Clinical Rheumatology

, Volume 24, Issue 3, pp 189–202 | Cite as

Have traditional DMARDs had their day?

Effectiveness of parenteral gold compared to biologic agents


This review tries to answer the question of whether in the face of the recently introduced biologics conventional disease-modifying antirheumatic drugs (DMARDs) can still be recommended in the treatment of rheumatoid arthritis (RA). We start with an overview of the oldest conventional DMARD, injectable gold (Au), which was introduced in the treatment of RA in the 1920s. The effect of gold is directed at a number of different sites of the immune system. A significant improvement of clinical and biochemical disease activity parameters as well as an inhibition of X-ray progression has been shown in many studies. Head-to-head comparisons between gold and high-dose methotrexate (MTX) demonstrated no significant difference but some advantages for gold. Since trials comparing biologics with gold will never be performed, an indirect comparison was done by analyzing the results of trials with gold with those with biologics. Conclusions from such comparisons have to be drawn with caution especially since the methodology for performing trials has changed with time. We selected four trials with gold (two open, one placebo-controlled, and one comparison with MTX) and five trials with biologics (three placebo-controlled, one dose escalation study, and one comparison with MTX). In all these trials baseline data regarding swollen joint count (SJC), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were roughly comparable and, with the exception of interleukin (IL)-1 RA, demonstrated a similar improvement of over 50% already after 6 months [with faster onset with tumor necrosis factor (TNF)-alpha blockade]. American College of Rheumatology (ACR) response data were not available for the older gold trials. European League Against Rheumatism (EULAR) response criteria could be calculated for the Au/MTX trial and were—for these compounds—only slightly inferior to the results with adalimumab. X-ray response is especially difficult to compare across studies. Although an inhibition with Au and MTX could be demonstrated, this occurred—similar to corticosteroid treatment—earlier and more pronounced with TNF-alpha blockers. We confirm the statement of Weinblatt that the most modern DMARDs do not appear to be much better than the oldest one indicating that conventional DMARDs are not outdated. Therefore, a sufficient trial of conventional DMARDs should precede the introduction of treatment with the very expensive biologics.


