Rheumatology International

, Volume 25, Issue 1, pp 15–22

An open, randomized comparison study of cyclosporine A, cyclosporine A + methotrexate and cyclosporine A + hydroxychloroquine in the treatment of early severe rheumatoid arthritis

  • Piercarlo Sarzi-Puttini
  • Enzo D’Ingianna
  • Mario Fumagalli
  • Magda Scarpellini
  • Tania Fiorini
  • Enrico Luigi Chérié-Lignière
  • Benedetta Panni
  • Franco Fiorentini
  • Vincenzo Corbelli
  • Nebiat Belai Beyene
  • Claudio Mastaglio
  • Carlo Severi
  • Maurizio Locati
  • Marco Cazzola
  • Guido Menozzi
  • Giuseppe Monti
  • Francesco Saccardo
  • Giuseppina Alfieri
  • Fabiola Atzeni
Original Article



To determine whether a regimen of cyclosporine (CSA) and methotrexate (MTX), or CSA and hydroxychloroquine (HCQ) introduced in early rheumatoid arthritis (RA) can produce a significant improvement in clinical outcome and/or retard radiographic damage in comparison with standard monotherapy with CSA alone.


One hundred five patients with active RA of less than 36 months duration, who had never previously been treated with immunosuppressive agents, were included in a 12-month, multi-center, open, randomized trial. Patients who fulfilled the criteria for early severe RA were randomized to receive either combination therapy (CSA+MTX n=34, CSA+HCQ n=35) or CSA alone (n=36).


CSA+MTX was more effective than the other two treatment groups in controlling RA symptoms. CSA+MTX did not show a significant radiographic progression according to Larsen–Dale (0.90±3.89 compared to baseline values, P>0.05); moreover, patients treated with CSA alone or CSA+HCQ showed a significant worsening of Larsen–Dale score (2.91±5.99 and 2.97±4.28 respectively vs baseline values, P<0.05), although not significant when compared with the CSA+HCQ group (P=0.56 and 0.39, respectively).


This trial indicated that CSA+MTX was more effective than the other two treatments in improving clinical data and inhibiting radiographic progression, although the differences were not significant in this relatively small study. However, the difference was significant in favor of CSA+MTX regarding ACR 50% response.


