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Safety and Efficacy of Disease-Modifying Anti-Rheumatic Agents

Focus on the Benefits and Risks of Etanercept

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Abstract

The traditional approach to the treatment of rheumatoid arthritis (RA) has been the use of nonsteroidal anti-inflammatory drugs usually in combination with a disease-modifying antirheumatic drug (DMARD) such as hydroxychloroquine, gold, sulfasalazine, methotrexate, leflunomide or cyclosporin. Each of these DMARDs has its own distinct toxicities but has also been shown to be effective in reducing signs and symptoms of disease and to some extent, reduce radiological progression.

Within the past 10 years, the combination of several traditional DMARDs has been shown to have increased efficacy over monotherapy without a significant increase in toxicity in a majority of studies.

Recently, the US Food and Drug Administration has approved infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF)-α in combination with methotrexate, for the treatment of signs and symptoms of RA, delay of radiological progression of disease and improvement of physical function while anakinra, an interleukin-1 receptor antagonist, has been approved for the treatment of the signs and symptoms of RA either as monotherapy or in combination with methotrexate.

Etanercept is the first biological response modifier approved for use in RA in the US. Double-blind, randomised controlled studies have shown etanercept to be effective therapy in patients with RA who have had inadequate response to DMARDs, in combination with methotrexate, and as early monotherapy. Similar results were seen in juvenile and psoriatic arthritis in DMARD nonresponders. Open-label studies have shown efficacy in adult Still’s disease, ankylosing spondylitis, progressive systemic sclerosis, Wegener’s granulomatosis and chronic uveitis.

Safety issues are a concern because of the ubiquitous role of TNF. To date the only consistent adverse event seen with etanercept has been injection site reactions. Infections occur at the same rate and with the same frequency as the placebo population. There should be caution, however, with using etanercept in patients with a serious infection, or recurrent infections or patients with untreated or latent tuberculosis. As of yet there has not been seen an increase of malignancies. Rare neurological and haematological events have been noted.

Etanercept has been a significant addition to the armamentarium of medications for the treatment of RA, juvenile and psoriatic arthritis. Preliminary data show that it may be well tolerated and effective in other rheumatic diseases in which there is over production of TNFα.

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References

  1. Koopman WJ, editor. Arthritis and allied conditions. 14th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2001

    Google Scholar 

  2. Hochberg MC, Spector TD. Epidemiology of rheumatoid arthritis: update. Epidemiol Rev 1990; 12: 247–52

    PubMed  CAS  Google Scholar 

  3. Lawrence RC, Hochberg MC, Kelsey JL, et al. Estimates of the prevalence of selected arthritic and musculoskeletal diseases in the United States. J Rheumatol 1989; 16: 427–41

    PubMed  CAS  Google Scholar 

  4. Spector TD, Scott DL. What happens to patients with rheumatoid arthritis? Long term outcome of treatment. Clin Rheumatol 1998; 7: 315–30

    Google Scholar 

  5. Sangha O. Epidemiology of rheumatic diseases. Rheumatology 2000; 39Suppl. 2: 3–12

    PubMed  Google Scholar 

  6. Pinals RS. Survival in rheumatoid arthritis. Arthritis Rheum 1987; 30: 473–5

    PubMed  CAS  Google Scholar 

  7. Gabriel S, Crowson C, O’Fallon WM. Heart disease in rheumatoid arthritis. Arthritis Rheum 1998; 41(9 Suppl.): S132

    Google Scholar 

  8. Barrett EM, Scott DGI, Wiles NJ, et al. The impact of rheumatoid arthritis on employment status in the early years of disease: a UK community based study. Rheumatology 2000; 39: 1403–9

    PubMed  CAS  Google Scholar 

  9. Borigini MJ, Paulus HE. Rheumatoid arthritis. Treatment of rheumatic disease companion to Kelley’s Textbook of rheumatology. 2nd ed. Philadelphia (PA): WB Saunders Company, 2001: 217–9

    Google Scholar 

  10. Brooks P. Disease-modifying antirheumatic drugs. Primer on the rheumatic diseases. 11th ed. Atlanta, Georgia: Arthritis Foundation, 1997: 432–6