Biologics Clinical studies DMARDs Gold Rheumatoid arthritis Treatment evaluation 


  1. 1.
    Bathon JM, Martin RW, Fleischmann RM, et al. (2000) A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 343:1586–1593CrossRefPubMedGoogle Scholar
  2. 2.
    Genovese MC, Bathon JM, Martin RW, Fleischmann RM, Tesser JR, et al. (2002) Etanercept versus methotrexate in patients with early rheumatoid arthritis. Two-year radiographic and clinical outcomes. Arthritis Rheum 45:1443–1450CrossRefGoogle Scholar
  3. 3.
    Lipsky PE, van der Heijde DMFM, St. Clair EW, et al. (2000) Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 343:1586–1593CrossRefPubMedGoogle Scholar
  4. 4.
    Bresnihan B, Alvaro-Gracia JM, Cobby M, Doherty M, Domljan Z, et al. (1998) Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheum 41:2196–2204CrossRefPubMedGoogle Scholar
  5. 5.
    Rau R (2002) 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 61 [Suppl II]:ii70–ii73Google Scholar
  6. 6.
    Rau R, Herborn G, Sander O, van de Putte LBA, et al. (1999) Long-term treatment with the fully human anti-TNF antibody D2E7 slows radiographic disease progression in rheumatoid arthritis (abstract). Arthritis Rheum 42:S400Google Scholar
  7. 7.
    Tugwell P, Boers M, OMERACT Committee (1993) Development of consensus on preliminary core efficacy endpoints for rheumatoid arthritis. J Rheumatol 20:555–561PubMedGoogle Scholar
  8. 8.
    van der Heijde D, Boonen A, Boers M, Kostense P, van der Linden S (1999) Reading radiographs in chronological order, in pairs or as single films has important implications for the discriminative power of rheumatoid arthritis clinical trials. Rheumatology 38:1213–1220CrossRefPubMedGoogle Scholar
  9. 9.
    Forestier J (1935) Rheumatoid arthritis and its treatment by gold salts. J Lab Clin Med 20:827Google Scholar
  10. 10.
    Hartfall SJ, Garland HG, Goldie W (1937) Gold treatment of arthritis: a review of 900 cases. Lancet 233:838CrossRefGoogle Scholar
  11. 11.
    Ellmann P, Lawrence JS, Thorhold GPT (1940) Gold therapy in rheumatoid arthritis. Br Med J 2:312Google Scholar
  12. 12.
    Adams CH, Cecil RL (1950) Gold therapy in early rheumatoid arthritis. Ann Intern Med 33:163Google Scholar
  13. 13.
    Lockie LM, Norcross BM, Roirdan DJ (1958) Gold in the treatment of rheumatoid arthritis. JAMA 167:1204Google Scholar
  14. 14.
    Empire Rheumatism Council (1960) Gold therapy in rheumatoid arthritis. Ann Rheum Dis 19:95PubMedGoogle Scholar
  15. 15.
    Empire Rheumatism Council (1961) Gold therapy in rheumatoid arthritis: final report of a multicentre controlled trial. Ann Rheum Dis 20:316Google Scholar
  16. 16.
    Parente JE, Wong K, Davis P (1986) The paradox of gold compounds: activators or inhibitors (editorial)? J Rheumatol 13:846–848PubMedGoogle Scholar
  17. 17.
    Lorber A (1977) Monitoring gold plasma levels in rheumatoid arthritis. Clin Pharmacokinet 2:127–146PubMedGoogle Scholar
  18. 18.
    Clark P, Tugwell P, Bennett K, Bombardier C (1989) Meta-analysis of injectable gold in rheumatoid arthritis. J Rheumatol 16:442–447PubMedGoogle Scholar
  19. 19.
    Ward JR, Williams HJ, Boyce E, Egger MJ, Reading JC, Samuelson CO (1983) Comparison of auranofin, gold sodium thiomalate and placebo in the treatment of rheumatoid arthritis. Am J Med 75:133–137CrossRefGoogle Scholar
  20. 20.
    Capell HA, Lewis D, Carey J (1986) A three year follow up of patients allocated to placebo, or oral or injectable gold therapy for rheumatoid arthritis. Ann Rheum Dis 45:705–711PubMedGoogle Scholar
  21. 21.
    Davis P, Menard H, Thompson J, et al. (1985) One-year comparative study of gold sodium thiomalate and auranofin in the treatment of rheumatoid arthritis. J Rheumatol 12:60–67PubMedGoogle Scholar
  22. 22.
    Schattenkirchner M, Bröll H, Kaik B, et al. (1988) Auranofin and gold sodium thiomalate in the treatment of rheumatoid arthritis: a one-year double-blind comparative multicenter study. Klin Wochenschr 66:167–174PubMedGoogle Scholar
  23. 23.
    Rau R, Schattenkirchner M, Müller-Fassbender H, et al. (1990) A three year comparative study of auranofin and gold sodium thiomalate in rheumatoid arthritis. Clin Rheumatol 9:461–474PubMedGoogle Scholar
