Semin Respir Crit Care Med 2004; 25(5): 581-594
DOI: 10.1055/s-2004-836149
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Advances in Immunosuppressive Drug Therapy for Use in Autoimmune Disease and Systemic Vasculitis

Wendy Marder1 , W. Joseph McCune1
  • 1Department of Internal Medicine, Division of Rheumatology, University of Michigan Health System, Ann Arbor, Michigan
Further Information

Publication History

Publication Date:
09 November 2004 (online)

Several recent advances in the use of immunosuppressive drugs in autoimmune disease are relevant to management of autoimmune pulmonary disease. Sequential immunosuppression combining remission induction with cyclophosphamide with less toxic maintenance therapy such as azathioprine, methotrexate, or mycophenolate mofetil is described in Wegener’s granulomatosis, systemic vasculitis, and lupus. Less aggressive forms of diseases that have been routinely treated with cyclophosphamide have been treated with alternate regimens (e.g., methotrexate treatment of limited Wegener’s granulomatosis, and mycophenolate mofetil for lupus). Finally, strategies to minimize severe side effects of immunosuppression include genetic testing for predisposition to drug toxicity and proposed techniques for fertility preservation during cyclophosphamide treatment. We review established principles of immunosuppressive drug use and focus on clinical trials in autoimmune diseases that illustrate therapeutic approaches which are likely to be applied more widely in the future. More detailed reviews of treatment of individual diseases will be found in elsewhere in this issue.

