheumatoid arthritis [abstract]. Arthritis Rheum 2002 Oct; 46(9S): 536

    Google Scholar 

  57. Fitzcharles M-A, Clayton D, Menard HA. The use of infliximab in academic rheumatology practice: an audit of early clinical experience. J Rheumatol 2002 Dec; 29(12): 2525–30

    PubMed  CAS  Google Scholar 

  58. The Food and Drug Administration Centre for Biologies Evaluation and Research. Safety update on TNFα antagonists: infliximab and etanercept. Rockville (MD): The Food and Drug Administration Centre for Biologies Evaluation and Research, 2001 Aug 17

  59. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001 Oct 11; 345(15): 1098–104

    Article  PubMed  CAS  Google Scholar 

  60. Brown SL, Green MH, Gershon SK, et al. Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 2002; 46(12): 3151–8

    Article  PubMed  CAS  Google Scholar 

  61. Bresnihan B, Alvaro-Gracia JM, Cobby M, et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 1998 Dec; 41(12): 2196–204

    Article  PubMed  CAS  Google Scholar 

  62. Nuki G, Bresnihan B, Bear MB. Long-term safety and maintenance of clinical improvement following treatment with anakinra (recombinant human interleukin-1 receptor antagonist) in patients with rheumatoid arthritis: extension phase of a randomized double-blind, placebo-controlled trial. Arthritis Rheum 2002 Nov; 46(11): 2838–46

    Article  PubMed  CAS  Google Scholar 

  63. Jiang Y, Genant HK, Watt I, et al. A multicenter, double-blind, dose ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: radiologie progression and correlation of Genant and Larsen scores. Arthritis Rheum 2000 May; 43(5): 1001–9

    Article  PubMed  CAS  Google Scholar 

  64. Bresnihan B, Chan WW, Woolley JM. Productivity improvement in patients with rheumatoid arthritis receiving anakinra (IL-1ra) treatment [abstract no. 0074]. Annual European Congress of Rheumatology EULAR; 2002 Jun 12–15; Stockholm

  65. Schiff M, Bulpit K, Weaver AA, et al. Safety of combination therapy with anakinra and etanercept in patients with rheumatoid arthritis. Arthritis Rheum 2001; 44S: S79

  66. van Vollenhoven, Brannemark S, Lindblad S, et al. Treatment with TNFα antagonists results in significant gradual increases in workforce participation: data from the STURE registry [abstract]. Arthritis Rheum 2002; 46: S535

    Google Scholar 

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Acknowledgements

No sources of funding were used to assist in the preparation of this manuscript. The author has in the past served in an advisory capacity for Schering and Amgen and has participated in research trials for Abbott.

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  1. Division of Rheumatology, University of British Columbia, Vancouver, British Columbia, Canada

    Alice Klinkhoff

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Klinkhoff, A. Biological Agents for Rheumatoid Arthritis. Drugs 64, 1267–1283 (2004). https://doi.org/10.2165/00003495-200464120-00001

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Keywords

  • Rheumatoid Arthritis
  • Methotrexate
  • Infliximab
  • Etanercept
  • Adalimumab