  24. 24.
    Peltomaa R, Paimela L, Helve T, Leirisalo-Repo M (1995) Comparison of intramuscular gold and sulphasalazine in the treatment of early rheumatoid arthritis. Scand J Rheumatol 24:330–335PubMedGoogle Scholar
  25. 25.
    Rau R, Herborn G, Menninger H, Blechschmidt J (1997) Comparison of intramuscular methotrexate and gold sodium thiomalate in the treatment of early erosive rheumatoid arthritis: 12 month data of a double-blind parallel study of 174 patients. Br J Rheumatol 36:345–352CrossRefPubMedGoogle Scholar
  26. 25a.
    Rau R, Herborn G, Menninger H, Sangha O (1998) Progression in early erosive rheumatoid arthritis: 12 month results from a randomized controlled trial comparing methotrexate and gold sodium thiomalate. Br J Rheumatol 37:1220–1226CrossRefPubMedGoogle Scholar
  27. 26.
    Menninger H, Herborn G, Blechschmidt J, Rau R (1998) A 36-month comparative trial of methotrexate and gold sodium thiomalate in the treatment of early active and erosive rheumatoid arthritis. Br J Rheumatol 37:1060–1068CrossRefPubMedGoogle Scholar
  28. 27.
    Sander O, Herborn G, Bock E, Rau R (1999) Prospective six year follow up of patients withdrawn from a randomised study comparing parenteral gold salt and methotrexate. Ann Rheum Dis 58:281–287PubMedGoogle Scholar
  29. 28.
    Hernandez Garcia C, Jover JA, Morado IC, Banares A (1997) Gold salts and methotrexate in daily practice. Short-term safety and efficacy in rheumatoid arthritis (abstract). Arthritis Rheum 40 [Suppl]:S51Google Scholar
  30. 29.
    Hamilton J, Mc Innes IB, Thomson EA, Porter D, Hunter JA, et al. (2001) Comparative study of intramuscular gold and methotrexate in a rheumatoid arthritis population from a socially deprived area. Ann Rheum Dis 60:566–572CrossRefPubMedGoogle Scholar
  31. 30.
    Felson DT, Anderson JJ, Meenan RF (1990) The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Arthritis Rheum 33:1449–1461PubMedGoogle Scholar
  32. 31.
    Maetzel A, Wong A, Strand V, Tugwell P, et al. (2000) Meta-analysis of treatment termination rates among RA patients receiving slow-acting anti-rheumatic agents. Rheumatology 39:975–981CrossRefPubMedGoogle Scholar
  33. 32.
    Graudal N, Tahp U, Jurik AG, Galloe AM, Garred P, Milman N, Graudal HK (2000) Inflammatory patterns in rheumatoid arthritis estimated by the number of swollen and tender joints, the erythrocyte sedimentation rate, and hemoglobin: long-term course and association to radiographic progression. J Rheumatol 27:47–57PubMedGoogle Scholar
  34. 33.
    Rau R, Herborn G, Butgereit P (1989) Reinvestigation of 205 patients with rheumatoid arthritis (RA) 7 years after institution of gold treatment (abstract). ILAR Congress, Rio de Janeiro, 17–24 September 1989Google Scholar
  35. 34.
    Rau R, Schleusser B, Herborn G, Karger T (1998) Long-term combination therapy of refractory and destructive rheumatoid arthritis with methotrexate (MTX) and intramuscular gold or other disease modifying antirheumatic drugs compared to MTX monotherapy. J Rheumatol 25:1485–1492PubMedGoogle Scholar
  36. 35.
    Sharp JT, Lidsky MD, Duffy J, et al. (1977) Comparison of two dosage schedules of gold salts in the treatment of rheumatoid arthritis. Arthritis Rheum 20:1179–1187PubMedGoogle Scholar
  37. 36.
    Fries JF, Williams CA, Singh G, Ramey DR (1997) Response to therapy in rheumatoid arthritis is influenced by immediately prior therapy. J Rheumatol 24:838–844PubMedGoogle Scholar
  38. 37.
    Singh G, Ramey DR, Fries JF (1994) Effectiveness and toxicity profiles of drug treatment in RA (abstract). Arthritis Rheum 37:S196Google Scholar
  39. 38.
    Hurst S, Kallan MJ, Wolfe FJ, et al. (2002) Methotrexate, hydroxychloroquine, and intramuscular gold in rheumatoid arthritis: relative area under the curve effectiveness and sequence effects. J Rheumatol 29:1639–1645PubMedGoogle Scholar
  40. 39.
    Munroe R, Hamson R, Mc Entegard A, et al (1998) Improved functional outcome in patients with early rheumatoid arthritis treated with intramuscular gold: results of a 5 year prospective study. Ann Rheum Dis 57:88–93PubMedGoogle Scholar
  41. 40.
    Fumagalli M, Incorvaia C, Nitti F, Broggini M, Baratelli E, et al. (2002) The assessment of quality of life as a measure of gold salts treatment efficacy in rheumatoid arthritis. Minerva Med 93:199–202PubMedGoogle Scholar
