• Arno W. R. van Kuijk
  • Ben A. C. Dijkmans
Part of the Progress in Inflammation Research book series (PIR)


Cyclosporin A (CsA) was discovered and isolated in 1971 as a fungal metabolite produced by Tylopocladium inflatum with only weak antimicrobial properties. After the initial deception the immunosuppressive effect of CsA was discovered and explored in the Sandoz laboratories in the years thereafter [1, 2]. Since its first use in humans in 1978 CsA has led to a dramatic improvement in the field of organ transplantation [3]. Based on its mode of action it has also been used as an immunosuppressive agent in many other diseases, mainly autoimmune or rheumatologic conditions. The success of CsA in the clinical treatment of organ transplant patients was never equalled in rheumatology, but CsA certainly has a place as immunosuppressive agent in the treatment of many autoimmune diseases, especially in rheumatoid arthritis (RA).


Rheumatoid Arthritis Early Rheumatoid Arthritis Microemulsion Formulation Parenteral Gold Refractory Rheumatoid Arthritis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Heusler K, Pletscher A (2001) The controversial history of cyclosporin. Swiss Med Wkly 131:299–302PubMedGoogle Scholar
  2. 2.
    Borel JF (1976) Comparative study of in vitro and in vivo drug effects on cell mediated cytotoxicity. Immunol 31:631–641Google Scholar
  3. 3.
    Kahan BD (1989) Cyclosporine. N Engl J Med 321: 1725–1738PubMedGoogle Scholar
  4. 4.
    Van Rijthoven AW, Dijkmans BA, Goei The HS, Hermans J, Montnor-Beckers ZL, Jacobs PC, Cats A (1986) Cyclosporin treatment for rheumatoid arthritis: A placebo controlled, double blind multicentre study. Ann Rheum Dis 45: 726–731CrossRefPubMedGoogle Scholar
  5. 5.
    Weinblatt ME, Coblyn JS, Fraser PA, Anderson RJ, Spragg J, Trentham DE, Austen KF (1987) Cyclosporin A treatment of refractory rheumatoid arthritis. Arthritis Rheum 30: 11–17CrossRefPubMedGoogle Scholar
  6. 6.
    Forre O, Bjerkhoel F, Salvesen CF, Berg KJ, Rugstad HE, Saelid G, Mellbye OJ, Kass E (1987) An open, controlled, randomized comparison of cyclosporine and azathioprine in the treatment of rheumatoid arthritis: A preliminary report. Arthritis Rheum 30: 88–92CrossRefPubMedGoogle Scholar
  7. 7.
    Tugwell P, Bombardier C, Gent M, Bennett KJ, Ludwin D, Grace E, Buchanan WW, Bensen WG, Bellamy N, Murphy GF (1987) Low dose cyclosporine in rheumatoid arthritis: A pilot study. J Rheumatol 14: 1108–1114PubMedGoogle Scholar
  8. 8.
    Dougados M, Duchesne L, Awada H, Amor B (1989) Assessment of efficacy and acceptability of low dose cyclosporin in patients with rheumatoid arthritis. Ann Rheum Dis 48: 550–556CrossRefPubMedGoogle Scholar
  9. 9.
    Panayi GS, Tugwell P (1997) The use of cyclosporin A microemulsion in rheumatoid arthritis: Conclusions of an international review. Br J Rheumatol 36: 808–811CrossRefPubMedGoogle Scholar
  10. 10.
    Wiederrecht G, Lam E, Hung S, Martin M Sigal N (1993) The mechanism of action of FK-506 and cyclosporin A. Ann NY Acad Sci 696: 9–19PubMedCrossRefGoogle Scholar
  11. 11.
    Schreiber SL, Crabtree GR (1992) The mechanism of action of cyclosporin A and FK506. Immunol Today 13: 136–142CrossRefPubMedGoogle Scholar
  12. 12.
    Timmerman LA, Clipstone NA, Ho SN, Northrop JP, Crabtree GR (1996) Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression. Nature 383: 837–840CrossRefPubMedGoogle Scholar
  13. 13.
