Drugs

, Volume 50, Supplement 1, pp 26–36 | Cite as

Clinical Use of Cyclosporin in Rheumatoid Arthritis

  • Charles Richardson
  • Paul Emery
Article

Summary

Rheumatoid arthritis is a chronic immune-mediated disease characterised by an inflammatory synovitis and extra-articular manifestations. There is an expanding body of evidence to indicate that the activation of T lymphocytes is central in the initiation and perpetuation of this disease. Cyclosporin is an immunomodulator and a highly specific inhibitor of T-lymphocyte function, and has demonstrated disease-modifying properties in clinical studies in patients with rheumatoid arthritis. A concern with the use of cyclosporin has been the development of dose-dependent adverse effects, in particular renal dysfunction. Cyclosporin is lipophilic by nature and the conventional oral formulation (Sandimmun®) was subject to incomplete and highly variable absorption, resulting in substantial inter- and intrasubject variations in peak concentrations and systemic bioavailability. A microemulsion-based formulation of cyclosporin (Neoral®)1 has recently been developed, and possesses more predictable and improved absorption with a consequent increased peak concentration and systemic bioavailability. The improved predictability of absorption, and hence blood concentrations, facilitates the ability to ‘tailor’ therapy to an individual patient, which, in theory, could translate into an improved efficacy and safety profile.