    Google Scholar 

  11. Fox RI, Kang H. Mechanism of action of antimalarial drugs: inhibition of antigen processing and presentation. Lupus 1993; 2Suppl. 1: S9

    PubMed  CAS  Google Scholar 

  12. Sigler JW, Bluhm GB, Duncan H, et al. Gold salts in the treatment of rheumatoid arthritis. A double-blind study. Ann Intern Med 1974; 80: 21–6

    PubMed  CAS  Google Scholar 

  13. Luukkainen R. Chrysotherapy in rheumatoid arthritis with particular emphasis on radiograph changes and on the optimal time of initiation of therapy. Scand J Rheumatol Suppl. 1980; 34: 1–56

    PubMed  CAS  Google Scholar 

  14. Gordon DA, Klinkhoff AV. Gold and penicillamine. Ruddy: Kelley’s textbook of rheumatology. 6th ed. St Louis (MO): WB Saunders Company, 2001: 869–78

    Google Scholar 

  15. Svartz N. The treatment of rheumatic polyarthritis with acid azo compounds. Rheumatism 1948; 56: 1–6

    Google Scholar 

  16. Kuzell WC, Gardner GM. Salicylazosulfapyridine (salazopyrin or azopyrin) in rheumatoid arthritis and experimental polyarthritis. Calif Med 1950; 73: 476–80

    PubMed  CAS  Google Scholar 

  17. McConkey B, Amos RS, Butler EP, et al. Salazopyrin in rheumatoid arthritis. Agents Actions 1978 Jun; 8(4): 438–41

    PubMed  CAS  Google Scholar 

  18. McConkey B, Amos RS, Durham S, et al. Sulphasalazine in rheumatoid arthritis. BMJ 1980 Feb 16; 280(6212): 442–4

    PubMed  CAS  Google Scholar 

  19. Sinclair RJG, Duthie JJR. Salazopyrin in the treatment of rheumatoid arthritis. Ann Rheum Dis 1949; 8: 226–31

    PubMed  CAS  Google Scholar 

  20. Neumann VC, Grindulis KA, Hubbal S, et al. Comparison between penicillamine and sulphasalazine in rheumatoid arthritis: Leeds-Birmingham trial. BMJ 1983; 287: 1099–102

    PubMed  CAS  Google Scholar 

  21. Pullar T, Hunter JA, Cappell HA. Sulphasalazine in rheumatoid arthritis: a double-blind comparison of sulphasalazine with placebo and sodium aurothiomalate. BMJ 1983; 287: 1102–4

    PubMed  CAS  Google Scholar 

  22. Bax DE, Amos RS. Sulphasalazine: a safe, effective agent for prolonged control of rheumatoid arthritis. A comparison with sodium aurothiomalate. Ann Rheum Dis 1985 Mar; 44(3): 194–8

    PubMed  CAS  Google Scholar 

  23. Pinals RS, Kaplan SB, Lawson JG, et al. Sulfasalazine in rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum 1986 Dec; 29(12): 1427–34

    PubMed  CAS  Google Scholar 

  24. Williams HJ, Ward JR, Dahl SL, et al. A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. Arthritis Rheum 1988 Jun; 31(6): 702–13

    PubMed  CAS  Google Scholar 

  25. The Australian Multicentre Clinical Trial Group. Sulfasalazine in early rheumatoid arthritis. J Rheumatol 1992 Nov; 19 (11): 1672–7

    Google Scholar 

  26. Mottonen T, Hannonen P, Hakola M, et al. Sulfasalazine in early RA. Arthritis Rheum 1993; 36: 1501–9

    PubMed  Google Scholar 

  27. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis: results of two meta-analyses. Arthritis Rheum 1990; 33: 1449–61

    PubMed  CAS  Google Scholar 

  28. Taffet SL, Das KM. Sulfasalazine: adverse effects and desensitization. Dig Dis Sci 1983; 28: 833–42

    PubMed  CAS  Google Scholar 

  29. Williams HJ, Willkens RF, Samuelson Jr CO, et al. Comparison of low-dose oral pulse methotrexate and placebo in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1985 Jul; 28(7): 721–30

