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Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or with other DMARDs

Nature Clinical Practice Rheumatology volume 3, pages 450–458 (2007)Cite this article

Abstract

Early aggressive treatment of rheumatoid arthritis is associated with improved disease control, slower radiological progression and improved functional outcomes. Tumor necrosis factor blocking therapy is effective but there remain concerns about long-term risks. Combining disease-modifying antirheumatic drugs (DMARDs) is a widely used therapeutic alternative; however, there is uncertainty surrounding the most effective regimen. A popular combination is methotrexate plus sulfasalazine, but each of these DMARDs can also be used in combination with other DMARDs and in triple therapy regimens. However, wide variations in study size, design, steroid usage and approaches to combination therapy have made it difficult to form firm conclusions regarding their efficacy. Generally, combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy. Methotrexate–sulfasalazine, methotrexate–chloroquine, methotrexate–ciclosporin, methotrexate–leflunomide, methotrexate–intramuscular-gold and methotrexate–doxycycline are effective combination regimens. Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Further investigation is required to determine the most effective regimen and approach to combination therapy.

Key Points

  • Aggressive management of active rheumatoid arthritis often requires early use of simultaneous disease-modifying antirheumatic drugs (DMARDs) to prevent long-term disability

  • Adverse event rates for combination DMARD therapy are similar to those of monotherapy

  • Randomized controlled trials suggest that methotrexate-based combination therapy regimens are effective. Effective regimens have combined methotrexate with sulfasalazine, chloroquine, ciclosporin, leflunomide, intramuscular gold or doxcycline. Sulfasalazine-based combination therapy regimens have not been fully investigated

  • Several trials have shown methotrexate–sulfasalazine–hydroxychloroquine triple combination therapy to be more effective than various dual and monotherapy regimens

  • Radiological progression may occur despite combination DMARD therapy

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Figure 1: Therapeutic approaches to combination DMARD therapy

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References

  1. Geborek P et al. (2005) Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis 64: 699–703

    Article  CAS  Google Scholar 

  2. Mottonen T et al. (2002) Delay to institution of therapy and induction of remission using single-drug or combination-disease modifying antirheumatic drug therapy in early rheumatoid arthritis. Arthritis Rheum 46: 894–898

    Article  CAS  Google Scholar 

  3. Egsmose C et al. (1995) Patients with rheumatoid arthritis benefit from early 2nd line therapy. 5 year follow-up of a prospective double blind placebo controlled study. J Rheumatol 22: 2208–2213

    CAS  PubMed  Google Scholar 

  4. Jobanputra P et al. (2004) A survey of British rheumatologists' DMARD preferences for rheumatoid arthritis. Rheumatology 43: 206–210

    Article  CAS  Google Scholar 

  5. ACR Guidelines for the management of rheumatoid arthritis: 2002 update. American College of Rheumatology. Arthritis Rheum 46: 328–346

  6. SIGN Guideline 48 (2002) Management of early rheumatoid arthritis. Edinburgh: Scottish Intercollegiate Guidelines Network

  7. Tugwell P et al. (2004) Evidence-Based Rheumatology. London: BMJ Publishing Group

    Google Scholar 

  8. Felson D et al. (1994) The efficacy and toxicity of combination therapy in rheumatoid arthritis—a meta-analysis. Arthritis Rheum 37: 1487–1491

    Article  CAS  Google Scholar 

  9. Verhoeven A et al. (1998) Combination therapy in rheumatoid arthritis: updated systematic review. Br J Rheumatol 37: 612–619

    Article  CAS  Google Scholar 

  10. Goekoop Y et al. (2001) Combination therapy in rheumatoid arthritis. Curr Opin Rheumatol 13: 177–183

    Article  CAS  Google Scholar 

  11. Smolen J et al. (2005) Superior efficacy of combination therapy in rheumatoid arthritis: fact or fiction? Arthritis Rheum 52: 2975–2983

    Article  CAS  Google Scholar 

  12. Haagsma CJ et al. (1997) Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomised, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 36: 1082–1088

