Skip to main content
Log in

Drug Treatment of Rheumatic Diseases in the 1990s

Achievements and Future Developments

  • Leading Article
  • Published:
Drugs Aims and scope Submit manuscript

Summary

There have been several advances in the therapy of arthritis. These are based on better understanding of the pathogenesis of rheumatic diseases, re-evaluation of previous therapeutic concepts such as combination therapy, and developments within biotechnology. There are 4 main areas of development, mainly involving the treatment of inflammatory synovitis.

The first is with anti-inflammatory drugs, where there has been a focus on reducing gastrointestinal toxicity through the use of combination preparations such as diclofenac-misoprostol, and the introduction of drugs with more selectivity for cyclo-oxygenase-2 inhibition such as meloxicam. An additional approach has been the development of anti-inflammatory drugs such as tenidap which also control cytokine metabolism. The second area is slow-acting antirheumatic drugs with the introduction of cyclosporin as a single agent or in combination with methotrexate, the development of immunomodulating drugs such as leflunomide, and the demonstration that some antibiotics such as minocycline have slow-acting effects. The third area is the use of corticosteroids including the development of deflazacort as a bone sparing agent, the greater use of intramuscular depot steroids and the validation of low-dose oral corticosteroids in early rheumatoid arthritis. Finally, there have been advances in the biotechnology area with the demonstration that cytokine immunotherapy such as antibodies to tumour necrosis factor can rapidly improve the symptoms of rheumatoid arthritis, and that T cell immunotherapy with antibodies to the CD4 receptor may be effective in reducing synovitis.

Many of these agents have not yet been introduced into clinical practice but they show the diversity of drug development and suggest the likelihood of major therapeutic benefits in the next few years.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Edmonds JP, Scott DL, Furst DE, et al. Anti-rheumatic drugs: a proposed new classification. Arthritis Rheum 1993; 36: 336–9

    Article  PubMed  CAS  Google Scholar 

  2. Edmonds JP, Scott DL, Furst DE, et al. New classification of antirheumatic drugs: the evolution of a concept. J Rheumatol 1993; 20: 585–7

    PubMed  CAS  Google Scholar 

  3. Felson DT, Andersen JJ, Boers M, et al. The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 1993; 36: 729–40

    Article  PubMed  CAS  Google Scholar 

  4. Tugwell P, Boers M. OMERACT Conference on outcome measures in rheumatoid arthritis clinical trials. J Rheumatol 1993; 20: 527–90

    Google Scholar 

  5. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature 1971; 231: 232–5

    CAS  Google Scholar 

  6. Mitchell JA, Akarasereenont P, Theimermann C, et al. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Natl Acad Sci USA 1993; 90: 11693–7

    Article  PubMed  CAS  Google Scholar 

  7. Vane JR, Botting RM. New insights into the mode of action of anti-inflammatory drugs. Inflamm Res 1995; 44: 1–10

    Article  PubMed  CAS  Google Scholar 

  8. Ballinger A, Kumar P, Scott DL. Misoprostol and the prevention of gastroduodenal damage due to non-steroidal anti-inflammatory drugs. Ann Rheum Dis 1992; 51: 1089–93

    Article  PubMed  CAS  Google Scholar 

  9. Bardhan KD, Bjarnason I, Scott DL, et al. Misoprostol in the prevention and healing of NSAID-associated gastric and duodenal mucosal damage. Br J Rheumatol 1993; 32: 990–5

    Article  PubMed  CAS  Google Scholar 

  10. Fenn GC, Morant S, Scott DL. Efficacy of misoprostol in ulcer healing with continued NSAID therapy [abstract]. Br J Rheumatol 1996; 35 Suppl. 1: 222

    Google Scholar 

  11. Bolten W, Melo Gomes JA, Stea H,et al. The gastroduodenal safety and efficacy of the fixed combination of diclofenac and misoprostol in the treatment of osteoarthritis. Br J Rheumatol 1992; 31: 753–8

    Article  PubMed  CAS  Google Scholar 

  12. Henry D, Lim LLY, Rodriguez LAG, et al. Variability in risk of gastro-intestinal complications with individual anti-inflammatory drugs: results of a collaborative meto-analysis. BMJ 1996; 312: 1563–6

    Article  PubMed  CAS  Google Scholar 

  13. Fries J. Toward an understanding of NSAID-related adverse events: the contribution of longitudinal data. Scand J Rheumatol Suppl 1996; 102: 3–8