    PubMed  CAS  Google Scholar 

  30. Thompson RN, Watts C, Edelman J, et al. A controlled two-centre trial of parenteral methotrexate therapy for refractory rheumatoid arthritis. J Rheumatol 1984 Dec; 11(6): 760–3

    PubMed  CAS  Google Scholar 

  31. Andersen PA, West SG, O’Dell JR, et al. Weekly pulse methotrexate in rheumatoid arthritis. Clinical and immunologic effects in a randomized, double blind study. Ann Intern Med 1985 Oct; 103(4): 489–96

    PubMed  CAS  Google Scholar 

  32. Weinblatt ME, Coblyn JS, Fox DA, et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N Engl J Med 1985 Mar 28; 312 (13): 818–22

    Google Scholar 

  33. Tugwell P, Bennett K, Gent M. Methotrexate in rheumatoid arthritis. Indications, contraindications, efficacy, and safety. Ann Intern Med 1987 Sep; 107(3): 358–66

    PubMed  CAS  Google Scholar 

  34. Becerra F. Manejo de la. Artritis reumatoide con metotrexate. Evaluacion preliminar en 50 pacientes. [Management of rheumatoid arthritis with methotrexate: preliminary evaluation in 50 patients] [in Spanish]. Bull Assoc Peru Rheum 1987; 7: 2–6

    Google Scholar 

  35. Carvallo AV, Wolff CF, Armas RM, et al. Artritis reumatoidea. Eficacia terapéutica del metotrexate y sus efectos hepatotoxicos [Rheumatoid arthritis: therapeutic efficacy of methotrexate and its hepatotoxic effects] [in Spanish]. Rev Med Chil 1993; 121: 777–84

    PubMed  CAS  Google Scholar 

  36. Hanrahan PS, Scrivens GA, Russell AS. Prospective long term follow-up of methotrexate therapy in rheumatoid arthritis: toxicity, efficacy and radiological progression. Br J Rheumatol 1989 Apr; 28(2): 147–53

    PubMed  CAS  Google Scholar 

  37. Bannwarth B, Vernhes J, Schaeverbeke T, et al. The facts about methotrexate in rheumatoid arthritis [letter]. Rev Rheum 1995; 62: 471–3

    CAS  Google Scholar 

  38. O’Dell JR. Methotrexate use in rheumatoid arthritis. Rheum Dis Clin North Am 1997 Nov; 23(4): 779–96

    PubMed  Google Scholar 

  39. Boerbooms AM, Jeurissen ME, Westgeest AA, et al. Methotrexate in refractory rheumatoid arthritis. Clin Rheumatol 1988 Jun; 7(2): 249–56

    PubMed  CAS  Google Scholar 

  40. Kremer JM, Lee JK. A long-term prospective study of the use of methotrexate in rheumatoid arthritis. Update after a mean of fifty-three months. Arthritis Rheum 1988 May; 31(5): 577–84

    PubMed  CAS  Google Scholar 

  41. Willkens RF. Resolve: methotrexate is the drug of choice after NSAIDs in rheumatoid arthritis. Semin Arthritis Rheum 1990 Oct; 20(2): 76–80

    PubMed  CAS  Google Scholar 

  42. Alarcon GS. Methotrexate for the treatment of rheumatoid arthritis in the late 1990s. Rheum Arthritis Idx Rev 1999; 1: 4–5

    Google Scholar 

  43. Galindo-Rodriguez G, Avina-Zubieta JA, Fitzgerald A, et al. Variations and trends in the prescription of initial second line therapy for patients with rheumatoid arthritis. J Rheumatol 1997 Apr 24(4): 633–8

    PubMed  CAS  Google Scholar 

  44. Felson DT, Anderson JJ, Meenan RF. Comparative efficacy and toxicity of second line drugs in RA. Arthritis Rheum 1990 Oct; 33(10): 1449–61

    PubMed  CAS  Google Scholar 

  45. Mladenovic V, Domljan Z, Rozman B, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995 Nov; 38(11): 1595–603

    PubMed  CAS  Google Scholar 

  46. Strand V, Cohen S, Schiff M, et al. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group. Arch Intern Med 1999 Nov 22; 159(21): 2542–50