    Article  CAS  Google Scholar 

  13. Dougados M et al. (1999) Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 58: 220–225

    Article  CAS  Google Scholar 

  14. Haagsma CJ et al. (1994) Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomised open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol 33: 1049–1055

    Article  CAS  Google Scholar 

  15. Capell H et al. (2006) Combination therapy with sulphasalazine and methotrexate is more effective than either drug alone in rheumatoid arthritis (RA) patients with a suboptimal response to sulphasalazine: results from the double blind placebo controlled MASCOT study. Ann Rheum Dis 66: 235–241

    Article  Google Scholar 

  16. Ferraz M et al. (1994) Combination therapy with methotrexate and chloroquine in rheumatoid arthritis. Scand J Rheumatol 23: 231–236

    Article  CAS  Google Scholar 

  17. Clegg DO et al. (1997) Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine. J Rheumatol 24: 1896–1902

    CAS  PubMed  Google Scholar 

  18. Carmichael S et al. (2002) Combination therapy with methotrexate and hydroxychloroquine for rheumatoid arthritis increases exposure to methotrexate. J Rheumatol 29: 2077–2083

    CAS  PubMed  Google Scholar 

  19. Tugwell P et al. (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 333: 137–141

    Article  CAS  Google Scholar 

  20. Stein M et al. (1997) Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks. An open-label extension study. Arthritis Rheum 40: 1843–1851

    Article  CAS  Google Scholar 

  21. Gerards A et al. (2003) Cyclosporin A monotherapy versus cyclosporin A and methotrexate combination therapy in patients with early rheumatoid arthritis: a double blind randomised placebo controlled trial. Ann Rheum Dis 62: 291–296

    Article  CAS  Google Scholar 

  22. Marchesoni A et al. (2002) Step-down approach using either cyclosporin A or methotrexate as maintenance therapy in early rheumatoid arthritis. Arthritis Rheum 47: 59–66

    Article  CAS  Google Scholar 

  23. Marchesoni A et al. (2003) Radiographic progression in early rheumatoid arthritis: a 12-month randomised controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology 42: 1545–1549

    Article  CAS  Google Scholar 

  24. Kremer J et al. (2002) Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate. A randomised, double-blind, placebo-controlled trial. Ann Intern Med 137: 726–733

    Article  CAS  Google Scholar 

  25. Kremer J et al. (2004) Combination leflunomide and methotrexate therapy for patients with active rheumatoid arthritis failing methotrexate monotherapy: open label extension of a randomised, double-blind, placebo controlled trial. J Rheumatol 31: 1521–1531

    CAS  PubMed  Google Scholar 

  26. Williams H et al. (1992) Comparison of auranofin, methotrexate and the combination of both in the treatment of rheumatoid arthritis. A controlled clinical trial. Arthritis Rheum 35: 259–269

    Article  CAS  Google Scholar 

  27. Lopez-Mendez A et al. (1993) Radiographic assessment of disease progression in rheumatoid arthritis patients enrolled in the Cooperative Systematic Studies of the Rheumatic Diseases Program randomised clinical trial of methotrexate, auranofin, or a combination of the two. Arthritis Rheum 36: 1364–1369

    Article  CAS  Google Scholar 

  28. Lehman A et al. (2005) A 48 week randomised, double-blind, double observer, placebo-controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis. Results of the METGO Study. Arthritis Rheum 52: 1360–1370

    Article  CAS  Google Scholar 

  29. Willkens R et al. (1992) Comparison of azathioprine, methotrexate and the combination of both in the treatment of rheumatoid arthritis. Arthritis Rheum 35: 849–856

    Article  CAS  Google Scholar 

  30. Willkens R et al. (1995) Comparison of azathioprine, methotrexate and the combination of both in the treatment of rheumatoid arthritis. A forty-eight week controlled clinical trial with radiologic outcome assessment. Arthritis Rheum 38: 1799–1806

    Article  CAS  Google Scholar 

  31. Willkens R and Stablein D (1996) Combination treatment of rheumatoid arthritis using azathioprine and methotrexate: a 48 week controlled clinical trial. J Rheumatol Suppl 44: 64–68