    Herold KC, Lanki DW, Moldwin RL, Fitch FW (1986) Immunosuppressive effects of cyclosporin A on cloned T cells. J Immunol 136: 1315–1321PubMedGoogle Scholar
  14. 14.
    Granelli-Piperno A (1988) In situ hybridization for interleukin 2 and interleukin 2 receptor mRNA in T cells activated in the presence of absence of cyclosporin A. J Exp Med 168: 1649–1658CrossRefPubMedGoogle Scholar
  15. 15.
    Cho ML, Kim WU, Min S Y, Min DJ, Min JK, Lee SH, Park SH, Cho CS, Kim H Y (2002) Cyclosporine differentially regulates interleukin-10, interleukin-15, and tumor necrosis factor a production by rheumatoid synoviocytes. Arthritis Rheum 46: 42–51CrossRefPubMedGoogle Scholar
  16. 16.
    Cho ML, Cho CS, Min SY, Kim SH, Lee SS, Kim WU, Min DJ, Min JK, Youn J, Hwang S Y et al (2002) Cyclosporine inhibition of vascular endothelial growth factor production in rheumatoid synovial fibroblasts. Arthritis Rheum 46: 1202–1209CrossRefPubMedGoogle Scholar
  17. 17.
    Kim WU, Cho ML, Kim SI, Yoo WH, Lee SS, Joo YS, Min JK, Hong YS, Lee SH, Park SH et al (2000) Divergent effect of cyclosporine on Th1/Th2 type cytokines in patients with severe, refractory rheumatoid arthritis. J Rheumatol 27: 324–331PubMedGoogle Scholar
  18. 18.
    Yocum DE, Wilder RL, Dougherty S, Klippel JH, Pillemer S, Wahl S (1990) Immunologic parameters of response in patients with rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 33: 1310–1316CrossRefPubMedGoogle Scholar
  19. 19.
    Yocum DE (1993) Immunological actions of cyclosporin A in rheumatoid arthritis. Br J Rheumatol 32 (Suppl 1): 38–41PubMedGoogle Scholar
  20. 20.
    Fahr A (1993) Cyclosporin clinical pharmacokinetics. Clin Pharmacokinet 24: 472–495CrossRefPubMedGoogle Scholar
  21. 21.
    Kahan BD, Dunn J, Fitts C, Van Buren D, Wombolt D, Pollak R, Carson R, Alexander JW, Choc M, Wong R (1995) Reduced inter-and intrasubject variability in cyclosporine pharmacokinetics in renal transplant recipients treated with microemulsion formulation in conjunction with fasting, low-fat meals, or high-fat meals. Transplantation 59: 505–511PubMedGoogle Scholar
  22. 22.
    Kolars JC, Awni WM, Merion RM, Watkins PB (1991) First-pass metabolism of cyclosporin by the gut. Lancet 338: 1488–1490CrossRefPubMedGoogle Scholar
  23. 23.
    Friman S, Backman L (1996) A new microemulsion formulation of cyclosporin: Pharmacokinetic and clinical features. Clin Pharmacokinet 30: 181–193CrossRefPubMedGoogle Scholar
  24. 24.
    Van den Borne BE, Landewe RB, Goei The HS, Mattie H, Breedveld FC, Dijkmans BA (1995) Relative bioavailibility of a new oral form of cyclosporin A in patients with rheumatoid arthritis. Br J Clin Pharmacology 39: 172–173Google Scholar
  25. 25.
    Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ et al (1997) Role of intestinal P-glycoprotein (mdrl) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 62:248–260CrossRefPubMedGoogle Scholar
  26. 26.
    Tjia JF, Webber IR, Back DJ (1991) Cyclosporin metabolism by the gastrointestinal mucosa. Br J Clin Pharmacol 31: 344–346PubMedGoogle Scholar
  27. 27.
    Rodl S, Khoshsorur G (1990) Binding of cyclosporine A to human serum lipoproteins. Transplant Proc 22: 287–288PubMedGoogle Scholar
  28. 28.
    Kivisto KT (1992) A review of assay methods for cyclosporin. Clinical implications. Clin Pharmacokinet 23: 173–190CrossRefPubMedGoogle Scholar
  29. 29.