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References

  1. 1.
    Gough A, Faint J, Salmon M, et al. Genetic typing of patients with inflammatory arthritis at presentation can be used to predict outcome. Arthritis Rheum 1994; 378: 1166–70.CrossRefGoogle Scholar
  2. 2.
    Janossy G, Panayi G, Duke O, et al. Rheumatoid arthritis: a disease of T lymphocyte/macrophage immunoregulation. Lancet 1981; 2: 839–42.PubMedCrossRefGoogle Scholar
  3. 3.
    Wordsworth BP, Lanchbury JSS, Sakkas LI, et al. DR 4 subtype frequencies in rheumatoid arthritis indicate that Drβl is the major susceptibility locus within the HLA class II region. Proc Natl Acad Sci USA 1989; 86: 10049–53.PubMedCrossRefGoogle Scholar
  4. 4.
    Emery P, Smith GN, Panayi GS. Lymphocytapharesis — a feasible treatment for rheumatoid arthritis. Br J Rheumatol 1986; 25: 40–3.PubMedCrossRefGoogle Scholar
  5. 5.
    Gaston JSH, Strober S, Solvera JJ. Dissection of the mechanism of immune injury in rheumatoid arthritis using total lymphoid irradiation. Arthritis Rheum 1983; 31: 21–30.CrossRefGoogle Scholar
  6. 6.
    Sieper J, Kingsley G, Palacios-Box A. Synovial T lymphocyte specific immune response to Chlamydia trachomatis in Reiter’s disease. Arthritis Rheum 1991; 34: 588–98.PubMedCrossRefGoogle Scholar
  7. 7.
    Cohen IR, Holoshitz J, van Eden W, et al. T lymphocyte clones illuminate pathogenesis and effect therapy of experimental arthritis. Arthritis Rheum 1985; 28: 841–5.PubMedCrossRefGoogle Scholar
  8. 8.
    Borel J, Feurer C, Magnee C, et al. Effects of the new anti-lymphocyte cyclosporin A in animals. Immunology 1997; 32: 1017–1025.Google Scholar
  9. 9.
    Reems GH, Cook LA, Palladino MA. Cyclosporin A inhibits interleukin 2 and gamma interferon synthesis by human thymocytes. Transplant Proc 1983; 15: 2387–9.Google Scholar
  10. 10.
    Granelli-Pipemo A, Andrus L, Steinman RM. Lymphokine and non-lymphocytic mRNA levels in stimulated TR cells: kinetics, mitogen requirements and effects of cyclosporin A. J Exp Med 1986; 163: 922–37.CrossRefGoogle Scholar
  11. 11.
    Foxwell B, Simon J, Herrero J et al. Anti-CD3 antibody-induced expression of both p55 and p75 chains of the high affinity interleukin 2 receptor on human T lymphocytes is inhibited by cyclosporin A. Immunology 1990; 69: 104–9.PubMedGoogle Scholar
  12. 12.
    Furue M, Katz SI, Kawakami Y. Coordinate expression of src family proto-oncogenes in T cell activation and its modulation by cyclosporine. J Immumol 1990; 144: 736–9.Google Scholar
  13. 13.
    Morris R. Modes of action of FK506, cyclosporin A, and rapamycin. Transplant Proc 1994; 26(5): 3272–5.PubMedGoogle Scholar
  14. 14.
    Wiederrecht G, Lam E, Hung S, et al. The mechanism of action of FK-506 and cyclosporine A. Ann NY Acad Sci 1993; 696: 9–19.PubMedCrossRefGoogle Scholar
  15. 15.
    Mueller EA, Kovarik JM, van Bree JB, et al. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation. Pharm Res 1994; 11(2): 301–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Roy M, Waldschmidt T, Aruffo A, et al. The regulation of expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol 1993; 151(5): 2497–510.PubMedGoogle Scholar
  17. 17.
    Durie FH, Foy TM, Masters SR, et al. The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol Today 1994; 15(9): 406–11.PubMedCrossRefGoogle Scholar
  18. 18.
    Fuleihan R, Ramesh N, Homer A, et al. Cyclosporin A inhibits CD40 ligand expression in T lymphocytes J Clin Invest 1994; 93(3): 1315–20.PubMedCrossRefGoogle Scholar
  19. 19.
    Grevel J. Absorption of cyclosporine A after oral dosing. Transplant Proc 1988; 18(5): 9–12.Google Scholar
  20. 20.
    Fahr A. Cyclosporine clinical pharmacokinetics. Clin Pharmacokinet 1993; 24(6): 472–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Noble S, Markham A. Cyclosporin: a review of the pharmacokinetic properties, immunosuppressive efficacy and tolerability of a microemulsion-based formulation (Neoral®). Drugs 1995; 50(5): 951–68.CrossRefGoogle Scholar
  22. 22.
    Van Den Borne BEEM, Landewé RBM, Goei Thè 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.PubMedCrossRefGoogle Scholar
  23. 23.
    Kovarik JM, Muellar EA, van Bree JB, et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation — a multicentre investigation in kidney transplant patients. Transplantation 1994; 58(6): 658–63.PubMedGoogle Scholar
  24. 24.
    Taesch S, Niese D. Safety and tolerability of a new oral formulation of cyclosporin A, Sandimmun Neoral, in renal transplant patients. Transpl Int 1994; 7 Suppl. 1: S263–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Jönsson B, Kaarels K. Economic consequences of the progression of rheumatoid arthritis. First results of a 15-year cohort analysis [abstract]. 13th European Congress of Rheumatology, 1995 Jun 18–23, Amsterdam: 1995.Google Scholar
  26. 26.
    Simon DG. A cost effectiveness analysis of cyclosporin in cadaveric kidney transplantation. Med Decis Making 1986; 6: 199–207.PubMedCrossRefGoogle Scholar
  27. 27.
    Framptom JE, Faulds D. Cyclosporin: a pharmacoeconomic evaluation of its use in renal transplantation. Pharmacoeconomics 1993; 4: 366–95.CrossRefGoogle Scholar
  28. 28.