    Article  PubMed  CAS  Google Scholar 

  14. Roth SH. NSAID gastropathy — new understandings. Arch Intern Med 1996; 156: 1623–8

    Article  PubMed  CAS  Google Scholar 

  15. Dahl SL. Nabumetone: a ‘nonacidic’ nonsteroidal anti-inflammatory drug. Ann Pharmacother 1993; 27: 456–63

    PubMed  CAS  Google Scholar 

  16. Lister BJ, Poland M, DeLapp RE. Efficacy of nabumetone versus diclofenac, naproxen, ibuprofen, and piroxicam in osteoarthritis and rheumatoid arthritis. Am J Med 1993; 95(2A): 2S–9S

    Article  PubMed  CAS  Google Scholar 

  17. Helfgott SM. Nabumetone: a clinical appraisal. Semin Arthritis Rheum 1994; 23: 341–6

    Article  PubMed  CAS  Google Scholar 

  18. Roth SH, Bennett R, Caldron P, et al. A longterm endoscopic evaluation of patients with arthritis treated with nabumetone vs naproxen. J Rheumatol 1994; 21: 1118–23

    PubMed  CAS  Google Scholar 

  19. Roth SH, Tindall EA, Jain AK, et al. A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa. Arch Intern Med 1993; 153: 2565–71

    Article  PubMed  CAS  Google Scholar 

  20. Engelhardt G, Homma D, Schlegel K, et al. Anti-inflammatory, analgesic, antipyretic and related properties of meloxicam, a new non-steroidal anti-inflammatory agent with favourable gastrointestinal tolerance. Inflamm Res 1995; 44: 423–33

    Article  PubMed  CAS  Google Scholar 

  21. Engelhardt G, Bogel R, Schnitzler C, et al. Meloxicam: influence on arachidonic acid metabolism. Part II. In vivo findings. Biochem Pharmacol 1996; 51: 29–38

    Article  PubMed  CAS  Google Scholar 

  22. Wojtuliewski JA, Schattenkirchner M, Barcelo P, et al. A six-month double-blind trial to compare the efficacy and safety of meloxicam 7.5mg daily and naproxen 750mg daily in patients with rheumatoid arthritis. Br J Rheumatol 1996; 35 Suppl. 1:22–8

    Article  Google Scholar 

  23. Mahmud T, Scott DL, Bjarnason I. A unifying hypothesis for the mechanism of NSAID related gastrointestinal toxicity. Ann Rheum Dis 1996; 55: 211–3

    Article  PubMed  CAS  Google Scholar 

  24. Wallance JL, Reuter B, Cicala C, et al. Novel nonsteroidal anti-inflammatory drug derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology 1994; 107: 173–90

    Google Scholar 

  25. Elliot SN, McKnight W, Cirino G, et al. A nitric-oxide releasing nonsteroidal anti-inflammatory drug accelerates gastric ulcer healing in rats. Gastroenterology 1995; 109: 524–30

    Article  Google Scholar 

  26. Mazzuca SA, Brandt KD, Katz BP, et al. Therapeutic strategies distinguish community based primary care physicians from rheumatologists in the management of osteoarthritis. J Rheumatol 1993; 20: 80–6

    PubMed  CAS  Google Scholar 

  27. Dieppe PA, Frankel SJ, Toth B. Is research into the treatment of osteoarthritis with non-steroidal anti-inflammatory drugs misdirected? Lancet 1993; 341: 353–4

    Article  PubMed  CAS  Google Scholar 

  28. Bradley JD, Brandt KD, Katz BP, et al. Comparison of an anti-inflammatory dose of ibuprofen, an analgesic dose of ibuprofen, and acetaminophen in the treatment of patients with osteoarthritis of the knee. N Engl J Med 1991; 325: 87–91

    Article  PubMed  CAS  Google Scholar 

  29. March L, Irwig L, Schwarz J, et al. n Of 1 trials comparing a non-steroidal anti-inflammatory drug with paracetamol in osteo-arthritis. BMJ 1994; 309: 1041–5

    Article  PubMed  CAS  Google Scholar 

  30. Brandt KD. NSAIDs in the treatment of osteoarthritis. Friends or foes? Bull Rheum Dis 1993; 42: 1–4

    PubMed  CAS  Google Scholar 

  31. Brandt KD. Should nonsteroidal anti-inflammatory drugs be used to treat osteoarthritis? Rheum Dis Clin North Am 1993; 19: 29–44

    PubMed  CAS  Google Scholar 

  32. Brandt KD. Should osteoarthritis be treated with nonsteroidal anti-inflammatory drugs? Rheum Dis Clin North Am 1993; 19: 697–712