    PubMed  CAS  Google Scholar 

  47. Weinblatt ME, Kremer JM, Coblyn JS, et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999 Jul; 42(7): 1322–8

    PubMed  CAS  Google Scholar 

  48. Lopez-Mendez A, Daniel WW, Reading JC, et al. Radiographic assessment of disease progression in rheumatoid arthritis patients enrolled in the cooperative systematic studies of the rheumatic diseases program randomized clinical trial of methotrexate, auranofin, or a combination of the two. Arthritis Rheum 1993 Oct; 36(10): 1364–9

    PubMed  CAS  Google Scholar 

  49. Nordstrom DM, West SG, Andersen PA, et al. Pulse methotrexate therapy in rheumatoid arthritis. A controlled prospective roentgenographic study. Ann Intern Med 1987 Dec; 107(6): 797–801

    PubMed  CAS  Google Scholar 

  50. Jeurissen ME, Boerbooms AM, van de Putte LB, et al. Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. A randomized, double blind study. Ann Intern Med 1991 Jun 15; 114(12): 999–1004

    PubMed  CAS  Google Scholar 

  51. Rau R, Herborn G, Karger T, et al. Retardation of radiologic progression in rheumatoid arthritis with methotrexate therapy. A controlled study. Arthritis Rheum 1991 Oct; 34(10): 1236–44

    PubMed  CAS  Google Scholar 

  52. Weinblatt ME, Polisson R, Blotner SD, et al. The effects of drug therapy on radiographic progression of rheumatoid arthritis. Results of a 36-week randomized trial comparing methotrexate and auranofin. Arthritis Rheum 1993 May; 36(5): 613–9

    PubMed  CAS  Google Scholar 

  53. Drosos AA, Karantanas AH, Psychos D, et al. Can treatment with methotrexate influence the radiological progression of rheumatoid arthritis? Clin Rheumatol 1990 Sep; 9(3): 342–5

    PubMed  CAS  Google Scholar 

  54. Reykdal S, Steinsson K, Sigurjonsson K, et al. Methotrexate treatment of rheumatoid arthritis: effects on radiological progression. Scand J Rheumatol 1989; 18(4): 221–6

    PubMed  CAS  Google Scholar 

  55. Sharp JT, Strand V, Leung H, et al. Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of leflunomide in patients with active rheumatoid arthritis. Leflunomide Rheumatoid Arthritis Investigators Group. Arthritis Rheum 2000 Mar; 43(3): 495–505

    PubMed  CAS  Google Scholar 

  56. Pincus T, Marcum SB, Callahan LF. Long term drug therapy for RA in seven rheumatology private practices. J Rheumatol 1992; 19: 1885–1894

    PubMed  CAS  Google Scholar 

  57. Wolfe F. Epidemiology of drug treatment failure in RA. Clin Rheumatol 1995; 9: 619–32

    CAS  Google Scholar 

  58. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum 1992 Oct; 35(10): 1117–25

    PubMed  CAS  Google Scholar 

  59. Gispen JG, Alarcon GS, Johnson JJ, et al. Toxicity to methotrexate in RA. J Rheumatol 1987; 14: 74–9

    PubMed  CAS  Google Scholar 

  60. Sandoval DM, Alarcon GS, Morgan SL. Adverse events in methotrexate-treated rheumatoid arthritis patients. Br J Rheumatol 1995; 34: 49–56

    PubMed  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  62. Emery P, Breedveld F, Lemmel EM, et al. A phase III, randomized, double blind study of leflunomide versus methotrexate in rheumatoid arthritis. XIV European League against Rheumatism Congress [abstract]. Ann Rheum Dis 1999; 59: S133

    Google Scholar 

  63. Emery P, Breedveld FC, Jubb RW, et al. Efficacy and safety of leflunomide vs methotrexate in rheumatoid arthritis (RA): results of a double-blind, randomized, 2-year trial [abstract]. Arthritis Rheum 1999; 42: S271

    Google Scholar 

  64. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomized, multicentre trial. Lancet 1999; 353: 259–66

    PubMed  CAS  Google Scholar 

  65. Larsen A, Smolen JS, Kalden JR, et al. Radiographic analysis of disease progression with leflunomide vs placebo vs sulfasalazine in rheumatoid arthritis. XIV European League Against Rheumatism Congress [abstract]. Ann Rheum Dis 1999; 20: S209