Rheumatoid arthritis Cyclosporine A Methotrexate Hydroxychloroquine 


  1. 1.
    Harris ED Jr (1990) Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322:1277–1289PubMedGoogle Scholar
  2. 2.
    Hazes JM, Silman AJ (1990) Review of UK data on the rheumatic disease-2. Rheumatoid arthritis. Br J Rheumatol 29: 310–312PubMedGoogle Scholar
  3. 3.
    Mitchell JM, Burkhauser RV, Pincus T (1988) The importance of age, education, and comorbidity in the substantial earnings losses of individuals with symmetrical polyarthritis. Arthritis Rheum 31: 348–357PubMedGoogle Scholar
  4. 4.
    Vandenbroucke JP, Hazevoet HM, Cats A (1984) Survival and case of death in rheumatoid arthritis: a 25-year prospective follow-up. J Rheumatol 11: 158–161PubMedGoogle Scholar
  5. 5.
    Cash JM, Klippel JH (1994) Second-line drug therapy for rheumatoid arthritis. N Engl J Med 330: 1368–1375CrossRefPubMedGoogle Scholar
  6. 6.
    Devlin J, Gough A, Huisson A, Perkins P, Holder R, Reece R Arthur V, Emery P (1997) The acute phase and function in early rheumatoid arthritis: C-reactive protein levels correlate with functional outcome. J Rheumatol 24:9–13Google Scholar
  7. 7.
    Egsmose C, Lund B, Borg G, Petterson H, Berg E, Brodin U, Trang L (1995) Patients with rheumatoid arthritis benefit from early 2nd line therapy: 5-year follow-up of a prospective double blind controlled study. J Rheumatol 22:2208–2213PubMedGoogle Scholar
  8. 8.
    Fries JF, Williams CA, Morfeld D, Singh G, Sibley J (1996) Reduction in long-term disability in patients with rheumatoid arthritis by disease-modifying antirheumatic drug-based treatment strategies. Arthritis Rheum 39:616–622PubMedGoogle Scholar
  9. 9.
    Proudman SM, Conaghan PG, Richardson C, Griffiths B, Green MJ, McGonagle D, Wakefield RJ, Reece RJ, Miles S, Adebaio A, Gough A, Helliwell P, Martin M, Huston G, Pease C, Veale DJ, Isaacs J, van der Heide DM, Emery P (2000) Treatment of poor-prognosis early rheumatoid arthritis. A randomized study of treatment with methotrexate, cyclosporin A and intraarticular corticosteroids compared with sulfasalazine alone. Arthritis Rheum 43:1809–1819CrossRefPubMedGoogle Scholar
  10. 10.
    Boers M, Verhoeven AC, Markusse HM, van de Laar MA, Westhovens R, van Denderen JC, van Zeben D, Dijkmans BA, Peeters AJ, Jacobs P, van den Brink HR, Schouten HJ, van der Heijde DM, Boonen A, van der Linden S (1997) Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 350:309–318PubMedGoogle Scholar
  11. 11.
    Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G, McKendrey R, Tesser J, Baker P, Wells G (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 333:137–41CrossRefPubMedGoogle Scholar
  12. 12.
    Elliott MJ, Maini RN, Feldmann M, Long-Fox A, Charles P, Katsikis P, Brennan FM, Walker J, Bijl H, Grayeb J (1993) Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor. Arthritis Rheum 36:1681–1690PubMedGoogle Scholar
  13. 13.
    Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P (1999) Infliximab (chimeric anti-tumour necrosis factor α monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. Lancet 354:1932–1939PubMedGoogle Scholar
  14. 14.
    Sharp JT, Strand V, Leung H, Hurley F, Loew-Friedrich I (2000) Treatment with leflunomide slows radiographic progression of rheumatoid arthritis: results from three randomized controlled trials of lefluonomide in patients with rheumatoid arthritis. Lefluonomide Rheumatoid Arthritis Investigators Group. Arthritis Rheum 43:495–505CrossRefPubMedGoogle Scholar
  15. 15.
    Elliott JF, Lin Y, Mizel SB, Bleackley RC, Harnish DG, Paetkau V (1984) Induction of interleukin 2 messenger RNA inhibited by cyclosporine A. Science 226:1439–1441PubMedGoogle Scholar
  16. 16.
    Muraguchi A, Butler JL, Kehrol JH, Falkoff RJM, Fauci AS (1983) Selective suppression of an early step in human B cell activation by cyclosporin A. J Exp Med 158:690–702PubMedGoogle Scholar
  17. 17.