    PubMed  CAS  Google Scholar 

  33. Jones AC, Doherty M. The treatment of osteoarthritis. Br J Clin Pharmacol 1992; 3: 357–63

    Article  Google Scholar 

  34. Cicuttini FM, Spector TD. Osteoarthritis in the aged: epidemiological issues and optimal management. Drugs Aging 1995; 6: 409–20

    Article  PubMed  CAS  Google Scholar 

  35. Scott DL, Berry H, Woolf A, et al. Tiaprofenic acid and symptomatic benefit in osteoarthritis: results from a randomised placebo controlled trial [abstract]. Br J Rheumatol 1995; 34 Suppl. 2: 44

    Google Scholar 

  36. Blackburn WD, Heck LW, Loose LD, et al. Inhibition of 5-lipoxygenase product formation and polymorphonuclear cell degranulation by tenidap sodium in patients with rheumatoid arthritis. Arthritis Rheum 1991; 34: 204–10

    Article  PubMed  Google Scholar 

  37. Sipe JD, Bartle LM, Loose JD. Modification of proinflammatory cytokine production by the antirheumatic agents tenidap and naproxen: a possible correlate with clinical acute-phase response. J Immunol 1992; 148: 480–4

    PubMed  CAS  Google Scholar 

  38. Breedveld F. Tenidap: a novel cytokine-modulating antirheumatic drug for the treatment of rheumatoid arthritis. Scand J Rheumatol 1994; 23 Suppl. 100: 31–44

    Article  Google Scholar 

  39. Blackburn WD, Prupas HM, Silverfield JC, et al. Tenidap in rheumatoid arthritis: a 24 week double-blind comparison with hydroxychloroquine-plus-piroxicam and prioxicam alone. Arthritis Rheum 1995; 38: 1447–56

    Article  PubMed  CAS  Google Scholar 

  40. Mallya RK, de Beer FC, Berry H, et al. Correlation of clinical parameters of disease activity in rheumatoid arthritis with serum concentration of C-reactive protein and erythrocyte sedimentation rate. J Rheumatol 1982; 9: 224–8

    PubMed  CAS  Google Scholar 

  41. McKenna F. Clinical and laboratory assessment of outcome in rheumatoid arthritis. Br J Rheumatol 1988; 27 Suppl. 1:12–20

    PubMed  Google Scholar 

  42. Hassell AB, Davis MJ, Fowler PD. The relationship between serial measures of disease activity and outcome in rheumatoid arthritis. Q J Med 1993; 86: 601–7

    PubMed  CAS  Google Scholar 

  43. van Leeuwen MA, van der Heijde DMFM, van Rijswijk HH, et al. Interrelationship of outcome measures and process variables in early rheumatoid arthritis: a comparison of radiological damage, physical disability, joints counts, and acute phase reactants. J Rheumatol 1994; 21: 425–9

    PubMed  Google Scholar 

  44. Otterness I. The value of C-reactive protein measurment in rheumatoid arthritis. Semin Arthritis Rheum 1994; 24: 91–103

    Article  PubMed  CAS  Google Scholar 

  45. Wilke WS, Sweeney TJ, Calabrese LH. Early, aggressive therapy for rheumatoid arthritis: concerns, descriptions, and estimate of outcome. Semin Arthritis Rheum 1993; 23 Suppl. 1: 26–41

    Article  PubMed  CAS  Google Scholar 

  46. Cash JM, Wilder RL. Refractory rheumatoid arthritis: therapeutic options. Rheum Dis Clin North Am 1995; 21: 1–18

    PubMed  CAS  Google Scholar 

  47. Pincus T. Limitations of randomized clinical trials to recognize possible advantages of combination therapies in rheumatic diseases. Semin Arthritis Rheum 1993; 23 Suppl. 1: 2–10

    Article  PubMed  CAS  Google Scholar 

  48. Capell HA, Porter DR, Madhok R, et al. Second line (disease modifying) treatment in rheumatoid arthritis: which drug for which patient? Ann Rheum Dis 1993: 52: 423–8

    Article  PubMed  CAS  Google Scholar 

  49. Kremer JM, Phelps CT. Long-term prospective study ofthe use of methotrexate in the treatment of rheumatoid arthritis. Update after a mean of 90 months. Arthritis Rheum 1992; 35: 138–45

    Article  PubMed  CAS  Google Scholar 

  50. Weinblatt ME, Weissman BN, Holdsworth DE, et al. Long-term prospective study of methotrexate in the treatment of rheumatoid arthritis. 84-Month update. Arthritis Rheum 1992; 35(2): 129–37

    Article  PubMed  CAS  Google Scholar 

  51. Tishler M, Caspi D, Yaron M. Long-term experience with low dose methotrexate in rheumatoid arthritis. Rheumatol Int 1993; 13: 103–6