  42. 41.
    Graudal NA, Jurik AG, DeCavallo A, Graudal HK (1998) Radiographic progression in rheumatoid arthritis. Arthritis Rheum 41:1470–1480CrossRefPubMedGoogle Scholar
  43. 42.
    Rau R (1996) Does parenteral gold inhibit radiographic progression in RA (in German)? Z Rheumatol 55:307–318PubMedGoogle Scholar
  44. 43.
    Rau R, Menninger H, Herborn G, Sangha O (2002) Inhibition of radiographic progression over three years by parenteral gold and MTX: results of a comparative study in 174 patients with early erosive RA. Rheumatology 41:196–204CrossRefPubMedGoogle Scholar
  45. 44.
    Buckland-Wright JC, Clarke GS, Chikanza IC, Grahame R (1993) Quantitative microfocal radiography detects changes in erosion area in patients with early rheumatoid arthritis treated with myocrisine. J Rheumatol 20:243–247PubMedGoogle Scholar
  46. 45.
    Larsen A, Horton J, Howland C (1984) The effects of auranofin and parenteral gold in the treatment of rheumatoid arthritis: an x-ray analysis. Clin Rheumatol 3 [Suppl]:97–104Google Scholar
  47. 46.
    Fries JF, Williams CA, Ramey D, Bloch DA (1993) The relative toxicity of disease-modifying antirheumatic drugs. Arthritis Rheum 36:297–306PubMedGoogle Scholar
  48. 47.
    Rau R, Herborn G, Zueger S, Fenner H (2000) The effect of HLA-DRB1 genes, rheumatoid factor, and treatment on radiographic disease progression in rheumatoid arthritis over 6 years. J Rheumatol 27:2566–2575PubMedGoogle Scholar
  49. 48.
    Verstappen SMM, Jacobs JWG, Bijlsma JWJ (2002) How many early rheumatoid arthritis patients achieve remission (abstract). Ann Rheum Dis 61 [Suppl 1]:171Google Scholar
  50. 49.
    Caspi D, Tishler M, Yaron M (1989) Association between gold induced skin rash and remission in patients with rheumatoid arthritis. Ann Rheum Dis 48:730–732PubMedGoogle Scholar
  51. 50.
    Wolfe F, Hawley DJ, Cathey MA (1993) Measurement of gold treatment effect in clinical practice: evidence for effectiveness of intramuscular gold therapy. J Rheumatol 20:797–801PubMedGoogle Scholar
  52. 51.
    Rau R, Wassenberg S, Zeidler H (2000) Low dose prednisolone therapy (LDPT) retards radiographically detectable destruction in early rheumatoid arthritis—preliminary results of a multicenter, randomized, parallel, double-blind study. Z Rheumatol 59 [Suppl II]:90–96Google Scholar
  53. 52.
    Rau R, Sander O, den Broeder A, et al (1998) Long-term efficacy and tolerability of multiple i.v. doses of the fully human anti-TNF antibody D2E7 in patients with rheumatoid arthritis (abstract). Arthritis Rheum 41:S55Google Scholar
  54. 53.
    Jiang Y, Genant HK, Watt I, Cobby M, Bresnihan B, Aitchison R, et al. (2000) A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. Arthritis Rheum 43:1001–1009CrossRefPubMedGoogle Scholar
  55. 54.
    Hochberg MC, Tracy JK, Flores RH (2002) The comparative efficacy of anakinra, etanercept, infliximab and leflunomide when added to methotrexate in patients with active rheumatoid arthritis (abstract). Ann Rheum Dis 61 [Suppl 1]:170Google Scholar
  56. 55.
    Weinblatt M (2001) Disease modifying drugs in the treatment of rheumatoid arthritis (abstract). Ann Rheum Dis 60 [Suppl 1]:12Google Scholar
  57. 56.
    van de Putte LBA, Rau R, Breedfeld FC, Kalden JR, Malaise M, et al. (2004) Efficacy and safety of the fully human anti-TNF-alpha monoclonal antibody, adalimumab (D2E7), in DMARD-refractory patients with rheumatoid arthritis: a 12-week, phase II study. Ann Rheum Dis 62:1168–1177Google Scholar
  58. 57.
    Kirwan JR (1995) The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 333:142–146CrossRefPubMedGoogle Scholar
  59. 58.
    Boers M, Verhoeven AC, Markusse HM, van de Laar MAFJ, Westhovens R, et al. (1997) Randomised comparison of combined step-down prednisolone, methotrexate and sulfasalazine with sulphasalazine in early rheumatoid arthritis. Lancet 350:309–318CrossRefPubMedGoogle Scholar

Copyright information

© Clinical Rheumatology 2004

Authors and Affiliations

  1. 1.Department of RheumatologyEvangelisches FachkrankenhausRatingenGermany

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