    Google Scholar 

  66. Smolen JS, Larsen A, Kalden JR, et al. Retardation of structural damage with leflunomide in rheumatoid arthritis assessed by Larsen methodology: 2-year results [abstract]. Arthritis Rheum 1999; 42: S82

    Google Scholar 

  67. Weinblatt ME, Kremer JM, et al. Leflunomide plus methotrexate in refractory rheumatoid arthritis: a pilot study [abstract 974]. Arthritis Rheum 1997; 40: S193

    Google Scholar 

  68. Kremer JM, Caldwell JR, Cannon GW, et al. The combination of leflunomide (LEF) and methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who are failing on MTX treatment alone: a double-blind placebo (PLC) controlled study [abstract 948]. Arthritis Rheum 2000; 43: S224

    Google Scholar 

  69. O’Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996 May; 334(20): 1287–91

    PubMed  Google Scholar 

  70. Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 1995 July; 333(3): 137–141

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  72. Maini RN, Taylor PC. Anticytokine therapy for RA. Ann Rev Med 2000; 51: 207–29

    PubMed  CAS  Google Scholar 

  73. Saklatvala J. Tumor necrosis factora stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 1986; 322: 547–9

    PubMed  CAS  Google Scholar 

  74. Pettipher ER, Higgs GA, Henderson B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci U S A 1986; 83: 8749–53

    PubMed  CAS  Google Scholar 

  75. Choy EHS, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344:12: 907–16

    PubMed  CAS  Google Scholar 

  76. Shingu M, Nagai Y, Isayama T, et al. The effects of cytokines on metalloproteinase inhibitors (TIMP) and collagenase production by human chondrocytes and TIMP production by synovial cells and endothelial cells. Clin Exp Immunol 1993; 94: 145–9

    PubMed  CAS  Google Scholar 

  77. Girasole G, Passeri G, Jilka RL, et al. Interleukin-11: a new cytokine critical for osteoclast development. J Clin Invest 1994; 93: 1516–24

    PubMed  CAS  Google Scholar 

  78. Chin JE, Winterrowd GE, Krzesicki RF, et al. Role of cytokine in inflammatory synovitis: the coordinate regulation of intercellular adhesion molecule 1 and HLA class 1and class II antigens in rheumatoid synovial fibroblasts. Arthritis Rheum 1990; 33: 1776–86

    PubMed  CAS  Google Scholar 

  79. Pettipher ER, Higgs GA, Henderson B. Interleukin 1 induces leukocyte infiltration and cartilage proteoglycan degradation in the synovial joint. Proc Natl Acad Sci U S A 1986; 83: 8749–53

    PubMed  CAS  Google Scholar 

  80. Butler DM, Maini RN, Feldmann M, et al. Modulation of proinflammatory cytokine release in rheumatoid synovial membrane cell cultures: comparison of monoclonal anti TNF-α antibody withInterleukin-1 receptor antagonist. Eur Cytokine Netw 1995; 6: 225–30

    PubMed  CAS  Google Scholar 

  81. Knight DM, Trinh H, Le J, et al. Construction and initial characterization of mouse human chimeric anti TNF alpha antibody. Molecular Immunol 1993; 30: 1443–53

    CAS  Google Scholar 

  82. Siegel SA, Shealy DJ, Nakada MT, et al. The mouse/human chimeric monoclonal antibody (CA2) neutralizes TNF in vitro and protects transgenic mice from cachexia and TNF lethality in vivo. Cytokine 1995; 7: 15–25

    PubMed  CAS  Google Scholar 

  83. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of RA with chimeric monoclonal antibody to TNF alpha. Arthritis Rheum: 1993; 36: 1681–90

    PubMed  CAS  Google Scholar 

  84. Elliott MJ, Maini RN, Feldmann M, et al. Randomized double-blind comparison of chimeric monoclonal antibody to TNF alpha CA2 versus placebo in RA. Lancet 1994; 344: 1105–10