    Article  PubMed  CAS  Google Scholar 

  52. Alarcon GS, Lopez-Mendez A, Walter J, et al. Radiographic evidence of disease progression in methotrexate treated and nonmethotrexate disease modifying antirheumatic drug treated rheumatoid arthritis patients: a meta-analysis. J Rheumatol 1992; 19: 1868–73

    PubMed  CAS  Google Scholar 

  53. Tugwell P, Bombardier C, Gent M, et al. Low dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990; 335: 1051–5

    Article  PubMed  CAS  Google Scholar 

  54. Dougados M. Cyclosporin in rheumatoid arthritis. Clin Exp Rheumatol 1994; 12 Suppl. 11: S75–8

    PubMed  Google Scholar 

  55. Wells G, Tugwell P. Cyclosporin Ain rheumatoid arthritis: overview of efficacy. Br J Rheumatol 1993; 32 Suppl. 1: 51–6

    PubMed  Google Scholar 

  56. Forre O, Norwegian Arthritis Study Group. Radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporin: results of a 48-week multicentre study comparing low dose cyclosporin with placebo. Arthritis Rheum 1994; 37: 1506–12

    Article  PubMed  CAS  Google Scholar 

  57. Pasero G, Prioli F, Marubini E, et al. Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 1996; 39: 1006–15

    Article  PubMed  CAS  Google Scholar 

  58. van den Borne BE, Landewe RB, Goei The HS, et al. Relative bioavailability of a new oral form of cyclosporin A in patients with rheumatoid arthritis. Br J Clin Pharmacol 1995; 39: 172–5

    Article  PubMed  Google Scholar 

  59. Bartlett RR, Schleyerbach R. Immunopharmacological profile of a novel isoxazol derivative, HWA486, with potential anti-rheumatic activity: I. Disease modifying action on adjuvant arthritis of the rat. Int J Immunopharmacol 1985; 7: 7–18

    Article  PubMed  CAS  Google Scholar 

  60. Bartlett RR, Dimitrijevic M, Mattar T, et al. Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection. Agents Actions 1991; 32: 10–21

    Article  PubMed  CAS  Google Scholar 

  61. Bartlett RR, Anagnostopules H, Zielinski T, et al. Effects of leflunomide on the immune response and models of inflammation. Springer Semin Immunopathol 1993; 14: 381–94

    Article  PubMed  CAS  Google Scholar 

  62. Mladenovic V, Domlian Z, Rozman B, et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Arthritis Rheum 1995; 38: 1595–603

    Article  PubMed  CAS  Google Scholar 

  63. Barron KS, Sher MR, Silverman ED. Intravenous immunoglobulin therapy: magic or black magic. J Rheumatol 1992; 33 Suppl.: 94–7

    CAS  Google Scholar 

  64. Tumiati B, Casoli P, Veneziani M, et al. High-dose immunoglobulin therapy as an immunomodulatory treatment of rheumatoid arthritis. Arthritis Rheum 1992; 35: 1126–33

    Article  PubMed  CAS  Google Scholar 

  65. Sany J. Intravenous immunoglobulin therapy for rheumatic diseases. Curr Opin Rheumatol 1994; 6: 305–10

    Article  PubMed  CAS  Google Scholar 

  66. Kloppenburg M, Breedveld FC, Terwiel JP, et al. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum 1994; 37: 629–36

    Article  PubMed  CAS  Google Scholar 

  67. Tilley BC, Alarcon GS, Heyse SP, et al. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group. Ann Intern Med 1995; 122: 81–9

    PubMed  CAS  Google Scholar 

  68. Paulus HE. Minocycline treatment of rheumatoid arthritis. Ann Intern Med 1995; 122: 147–8

    PubMed  CAS  Google Scholar 

  69. Breedveld FC, Dijkmans BA, Mattie H. Minocycline treatment for rheumatoid arthritis: an open dose finding study. J Rheumatol 1990; 17: 43–6

    PubMed  CAS  Google Scholar 

  70. Langevitz P, Bank I, Zemer D, et al. Treatment of resistant rheumatoid arthritis with minocycline: an open study. J Rheumatol 1992; 19: 1502–4

    PubMed  CAS  Google Scholar 

  71. McConkey B, Situnayake RD. Rifampicin in rheumatoid arthritis [abstract]. J Rheumatol 1991; 18: 784

    PubMed  CAS  Google Scholar 

  72. Cox NL, Prowse MV, Maddison MC, et al. Treatment of early rheumatoid arthritis with rifampicin. Ann Rheum Dis 1992; 51: 32–4