    Yocum D (1993) Immunological actions of cyclosporine A in rheumatoid arthritis. Br J Rheumatol 32 (suppl 1):38–41PubMedGoogle Scholar
  18. 18.
    Bensen W, Tugwell P, Roberts RM, Ludwin D, Ross H, Grace E, Gent M (1994) Combination therapy of cyclosporine with methotrexate and gold in rheumatoid arthritis (2 pilot studies). J Rheumatol 21:2034–2038PubMedGoogle Scholar
  19. 19.
    Stein CM, Pincus T, Yocum D, Tugwell P, Wells G, Gluck O, Kraag G, Torley H, Tesser J, McKendrey R, Brooks RH (1997) Combination treatment of severe rheumatoid arthritis with cyclosporine and methotrexate for forty-eight weeks. Arthritis Rheum 40:1843–1851PubMedGoogle Scholar
  20. 20.
    Dawes PT, Tunn E, Fowler PD (1987) Combined gold and hydroxychloroquine in rheumatoid arthritis. Br J Rheumatol (suppl 1) 26:11–14Google Scholar
  21. 21.
    Cronstein BN (1996) Molecular therapeutics: methotrexate and its mechanism of action. Arthritis Rheum 16:662–666Google Scholar
  22. 22.
    Landewé RBM, Miltenburg AMM, Breedveld FC, Daha MR, Dijkmans BAC (1992) cyclosporine and chloroquine synergistically inhibit the interferon-γ production by CD4 positive and CD8 positive synovial T cell clones derived from a patient with rheumatoid arthritis. J Rheumatol 19:1353–1357PubMedGoogle Scholar
  23. 23.
    Salmeron G, Lipsky PE (1983) Immunosuppressive potential of antimalarials. Am J Med 75:19–24Google Scholar
  24. 24.
    Mackenzie AH, Scherbel AL (1980) Chloroquine and hydroxychloroquine in rheumatological therapy. Clin Rheum Dis 6:545–566Google Scholar
  25. 25.
    Ferraccioli GF, Bambara LM, Ferraris M, Perpigneno G, Cattaneo R, Porzio F, Accardo S, Mattara L, Zoppini A, Benucci M, Ostumi PA, Pasero G (1997) Effects of cyclosporin on joint damage in rheumatoid arthritis. Clin Exp Rheumatol 15 [Suppl 17] 83–89Google Scholar
  26. 26.
    Pasero G, Priolo F, Marubini E, Fantini F, Ferraccioli G, Magarò M, Marcolongo R, Oriente P, Pipitone V, Portioli I, Tirri G, Trotta F, Della Casa-Alberighi O (1996) Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 37:1006–1015Google Scholar
  27. 27.
    FØrre Ø and the Norwegian Arthritis Study group (1994) radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporin: results of a 48-week multicenter study comparing low-dose cyclosporin with placebo. Arthritis Rheum 37:1506–1512PubMedGoogle Scholar
  28. 28.
    Drosos AA, Voulgari PV, Katsaraki A, Zikou AK (2000) Influence of cyclosporin A on radiological progression in early rheumatoid arthritis patients: a 42-month prospective study. Rheumatol Int 19:113–118PubMedGoogle Scholar
  29. 29.
    Kushner I, Dawson NV (1992) Changing perspectives in the treatment of rheumatoid arthritis. J Rheumatol19:1831–1834Google Scholar
  30. 30.
    Arnett FC, Edworthy SM, Bloch DA (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31:315–324PubMedGoogle Scholar
  31. 31.
    Felson DT, Anderson JJ, Boers M, Bombardier C, Chernoff M, Fried B, Furst D, Goldsmith C, Kieszak S, Lighfoot R (1993) The American College of Rheumatology preliminary core set of disease activity measures for rheumatoid arthritis clinical trials. Arthritis Rheum 36:729–740PubMedGoogle Scholar
  32. 32.
    Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, Katz LM, Linghtfoot R Jr, Paulus H, Strand V (1995) The American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 38: 727–735PubMedGoogle Scholar
  33. 33.
    Larsen A, Dale K, Eek M (1977) Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn 18:481–491Google Scholar
  34. 34.
    Ranza R, Marchesoni A, Calori G, Bianchi G, Braga M, Canazza S, Canesi B, Fumagalli M, Mastaglio C, Mathieu A (1993) The Italian version of the functional disability index of the health assessment questionnaire. A reliable instrument for multicenter studies in rheumatoid arthritis. Clin Exp Rheumatol 11:123–128PubMedGoogle Scholar
  35. 35.