    PubMed  CAS  Google Scholar 

  85. Maini RN, Breedveld FC, Kalden JR, et al. Therapeutic efficacy of multiple IV infusions of anti TNF alpha monoclonal antibody combined with low dose weekly methotrexate in RA. Arthritis Rheum 1998; 41: 1552–63

    PubMed  CAS  Google Scholar 

  86. Maini RN, St Clair EW, Breedveld FC, et al. for ATTRACT group. Infliximab versus placebo in RA patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 1999; 354: 1932–9

    PubMed  CAS  Google Scholar 

  87. 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

    PubMed  CAS  Google Scholar 

  88. Lipsky PE, van der Heijde DMFM, St Clair EW, et al. 102-WK clinical and radiologic results from the ATTRACT trial: a 2 year, randomized, controlled, phase 3 trial of infliximab (Remicade) in pts with active RA despite MTX [abstract 1216]. Arthritis Rheum 2000; 43: S269

    Google Scholar 

  89. Remicade® (infliximab) for IV injection. Prescribing information [online]. Available from URL: http://www.remicade-ra.com/pdf/prescribing.pdf [Accessed 2002 Mar]

  90. Charles PJ, Smeenk RJ, De Jong J, et al. Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials. Arthritis Rheum 2000; 43(11): 2383–90

    PubMed  CAS  Google Scholar 

  91. Bresnihan B. The Safety and efficacy of interleukin-1 receptor antagonist in the treatment of rheumatoid arthritis. Semin Arthritis Rheum 2001; 2Suppl. 30: 17–22

    Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  94. Cohen S, Hurd E, Cush JJ, et al. Treatment of interleukin-1 receptor antagonist in combination with methotrexate in rheumatoid arthritis patients [abstract]. Arthritis Rheum 1999; 42: S273

    Google Scholar 

  95. Nam MH, Reda D, Boujoukos AJ, et al. Recombinant human dimeric tumor necrosis factor (TNF) receptor (TNFR: Fc): safety and pharmacokinetics in human volunteers [abstract]. Clin Res 1993; 41(2): 249A

    Google Scholar 

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

    CAS  Google Scholar 

  97. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor (p75)-Fc fusion protein. N Engl J Med 1997 Jul 17; 337: 141–7

    PubMed  CAS  Google Scholar 

  98. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1998; 31: 315–24

    Google Scholar 

  99. Moreland LW, Schiff MH, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled study. Ann Intern Med 1999; 130: 478–86

    PubMed  CAS  Google Scholar 

  100. 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: 253–9

    PubMed  CAS  Google Scholar 

  101. Finck B, Martin RW, Fleischmann RM, et al. A Phase III trial of etanercept vs methotrexate in early rheumatoid arthritis (Enbrel ERA trial) [abstract 280]. Arthritis Rheum 1999; 42Suppl.: S117

    Google Scholar 

  102. 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: 1586–93

    PubMed  CAS  Google Scholar 

  103. Genovese M, Martin RW, Fleischmann RM, et al. Enbrel (etanercept) vs. methotrexate in early rheumatoid arthritis (ERA trial): two-year follow-up [abstract 1217]. Arthritis Rheum 2000; 43: S268

    Google Scholar 

  104. Genovese M, Martin RW, Fleischmann RM, et al. Enbrel (Etanercept) vs. methotrexate (MTX) in early rheumatoid arthritis (ERA trial): two-year follow-up [abstract OPO121]. Ann Rheum Disease 2001; 60: 77

    Google Scholar 

  105. Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis. N Engl J Med 2000 March 16; 342: 763–69

    PubMed  CAS  Google Scholar 

  106. Mease PJ, Goffe BS, Metz J, et al. Etanercept in the treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet 2000 July 29; 356: 385–90

    PubMed  CAS  Google Scholar 

  107. Sharp JT, 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

    PubMed  CAS  Google Scholar 

  108. van der Heide DM, van Leewen MA, van Riel PL, et al. Biannual radiographic assessments of hands and feet in the three-year prospective follow-up of patients with early rheumatoid arthritis. Arthritis Rheum 1991; 35: 26–34

    Google Scholar 

  109. Weinblatt ME, Moreland LW, Schiff MH, et al. Long-term and Phase III treatment of DMARD failing rheumatoid arthritis patients with TNF receptor P75 fusion protein (TNFR: Fc: Enbrel) [abstract 572]. Arthritis Rheum 1997; 40: S126