    Frei U, Taesch S, Niese D. Use of Sandimmun Neoral in renal transplant patients. Part A. Transplant Proc 1994; 26: 2928–31.PubMedGoogle Scholar
  29. 29.
    Niese D. A double blind randomised study of Sandimmun Neoral versus Sandimmun in new renal transplant recipients: results after 12 months. Transplant Proc 1995; 27: 1849–56.PubMedGoogle Scholar
  30. 30.
    Van Rijthoven AW, Dijkmans BA, Goei Thè HS, et al. Comparison of cyclosporine and D-penicillamine for rheumatoid arthritis: a randomised double blind study. J Rheumatol 1991; 18: 815–20.PubMedGoogle Scholar
  31. 31.
    Kruger K, Schattenkirchner M. Cyclosporine A vs azathioprine in the treatment of rheumatoid arthritis — results of a controlled multicentre double blind study [abstract]. J Autoimmun 1992; 5xixGoogle Scholar
  32. 32.
    Førre Ø. Cyclosporin A in rheumatoid arthritis: a double-blind placebo-controlled study. The Norwegian Arthritis Study Group Scand J Rheumatol 1990; 85: 57.Google Scholar
  33. 33.
    Tugwell P, Bombardier C, Gent M, et al. Low dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990; 335: 1051–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Dougados M, Awada H, Amor B. Cyclosporin in rheumatoid arthritis: a double blind, placebo controlled study in 52 patients. Ann Rheum Dis 1988; 47: 127–33.PubMedCrossRefGoogle Scholar
  35. 35.
    Wells G, Tugwell P. Cyclosporin Ain rheumatoid arthritis; overview of efficacy. Br J Rheumatol 1993; 32 Suppl. 1: 51–6.PubMedGoogle Scholar
  36. 36.
    Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second line drugs in rheumatoid arthritis: results of two meta analyses. Arthritis Rheum 1990; 33: 1449–59.PubMedCrossRefGoogle Scholar
  37. 37.
    Førre Ø. Radiologic evidence of disease modification in rheumatoid arthritis patients treated with cyclosporine. Results of a 48-week multicentre study comparing low-dose cyclosporine with placebo. Norwegian Arthritis Study Group. Arthritis Rheum 1994; 37(10): 1506–12.PubMedCrossRefGoogle Scholar
  38. 38.
    Dijkmans BAC, Van Rijthoven AWAM, Gioe The HS, et al. Effect of cyclosporin on serum creatinine in patients with rheumatoid arthritis. Eur J Clin Pharmacol, 1987; 31: 541–5.PubMedCrossRefGoogle Scholar
  39. 39.
    An International Consensus report: the use of cyclosporin A in rheumatoid arthritis. Br J Rheumatol 1993; 32 Suppl. 1: 1-3Google Scholar
  40. 40.
    Panayi GS, Tugwell P. Conclusions of an international review. The use of cyclosporin A in rheumatoid arthritis. Br J Rheumatol 1994; 33: 967–9.PubMedCrossRefGoogle Scholar
  41. 41.
    Kon V, Sugiura M, Inagami T, et al. Role of endothelin in cyclosporine induced glomerular dysfunction. Kidney Int 1990; 37: 1487–91.PubMedCrossRefGoogle Scholar
  42. 42.
    Bloom IT, Bentley FR, Garrison RN. Acute cyclosporine induced vasoconstriction is mediated by endothelin I. Surgery 1993; 114: 480–8.PubMedGoogle Scholar
  43. 43.
    Brown Z, Neild GH, Willoughby JJ, et al. Increased factor VIII as an index of vascular injury in cyclosporin nephrotoxicity. Transplantation 1986; 42: 150–3.PubMedCrossRefGoogle Scholar
  44. 44.
    Penn I, Brunson ME. Concerns after cyclosporin therapy. In: Kahan BD, editor. Cyclosporin: therapeutic uses in transplantation. Philadelphia: Grune and Stratton, 1988: 885-92Google Scholar
  45. 45.
    Arellano F, Krupp P. Malignancies in rheumatoid arthritis patients treated with cyclosporin A. Br J Rheumatol 1993; 32 Suppl. 1: 72–5.PubMedGoogle Scholar
  46. 46.
    Kinlen LJ. Incidence of cancer in rheumatoid arthritis and other disorders after immunosuppressant treatment Am J Med 1985; 78 Suppl 1A: 44–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Silman AJ, Petrie J, Hazelman B, et al. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988; 47: 988–92.PubMedCrossRefGoogle Scholar
  48. 48.
    Cairns HS, Neild G. Cyclosporin nephrotoxicity. In: Cameron S, Davison AM, Grunfeld JU, et al., editors. Oxford textbook of clinical nephrology. Oxford: University Press, 1992: 1560–9Google Scholar
  49. 49.
    Landewé BR, Goei Thè HS, van Rijthoven AW, et al. A randomized double blind, 24 week controlled study of low dose cyclosporine versus chloroquine for early rheumatoid arthritis. Arthritis Rheum 1994; 37(5): 637–43.PubMedCrossRefGoogle Scholar
  50. 50.
    Portioli I, Pipitone V, Magaro M, et al. Low-dose cyclosporin vs conventional second-line drugs in patients with early active rheumatoid arthritis: 12-month results of a multicentre, prospective, randomised trial [abstract D60]. 13th European Congress of Rheumatology, 1995 Jun 18–23: Amsterdam: 1995.Google Scholar
  51. 51.
    Bannwoth B, Labat L, Moride Y, et al. Methotrexate in rheumatoid arthritis. Drugs 1994; 47(1): 25–50.CrossRefGoogle Scholar
  52. 52.
    Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 1995; 333(3): 137–41.PubMedCrossRefGoogle Scholar
  53. 53.
    Bensen W, Tugwell P, Roberts RM, et al. Combination therapy of cyclosporine with methotrexate and gold in rheumatoid arthritis (2 pilot studies) J Rheumatol 1994; 21(11): 2034–8.PubMedGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Charles Richardson
    • 1
  • Paul Emery
    • 1
  1. 1.Rheumatology and Rehabilitation Research UnitLeeds UniversityLeedsEngland

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