    Fries JF, Spitz PW, Young DY (1992) The dimensions of health outcomes: the health assessment questionnaire, disability and pain scales. J Rheumatol 9: 789–793Google Scholar
  36. 36.
    Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F (1992) The American college of Rheumatology Association 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 35: 498-502Google Scholar
  37. 37.
    Larsen A (1975) A radiologic method for grading the severity of rheumatoid arthritis. Scand J Rheumatol 4:225–233PubMedGoogle Scholar
  38. 38.
    Larsen A, Edgren J, Harju E, Laasonen L, Reitamo T (1979) Interobserver variation in the evaluation of radiologic changes of rheumatoid arthritis. Scand J Rheumatol 8:109–112PubMedGoogle Scholar
  39. 39.
    Larsen A (1999) How to apply Larsen score in evaluating radiographs of rheumatoid arthritis in long-term studies. J Rheumatol 10:1974–1975Google Scholar
  40. 40.
    Stuart AA (1955) A test for homogeneity of the marginal distributions in a two-way classification. Biometrica 42: 412–416Google Scholar
  41. 41.
    Paulus HE, Egger MJ, Ward JR, Williams HJ (1990) Analysis of improvement in individual rheumatoid arthritis patients treated with disease-modifying antirheumatic drugs, based on the findings in patients treated with placebo. The Cooperative Systematic Studies of Rheumatic Diseases Group. Arthritis Rheum 33: 477–484PubMedGoogle Scholar
  42. 42.
    Jeurissen ME, Boerbooms AM, van de Putte LB, Doesburg WH, Lemmens AM (1991) Influence of methotrexate and azathioprine on radiologic progression in rheumatoid arthritis. Ann Intern Med 114:999–1004PubMedGoogle Scholar
  43. 43.
    Stenger AAME, van Leewen MA, Houtman PM, Bruyn GAW, Speestra F, Barendsen BC, Velthuysen E, van Rijswijk MH (1998) Early effective suppression of inflammation in rheumatoid arthritis reduces radiographic progression. Br J Rheumatol 37:1157–1163CrossRefPubMedGoogle Scholar
  44. 44.
    Verhoven AC, Boers M, Tugwell P (1998) Combination therapy in rheumatoid arthritis: updated systematic review. Br J Rheumatol 37:612–619CrossRefPubMedGoogle Scholar
  45. 45.
    Farr M, Bacon PA (1995) How and when should combination therapy be used? The role of anchor drug. Br J Rheumatol [Suppl 2] 34:100–103Google Scholar
  46. 46.
    Panayi GS, Tugwell P (1994) The use of cyclosporin A in rheumatoid arthritis: conclusion of an international review. Br J Rheumatol 33 [Suppl 3] 967–969Google Scholar
  47. 47.
    Tugwell O, Baker P (1995) Guidelines for the use of cyclosporine in rheumatoid arthritis. Clin Rheumatol 14 [Suppl 2] 37–41Google Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Piercarlo Sarzi-Puttini
    • 1
  • Enzo D’Ingianna
    • 2
  • Mario Fumagalli
    • 3
  • Magda Scarpellini
    • 4
  • Tania Fiorini
    • 1
  • Enrico Luigi Chérié-Lignière
    • 5
  • Benedetta Panni
    • 1
  • Franco Fiorentini
    • 2
  • Vincenzo Corbelli
    • 2
  • Nebiat Belai Beyene
    • 5
  • Claudio Mastaglio
    • 6
  • Carlo Severi
    • 6
  • Maurizio Locati
    • 7
  • Marco Cazzola
    • 7
  • Guido Menozzi
    • 8
  • Giuseppe Monti
    • 9
  • Francesco Saccardo
    • 9
  • Giuseppina Alfieri
    • 2
  • Fabiola Atzeni
    • 1
  1. 1.Unità Operativa di ReumatologiaUniversity Hospital L. SaccoMilanItaly
  2. 2.Unità Operativa di Reumatologia-Medicina InternaAzienda Ospedaliera Sant’AnnaComoItaly
  3. 3.Divisione di Medicina RiabilitativaIstituti clinici di PerfezionamentoMilanItaly
  4. 4.Unità Operativa di Reumatologia-Medicina InternaOspedale Busto ArsizioBusto ArsizioItaly
  5. 5.Unità Operativa di Medicina InternaOspedale BassiniCinisello BalsamoItaly
  6. 6.Unità Operativa di Riabilitazione e ReumatologiaOspedale di GravedonaGravedonaItaly
  7. 7.Unità Operativa di RiabilitazioneOspedale di SaronnoSaronnoItaly
  8. 8.Unità Operativa di Medicina InternaOspedale di SondrioSondrioItaly
  9. 9.Unità Operativa di Medicina Interna e ReumatologiaOspedale di SaronnoSaronnoItaly

Personalised recommendations