    Google Scholar 

  110. Moreland LW, Baumgartner SW, Tindall EA, et al. Long-term safety and efficacy of TNF Receptor (P75) Fc Fusion protein [TNFR: Fc; Enbrel] in DMARD refractory rheumatoid arthritis (RA) [abstract 1989]. Arthritis Rheum 1998; 41: S363

    Google Scholar 

  111. Moreland LM, Cohen SB, Baumgartner SW, et al. Long-term use of etanercept in patients with DMARD-refractory rheumatoid arthritis [abstract 1981]. Arthritis Rheum 1999; 42: S401

    Google Scholar 

  112. Moreland LM, Cohen SB, Baumgartner SW, et al. Long-term use of Enbrel (etanercept) in patients with DMARD-refractory rheumatoid arthritis [abstract 1219]. Arthritis Rheum 2000; 43: S270

    Google Scholar 

  113. Moreland LW, Cohen SB, Baumgartner SW, et al. Long-term use of Enbrel (etanercept) in patients with DMARD-refractory rheumatoid arthritis [abstract FRI0080]. Ann Rheum Dis 2001; 60: 172

    Google Scholar 

  114. Weinblatt ME, Kremer JM, Lange DJ, et al. Long-term safety and efficacy of combination therapy with methotrexate (MTX) and etanercept (Enbrel) [abstract 1982]. Arthritis Rheum 1999; 42: S401

    Google Scholar 

  115. Kremer JM, Weinblatt ME, Fleischmann RM, et al. Etanercept (Enbrel) in addition to methotrexate (MTX) in rheumatoid arthritis (RA): long-term observations [abstract 1220]. Arthritis Rheum 2000; 43: S270

    Google Scholar 

  116. Fleischmann RM, Weinblatt ME, Kremer JM, et al. Enbrel (etanercept) in addition to methotrexate (MTX) in rheumatoid arthritis (RA): long term observations [abstract FRI0079]. Ann Rheum Dis 2001; 60: 172

    Google Scholar 

  117. Giannini EH, Ruperto N, Ravelli A, et al. Preliminary definition of improvement in juvenile arthritis. Arthritis Rheum 1997; 40: 1202–9

    PubMed  CAS  Google Scholar 

  118. Giannini EH, Lovell DJ, Felson DT, et al. Preliminary core set of outcome variables for use in RA clinical trials [abstract 1802]. Arthritis Rheum 1994; 37: S428

    Google Scholar 

  119. Clegg DO, Reda DJ, Mejias E, et al. Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. Arthritis Rheum 1996; 39: 2013–20

    PubMed  CAS  Google Scholar 

  120. Weinblatt ME, Maier AL, Overman SS, et al. Etanercept in Still’s disease in the adult [abstract 1949]. Arthritis Rheum 2000; 43: S391

    Google Scholar 

  121. Marzo-Ortega H, McGonagle D, O’Connor P, et al. A clinical and MRI assessment of the efficacy of the recombinant TNFα receptor:Fc fusion protein etanercept in the treatment of resistant spondyloarthropathy [abstract 209]. Arthritis Rheum 2000; 43: S101

    Google Scholar 

  122. Gorman JD, Sack KE, Davis JC, et al. Etanercept in the treatment of ankylosing spondylitis: a randomised, double blind, placebo controlled study [abstract 2020]. Arthritis Rheum 2000; 43: S403

    Google Scholar 

  123. Ellman MH, MacDonald PA, Hayes FA, et al. Etanercept as a treatment for diffuse scleroderma: a pilot study [abstract 1955]. Arthritis Rheum 2000; 43: S392

    Google Scholar 

  124. Stone JH, Uhlfelder ML, Hellman DB, et al. Etanercept combined with conventional treatment in Wegener’s granulomatosis. Arthritis Rheum 2001; 44: 1149–54

    PubMed  CAS  Google Scholar 

  125. Leavitt RY, Fauci AS, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of Wegener’s granulomatosis. Arthritis Rheum 1990; 33: 1101–7