    Fahr A, Hiestad P, Ryffel B (1990) Studies on the biologic activities of Sandimmun metabolites in humans and in animal models: Review and original experiments. Transplant Proc 22: 1116–1124PubMedGoogle Scholar
  30. 30.
    Tugwell P, Ludwin D, Gent M, Roberts R, Bensen W, Grace E, Baker P (1997) Interaction between cyclosporin A and nonsteroidal anti-inflammatory drugs. J Rheum 24: 1122–1125PubMedGoogle Scholar
  31. 31.
    Tak PP, Smeets TJ, Daha MR, Kluin PM, Meijers KA, Brand R, Meinders AE, Breedveld FC (1997) Analysis of the synovial cell infiltrate in early rheumatoid synovial tissue in relation to local disease activity. Arthritis Rheum 40: 217–225CrossRefPubMedGoogle Scholar
  32. 32.
    Amor B, Dougados M (1985) Cyclosporin in rheumatoid arthritis: open trials with different dosages. In: Schindler (ed): Cyclosporin in autoimmune diseases. Springer-Verlag, Berlin, Germany, 283–287Google Scholar
  33. 33.
    Bowles CA, Gabriel S, Bunch TW, Handwerger BS (1987) Cyclosporine (CsA) treatment for rheumatoid arthritis. Arthritis Rheum 30 (Suppl 9): S58–B12Google Scholar
  34. 34.
    Tugwell P, Bombardier C, Gent M, Bennett KJ, Bensen WG, Carette S, Chalmers A, Esdaile JM, Klinkhoff AV, Kraag GR et al (1990) Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 335: 1051–1055CrossRefPubMedGoogle Scholar
  35. 35.
    Van Rijthoven AW, Dijkmans BA, Goei The HS, Meijers KA, Montnor-Beckers ZL, Moolenburgh JD, Boers M, Cats A (1991) Comparison of cyclosporine and d-penicil-lamine for rheumatoid arthritis: A randomized, double blind, multicenter study. J Rheumatol 18: 815–820PubMedGoogle Scholar
  36. 36.
    Ahern MJ, Harrison W, Hollingsworth P, Bradley J, Laing B, Baylisse C (1991) A randomized double-blind trial of cyclosporin and azathioprine in refractory rheumatoid arthritis. Aust NZ J Med 21: 844–849Google Scholar
  37. 37.
    Kruger K, Schattenkirchner M (1994) Comparison of cyclosporin A and azathioprine in the treatment of rheumatoid arthritis — results of a double-blind multicentre study. Clin Rheumatology 13: 248–255Google Scholar
  38. 38.
    Forre O and the Norwegian Arthritis Study Group (1994) Results of a 48-week multi-center study comparing low-dose cyclosporine with placebo. Arthritis Rheum 37: 1506–1512CrossRefPubMedGoogle Scholar
  39. 39.
    Landewe RB, Goei The HS, Van Rijthoven AW, Breedveld FC, Dijkmans BA (1994) A randomized, double-blind, 24-week controlled study of low-dose cyclosporine versus chloroquine for early rheumatoid arthritis. Arthritis Rheum 37: 637–643CrossRefPubMedGoogle Scholar
  40. 40.
    Van den Borne BE, Landewe RB, Goei The HS, Breedveld FC, Dijkmans BA (1996) Low dose cyclosporine in rheumatoid arthritis: effective and safe after two years of therapy when compared with chloroquine. Scand J Rheumatol 25: 307–316CrossRefPubMedGoogle Scholar
  41. 41.
    Pasero G, Priolo F, Marubini E, Fantini F, Ferracioli G, Magaro M, Marcolongo R, Oriente P, Pipitone V, Portioli I et al (1996) Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A. Arthritis Rheum 39: 1006–1015CrossRefPubMedGoogle Scholar
  42. 42.
    Pasero G, Govoni M, Caramaschi P, Gorla R, Buticchi G, Lamontagna G (1996) The 24-month effect of glucocorticoids in combination with cyclosporin or DMARD’s on joint destruction in early active RA. Arthritis Rheum 39 (Suppl 9): S104–467Google Scholar
  43. 43.