    CAS  PubMed  Google Scholar 

  32. Kremer J et al. (2003) Tacrolimus in rheumatoid arthritis patients receiving concomitant methotrexate. Arthritis Rheum 48: 2763–2768

    Article  CAS  Google Scholar 

  33. O'Dell JR et al. (2006) Treatment of early seropositive rheumatoid arthritis: doxycycline plus methotrexate versus methotrexate alone. Arthritis Rheum 54: 621–627

    Article  CAS  Google Scholar 

  34. Dougados M et al. (2005) When a DMARD fails, should patients switch to sulfasalazine or add sulfasalazine to continuing leflunomide? Ann Rheum Dis 64: 44–51

    Article  CAS  Google Scholar 

  35. Faarvang K et al. (1993) Hydroxychloroquine and sulphasalazine alone and in combination in rheumatoid arthritis: a randomised double blind trial. Ann Rheum Dis 52: 711–715

    Article  CAS  Google Scholar 

  36. Rojkovich B et al. (1999) Cyclosporin and sulfasalazine combination in the treatment of early rheumatoid arthritis. Scand J Rheumatol 28: 216–221

    Article  CAS  Google Scholar 

  37. Taggart AJ et al. (1987) Sulfasalazine alone or in combination with [D]-penicillamine in rheumatoid arthritis. Br J Rheumatol 26: 32–36

    Article  CAS  Google Scholar 

  38. O'Dell JR et al. (1996) Treatment of rheumatoid arthritis with methotrexate alone, sulphasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 334: 1287–1291

    Article  CAS  Google Scholar 

  39. O'Dell JR et al. (2002) Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications. Results of a two-year, randomised, double-blind, placebo-controlled trial. Arthritis Rheum 46: 1164–1170

    Article  CAS  Google Scholar 

  40. Calguneri M et al. (1999) Combination therapy versus monotherapy for the treatment of patients with rheumatoid arthritis. Clin Exp Rheumatol 17: 699–704

    CAS  PubMed  Google Scholar 

  41. Mottonen T et al. (1999) Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 353: 1568–1573

    Article  CAS  Google Scholar 

  42. Ferraccioli G et al. (2002) Analysis of improvements, full responses, remission and toxicity in rheumatoid patients treated with step-up combination therapy (methotrexate, cyclosporin A, sulphasalazine) or monotherapy for three years. Rheumatology 41: 892–898

    Article  CAS  Google Scholar 

  43. Blair PS and Silman AJ (1991) Can clinical trials in rheumatology be improved? Curr Opin Rheumatol 3: 272–279

    Article  CAS  Google Scholar 

  44. Boers M et al. (1997) Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350: 309–318

    Article  CAS  Google Scholar 

  45. Goekoop-Ruiterman Y et al. (2005) Clinical and radiographic outcomes of four different treatment strategies in people with early rheumatoid arthritis (the BeSt Study). A randomized, controlled trial. Arthritis Rheum 52: 3381–3390

    Article  CAS  Google Scholar 

  46. Grigor CG et al. (2004) Effects of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single blind randomized controlled trial. Lancet 364: 263–269

    Article  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the invaluable help provided by L Garrity, librarian of Glasgow Royal Infirmary. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Authors and Affiliations

  1. J Dale is a Specialist Registrar at Ayr County Hospital, Ayr, UK.,

    James Dale

  2. N Alcorn is a Staff Grade Physician, H Capell is a Consultant Rheumatologist and Honorary Professor, and R Madhok is a Consultant Rheumatologist, all at the Centre for Rheumatic Diseases, Glasgow Royal Infirmary, Glasgow, UK.,

    Nicola Alcorn, Hilary Capell & Rajan Madhok

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Correspondence to James Dale.

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Dale, J., Alcorn, N., Capell, H. et al. Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or with other DMARDs. Nat Rev Rheumatol 3, 450–458 (2007). https://doi.org/10.1038/ncprheum0562

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