    PubMed  CAS  Google Scholar 

  126. Stone JH, Hoffman GS, Merkel PA, et al. A disease-specific activity index for Wegener’s granulomatosis: a modification of the Birmingham Vasculitis Activity Score. Arthritis Rheum 2001; 44: 912–20

    PubMed  CAS  Google Scholar 

  127. Reiff A, Takei S, Sadeghi S, et al. Prospective study of etanercept in children with chronic treatment-refractory uveitis [abstract 1887]. Arthritis Rheum 2000; 43(9 Suppl.): S381

    Google Scholar 

  128. Fleischmann RM, Baumgartner SW, Moreland LW, et al. Improvement in disability in RA patients with early vs established disease treated with Enbrel [abstract FRI081]. Ann Rheum Dis 2001; 60: 172

    Google Scholar 

  129. Moreland LW, Baumgartner SW, Schiff MH, et al. Optimal dose of TNF receptor P75 FC Fusion (TNFR:Fc, Enbrel); [abstract 157]. Arthritis Rheum 1998; 41: S59

    Google Scholar 

  130. Schiff MH, Mease PJ, Weinblatt ME, et al. Randomized controlled trial of 25-mg vs 50 mg Enbrel (etanercept) twice weekly in rheumatoid arthritis [abstract 1947]. Arthritis Rheum 2000; 43: S391

    Google Scholar 

  131. Baumgartner SW, Moreland LW, Schiff MH, et al. Response of elderly patients to TNF receptor P75 Fc fusion protein (TNFR: Fc; Enbrel); [abstract 159]. Arthritis Rheum 1998; 41: S59

    Google Scholar 

  132. Moreland LW, Bucy RP, Weinblatt ME, et al. Effects of TNF receptor (P75) fusion protein (TNFR: Fc; Enbrel) on immune function [abstract 158]. Arthritis Rheum 1998; 41: S59

    Google Scholar 

  133. Etanercept (Enbrel) Product Insert

  134. Mohan N, Edwards ET, Cupps TR, et al. Demyelination diagnosed during etanercept (TNF receptor fusion protein) therapy [abstract 970]. Arthritis Rheum 2000; 43: S228

    Google Scholar 

  135. Wooten MD, Reddy GV, Johnson RD. Atrial fibrillation occurring in a patient taking etanercept plus methotrexate for rheumatoid arthritis. Del Med J 2000 Dec; 72(12): 517–9

    PubMed  CAS  Google Scholar 

  136. Galaria NA, Werth VP, Schumacher HR. Leukocytoclastic vasculitis due to etanercept. J Rheumatol 2000 Aug; 27(8): 2041–4

    PubMed  CAS  Google Scholar 

  137. Bloom BJ. Development of diabetes mellitus during etanercept therapy in a child with systemic-onset juvenile rheumatoid arthritis. Arthritis Rheum 2000 Nov; 43(11): 2606–8

    PubMed  CAS  Google Scholar 

  138. Brion PH, Mittal-Henkle A, Kalunian KC. Autoimmune skin rashes associated with etanercept for rheumatoid arthritis [letter]. Ann Intern Med 1999; 131: 634

    PubMed  CAS  Google Scholar 

  139. Russell E, Zeihen M, Wergin S, et al. Patients receiving etanercept may develop antibodies that interfere with monoclonal antibody laboratory assays. Arthritis Rheum 2000; 43: 944

    PubMed  CAS  Google Scholar 

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Acknowledgements

There was no funding for this manuscript. Dr Fleischmann is on advisory boards and has been a consultant and performed clinical studies for Immunex, Wyeth-Ayerst, Centocor, Amgen and Aventis.

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  1. Radiant Research-Dallas, 5939 Harry Hines Boulevard, Suite 400, Dallas, Texas, 75235, USA

    Roy Fleischmann

  2. University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA

    Roy Fleischmann, Imran Iqbal, Pallavi Nandeshwar & Andres Quiceno

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Correspondence to Roy Fleischmann.

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Fleischmann, R., Iqbal, I., Nandeshwar, P. et al. Safety and Efficacy of Disease-Modifying Anti-Rheumatic Agents. Drug-Safety 25, 173–197 (2002). https://doi.org/10.2165/00002018-200225030-00004

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