    Zeidler HK, Kvien TK, Hannonen P, Wollheim FA, Forre O, Geidel H, Hafstrom I, Kaltwasser JP, Leirisalo-Repo M, Manger B et al (1998) Progression of joint damage in early active severe rheumatoid arthritis during 18 months of treatment: comparison of low-dose cyclosporin and parenteral gold. Br J Rheumatol 37: 874–882CrossRefPubMedGoogle Scholar
  44. 44.
    Drosos AA, Voulgari PV, Papadopoulos IA, Politi EN, Georgiou PE, Zikou AK (1998) Cyclosporine A in the treatment of early rheumatoid arthritis. A prospective, randomized, 24-month study. Clin Exp Rheumatol 16: 695–701PubMedGoogle Scholar
  45. 45.
    Bensen WG, 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
  46. 46.
    Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G, Me Kendry R, Tesser J, Baker P, Wells G (1995) Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 333: 137–141CrossRefPubMedGoogle Scholar
  47. 47.
    Stein CM, Pincus T, Yocum D, Tugwell P, Wells G, Gluck O, Kraag G, Torley H, Tesser J, McKendry R 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: 1843–1851CrossRefPubMedGoogle Scholar
  48. 48.
    Marchesoni A, Battafarano N, Arreghini M, Panni B, Gallazzi M, Tosi S (2003) Radiographic progression in early rheumatoid arthritis: a 12-month randomised controlled study comparing the combination of cyclosporin and methotrexate with methotrexate alone. Rheumatology (Oxford) 42: 1545–1549CrossRefGoogle Scholar
  49. 49.
    Fox RI, Morgan SL, Smith HT, Robbins BA, Choc MG, Baggott JE (2003) Combined oral cyclosporin and methotrexate therapy in patients with rheumatoid arthritis elevates methotrexate levels and reduces 7-hydroxymethotrexate levels when compared to methotrexate alone. Rheumatology (Oxford) 42: 989–994CrossRefGoogle Scholar
  50. 50.
    Bendix G, Bjelle A (1996) Adding low-dose cyclosporin A to parenteral gold therapy in rheumatoid arthritis: A double-blind placebo-controlled study. Br J Rheumatol 35: 1142–1149CrossRefPubMedGoogle Scholar
  51. 51.
    Van den Borne BE, Landewe RB, Goei The HS, Rietveld JH, Zwinderman AH, Bruyn GA, Breedveld FC, Dijkmans BA (1998) Combination therapy in recent onset rheumatoid arthritis: a randomized double blind trial of the addition of low dose cyclosporine to patients treated with low dose chloroquine. J Rheumatol 25: 1493–1498PubMedGoogle Scholar
  52. 52.
    Temekonidis TI, Georgiadis AN, Alamanos Y, Bougias DV, Voulgari PV, Drosos AA (2002) Infliximab treatment in combination with cyclosporin A in patients with severe refractory rheumatoid arthritis. Ann Rheum Dis 61: 822–825CrossRefPubMedGoogle Scholar
  53. 53.
    Voss BL, Hamilton KK, Samara EN, McKee PA (1988) Cyclosporin suppression of endothelial prostacyclin generation. A possible mechanism for nephrotoxicity. Transplantation 45: 793–796CrossRefPubMedGoogle Scholar
  54. 54.
    Boers M, Dijkmans BA, Van Rijthoven AW, Goei The HS, Cats A (1990) Reversible nephrotoxicity of cyclosporine in rheumatoid arthritis. J Rheumatol 17: 38–42PubMedGoogle Scholar
  55. 55.
    Landewe RB, Goei The HS, Van Rijthoven AW, Rietveld JR, Breedveld FC, Dijkmans BA (1994) Cyclosporin in common clinical practice: An estimation of the benefit/risk ratio in patients with rheumatoid arthritis. J Rheum 21: 1631–1636PubMedGoogle Scholar
  56. 56.
    Van den Borne BE, Landewe RB, Goei The HS, Breedveld FC, Dijkmans BA (1999) Cyclosporin A therapy in rheumatoid arthritis: Only strict application of the guidelines for safe use can prevent irreversible renal function loss. Rheumatology (Oxford) 38: 254–259CrossRefGoogle Scholar
  57. 57.