    Article  PubMed  CAS  Google Scholar 

  73. Borg AA, Davis MJ, Fowler PD, et al. Rifampicin in early rheumatoid arthritis. Scand J Rheumatol 1993; 22: 39–42

    Article  PubMed  CAS  Google Scholar 

  74. Corkill MM, Kirkham BW, Chikanza IC, et al. Intra-muscular depot methylprednisolone induction of chrysotherapy in rheumatoid arthritis: a 24 week randomised controlled trial. Br J Rheumatol 1990; 29: 274–9

    Article  PubMed  CAS  Google Scholar 

  75. Hansen TM, Kryger P, Elling H, et al. Double blind placebo controlled trial of pulse treatment with methylprednisolone combined with disease modifying drugs in rheumatoid arthritis. BMJ 1990; 301: 268–70

    Article  PubMed  CAS  Google Scholar 

  76. Kirwan J, The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995; 333: 142–6

    Article  PubMed  CAS  Google Scholar 

  77. Markham A, Bryson HM. Deflazacort: a review of its pharmacological properties and therapeutic efficacy. Drugs 1995 Aug; 50(2): 317–33

    Article  PubMed  CAS  Google Scholar 

  78. Avioli LV. Potency ratio — a brief synopsis. Br J Rheumatol 1993; 32 Suppl. 2: 24–6

    Article  PubMed  Google Scholar 

  79. Messina OD, Barreira JC, Zanchetta JR, et al. Effect of low doses of deflazacort vs prednisone on bone mineral content in premenopausal rheumatoid arthritis. J Rheumatol 1992; 19: 1520–6

    PubMed  CAS  Google Scholar 

  80. Hall GM, Daniels M, Doyle DV, et al. Effect of hormone replacement therapy on bone mass in rheumatoid arthritis patients treated with and without steroids. Arthritis Rheum 1994; 37: 1499–505

    Article  PubMed  CAS  Google Scholar 

  81. Hall GM, Spector TD, Delmas PD. Markers of bone metabolism in postmenopausal women with rheumatoid arthritis. Effects of corticosteroids and hormone replacement therapy. Arthritis Rheum 1995; 38: 902–6

    Article  PubMed  CAS  Google Scholar 

  82. Eggelmeijer F, Papapoulos SE, van Paassen HC, et al. Increased bone mass with pamidronate treatment in rheumatoid arthritis. Results of a three-year randomized double-blind trial. Arthritis Rheum 1996; 39: 396–402

    Article  PubMed  CAS  Google Scholar 

  83. Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporin and methotrexate in severe rheumatoid arthritis. N Engl J Med 1995; 333: 137–41

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  85. Elliott MT, Maini RN, Feldmann M, et al. Randomised double-blind comparison of chimeric monoclonal antibody to tumour necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Lancet 1994; 344: 1105–10

    Article  PubMed  CAS  Google Scholar 

  86. Elliott MJ, Maini RN, Feldmann M, et al. Repeated therapy with monoclonal antibody to tumour necrosis factor alph (cA2) in patients with rheumatoid arthritis. Lancet 1994; 344: 1125–7

    Article  PubMed  CAS  Google Scholar 

  87. Moreland LW, Pratt PW, Bucy RP, et al. Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody. Long-term followup of CD4+ T cell counts. Arthritis Rheum 1994; 37: 834–8

    Article  PubMed  CAS  Google Scholar 

  88. Choy EHS, Pitzalis C, Cauli A, et al. The amount of anti-CD4 monoclonal antibody entering the rheumatoid joint is associated with clinical improvement. Implications for the development of immunotherapeutic dosing regimens. Arthritis Rheum 1996; 39: 52–6

    Article  PubMed  CAS  Google Scholar 

  89. Kavanaugh AF, Davis LS, Nichols LA, et al. Treatment of refractory rheumatoid arthritis with a monoclonal antibody to intercellular adhesion molecule 1. Arthritis Rheum 1994; 37: 992–9

    Article  PubMed  CAS  Google Scholar 

  90. Trentham DE, Dynesius-Trentham RA, Orav EJ, et al. Effects of oral administration of type II collagen on rheumatoid arthritis. Science 1993; 261: 1727–30

    Article  PubMed  CAS  Google Scholar 

  91. Sieper J, Kary S, Sorensen H, et al. Oral type II collagen treatment in early rheumatoid arthritis: a double-blind, placebocontrolled, randomized trial. Arthritis Rheum 1996; 39: 41–51

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Choy, E.H.S., Scott, D.L. Drug Treatment of Rheumatic Diseases in the 1990s. Drugs 53, 337–348 (1997). https://doi.org/10.2165/00003495-199753030-00001

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199753030-00001

Keywords

Navigation