    Yocum DE, Stein M, Pincus T (1998). Longterm safety of cyclosporin/Sandimmune alone and in combination with methotrexate in the treatment of active rheumatoid arthritis: Analysis of open label extension studies. Arthritis Rheum 41: S364–1989Google Scholar
  58. 58.
    Pasero G and GRISAR (1997) Assessment of side effects of low dose cyclosporin doses in early rheumatoid arthritis after 3 years. Arthritis Rheum 40 (Suppl 9): S96–396Google Scholar
  59. 59.
    Feutren G, Mihatsch MJ (1992) Risk factors for cyclosporin-induced nephropathy in patients with autoimmune diseases. International Kidney Biopsy Registry of Cyclosporine in Autoimmune Diseases. N Engl J Med 326: 1654–1660PubMedCrossRefGoogle Scholar
  60. 60.
    Rodriguez F, Krayenbuhl JC, Harrison WB, Forre O, Dijkmans BA, Tugwell P, Miescher PA, Mihatsch MJ (1996) Renal biopsy findings and follow-up of renal function in rheumatoid arthritis patients treated with cyclosporin A. An update from the International Kidney Biopsy Registry. Arthritis Rheum 39: 1491–1498CrossRefPubMedGoogle Scholar
  61. 61.
    Boers M, Dijkmans BA, Breedveld FC, Camps JA, Chang PC, Van Brummelen P, Pauwels EK, Cats A (1990) Subclinical renal dysfunction in rheumatoid arthritis. Arthritis Rheum 33: 95–101CrossRefPubMedGoogle Scholar
  62. 62.
    Penn I (1987) Cancers following cyclosporine therapy. Transplantation 43: 32–35CrossRefPubMedGoogle Scholar
  63. 63.
    Bouwes Bavinck JN, Vermeer BJ, Van der Woude FJ, Vandenbroucke JP, Schreuder GM, Thorogood J (1991) Relation between skin cancer and HLA antigens in renal-transplant patients. N Engl J Med 325: 843–848PubMedCrossRefGoogle Scholar
  64. 64.
    Van den Borne BE, Landewe RB, Houkes I, Schild F, Van der Heyden PC, Vandenbroucke JP, Zwinderman AH, Goei The HS, Breedveld FC, Bernelot Moens HJ et al (1998) No increased risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis. Arthritis Rheum 41: 1930–1937CrossRefPubMedGoogle Scholar
  65. 65.
    Landewe RB, Van den Borne BE, Breedveld FC, Dijkmans DA (1999) Does cyclosporin A cause cancer? Nat Med 5: 714CrossRefPubMedGoogle Scholar
  66. 66.
    Starzl TE, Nalesnik MA, Porter KA, Ho M, Iwatsuki S, Griffith BP, Rosenthal JT, Hakala TR, Shaw BW Jr, Hardesty RL et al (1984) Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet 8377: 583–587CrossRefGoogle Scholar
  67. 67.
    Zijlmans JM, Van Rijthoven AW, Kluin PM, Jiwa NM, Dijkmans BA, Kluin-Nelemans JC (1992) Epstein-Barr virus-associated lymphoma in a patient with rheumatoid arthritis treated with cyclosporine. N Eng J Med 326: 1363Google Scholar
  68. 68.
    Kim JH, Perfect JR (1989) Infection and cyclosporine. Rev Infect Dis 11: 677–690PubMedGoogle Scholar
  69. 69.
    Gerards AH, Landewe RB, Prins AP, Bruyn GA, Goei The HS, Laan RF, Dijkmans BA (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: 291–296CrossRefPubMedGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2005

Authors and Affiliations

  • Arno W. R. van Kuijk
    • 1
    • 2
  • Ben A. C. Dijkmans
    • 2
    • 3
  1. 1.Department of Clinical Immunology and RheumatologyAcademic Medical CenterAmsterdamThe Netherlands
  2. 2.Jan van Breemen InstituteAmsterdamThe Netherlands
  3. 3.Department of RheumatologyVrije Universiteit Medical CentreAmsterdamThe Netherlands

Personalised recommendations