REFERENCES

  • 1 Turk J L, Poulter L W. Selective depletion of lymphoid tissue by cyclophosphamide.  Clin Exp Immunol. 1972;  10 285-296
  • 2 Clements P J, Yu D T, Levy  J et al.. Effects of cyclophosphamide on B- and T-lymphocytes in rheumatoid arthritis.  Arthritis Rheum. 1974;  17 347-353
  • 3 Hurd E R, Giuliano V J. The effect of cyclophosphamide on B and T lymphocytes in patients with connective tissue diseases.  Arthritis Rheum. 1975;  18 67-75
  • 4 McCune W J, Golbus  J, Zeldes  W et al.. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus.  N Engl J Med. 1988;  318 1423-1431
  • 5 Chiorazzi  N, Fox D A, Katz D H. Hapten-specific IgE antibody responses in mice, VI: Selective enhancement of IgE antibody production by low doses of X-irradiation and by cyclophosphamide.  J Immunol. 1976;  117(5 pt 1) 1629-1637
  • 6 Malik S W, Myers J L, DeRemee R A et al.. Lung toxicity associated with cyclophosphamide use: two distinct patterns.  Am J Respir Crit Care Med. 1996;  154(6 pt 1) 1851-1856
  • 7 Mark G J, Lehimgar-Zadeh  A, Ragsdale B D. Cyclophosphamide pneumonitis.  Thorax. 1978;  33 89-93
  • 8 Lynch III J P, Chavis A D. Chronic Interstitial Pulmonary Disorders. Boston; Little, Brown 1992
  • 9 Myers J L. Diagnosis of drug reactions in the lung. Monogr Pathol 1993 36: 32-53
  • 10 Hoffman G S, Kerr G S, Leavitt R Y et al.. Wegener granulomatosis: an analysis of 158 patients.  Ann Intern Med. 1992;  116 488-498
  • 11 Baker G L, Kahl L E, Zee B C et al.. Malignancy following treatment of rheumatoid arthritis with cyclophosphamide: long-term case-control follow-up study.  Am J Med. 1987;  83 1-9
  • 12 Talar-Williams  C, Hijazi Y M, Walther M M et al.. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis.  Ann Intern Med. 1996;  124 477-484
  • 13 Travis L B, Curtis R E, Glimelius B et al.. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin’s lymphoma.  J Natl Cancer Inst. 1995;  87 524-530
  • 14 Fox D A, McCune W J. Immunologic and clinical effects of cytotoxic drugs used in the treatment of rheumatoid arthritis and systemic lupus erythematosus.  Concepts Immunopathol. 1989;  7 20-78
  • 15 Radis C D, Kahl L E, Baker G L et al.. Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis: a 20-year followup study.  Arthritis Rheum. 1995;  38 1120-1127
  • 16 Ognenovski V, Marder W, Somers E et al.. Increased incidence of cervical intraepithelial neoplasia in women with systemic lupus erythematosus treated with intravenous cyclophosphamide. J Rheumatol 2004 31: 1763-1767
  • 17 Lynch III J P, McCune W J. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders.  Am J Respir Crit Care Med. 1997;  155 395-420
  • 18 Koyama H, Wada T, Nishizawa Y et al.. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer.  Cancer. 1977;  39 1403-1409
  • 19 Boumpas D T, Chrousos G P, Wilder R L et al.. Glucocorticoid therapy for immune-mediated diseases: basic and clinical correlates.  Ann Intern Med. 1993;  119 1198-1208
  • 20 Blumenfeld Z. Ovarian rescue/protection from chemotherapeutic agents.  J Soc Gynecol Investig. 2001;  8(suppl 1) S60-S64
  • 21 Blumenfeld Z, Shapiro D, Shteinberg M et al.. Preservation of fertility and ovarian function and minimizing gonadotoxicity in young women with systemic lupus erythematosus treated by chemotherapy.  Lupus. 2000;  9 401-405
  • 22 Pereyra Pacheco B, Mendez Ribas J M, Milone G et al.. Use of GnRH analogs for functional protection of the ovary and preservation of fertility during cancer treatment in adolescents: a preliminary report.  Gynecol Oncol. 2001;  81 391-397
  • 23 McCune W J, Somers E, Christman G et al.. Use of leuprolide acetate for ovarian protection during cyclophosphamide therapy of women with severe lupus.  Arthritis Rheum. 2002;  44 S2006
  • 24 Hoorweg-Nijman J J, Delemarre-van de Waal H A, de Waal F C et al.. Cyclophosphamide-induced disturbance of gonadotropin secretion manifesting testicular damage.  Acta Endocrinol (Copenh). 1992;  126 143-148
  • 25 Masala A, Faedda R, Alagna S et al.. Use of testosterone to prevent cyclophosphamide-induced azoospermia.  Ann Intern Med. 1997;  126 292-295
  • 26 Huynh-Do U, Gantenbein H, Binswanger U. Pneumocystis carinii pneumonia during immunosuppressive therapy for antineutrophil cytoplasmic autoantibody-positive vasculitis.  Arch Intern Med. 1995;  155 872-874
  • 27 Bradley J D, Brandt K D, Katz B P. Infectious complications of cyclophosphamide treatment for vasculitis.  Arthritis Rheum. 1989;  32 45-53
  • 28 de Groot K AduD, Savage C O. EUVAS (European vasculitis study group). The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review.  Nephrol Dial Transplant. 2001;  16 2018-2027
  • 29 Mitrovic D, Popovic M, Stefanovic D, Glisic B, Dimitrijevic M. Immunosuppressive therapy with cyclophosphamide pulse doses in Wegener’s granulomatosis. Transplant Proc 2001 33: 2378-2379
  • 30 Contreras G, Pardo V, Leclercq B et al.. Sequential therapies for proliferative lupus nephritis.  N Engl J Med. 2004;  350 971-980
  • 31 Lehman T J, Edelheit B S, Onel K B. Combined intravenous methotrexate and cyclophosphamide for refractory childhood lupus nephritis.  Ann Rheum Dis. 2004;  63 321-323
  • 32 Burt R K, Traynor A E. SLE: hematopoietic stem cell transplantation for systemic lupus erythematosus.  Arthritis Res Ther. 2003;  5 207-209
  • 33 Petri Jr M, Brodsky R A. High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus.  Arthritis Rheum. 2003;  48 166-173
  • 34 Langford C A, Talar-Williams C, Barron K S et al.. Use of a cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of Wegener’s granulomatosis: extended follow-up and rate of relapse.  Am J Med. 2003;  114 463-469
  • 35 Jayne D, Rasmussen N, Andrassy K et al.. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies.  N Engl J Med. 2003;  349 36-44
  • 36 Slot M C, Tervaert J W, Boomsma M M et al.. Positive classic antineutrophil cytoplasmic antibody (C-ANCA) titer at switch to azathioprine therapy associated with relapse in proteinase 3-related vasculitis.  Arthritis Rheum. 2004;  51 269-273
  • 37 Langford C A, Talar-Williams C, Sneller M C. Mycophenolate mofetil for remission maintenance in the treatment of Wegener’s granulomatosis.  Arthritis Rheum. 2004;  51 278-283
  • 38 Metzler C, Fink C, Lamprecht P et al.. Maintenance of remission with leflunomide in Wegener’s granulomatosis.  Rheumatology (Oxford). 2004;  43 315-320
  • 39 Cannon G W, Jackson C G, Samuelson Jr C O et al.. Chlorambucil therapy in rheumatoid arthritis: clinical experience in 28 patients and literature review.  Semin Arthritis Rheum. 1985;  15 106-118
  • 40 Steinberg A D. Chlorambucil in the treatment of patients with immune-mediated rheumatic diseases.  Arthritis Rheum. 1993;  36 325-328
  • 41 Hemady R, Tauber J, Foster C S. Immunosuppressive drugs in immune and inflammatory ocular disease.  Surv Ophthalmol. 1991;  35 369-385
  • 42 Reichert L J, Huysmans F T, Assmann K et al.. Preserving renal function in patients with membranous nephropathy: daily oral chlorambucil compared with intermittent monthly pulses of cyclophosphamide.  Ann Intern Med. 1994;  121 328-333
  • 43 Sinoway P A, Callen J P. Chlorambucil: an effective corticosteroid-sparing agent for patients with recalcitrant dermatomyositis.  Arthritis Rheum. 1993;  36 319-324
  • 44 Clements P, Lachenbruch P, Furst D et al.. The course of skin involvement in systemic sclerosis over three years in a trial of chlorambucil versus placebo.  Arthritis Rheum. 1993;  36 1575-1579
  • 45 Fauci A S, Haynes B F, Katz P et al.. Wegener’s granulomatosis: prospective clinical and therapeutic experience with 85 patients for 21 years.  Ann Intern Med. 1983;  98 76-85
  • 46 Lennard L, Van Loon J A, Weinshilboum R M. Pharmacogenetics of acute azathioprine toxicity: relationship to thiopurine methyltransferase genetic polymorphism.  Clin Pharmacol Ther. 1989;  46 149-154
  • 47 Present D H, Meltzer S J, Krumholz M P et al.. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity.  Ann Intern Med. 1989;  111 641-649
  • 48 Sterneck M, Wiesner R, Ascher N et al.. Azathioprine hepatotoxicity after liver transplantation.  Hepatology. 1991;  14 806-810
  • 49 Bottomley W W, Ford G, Cunliffe W J et al.. Aggressive squamous cell carcinomas developing in patients receiving long-term azathioprine.  Br J Dermatol. 1995;  133 460-462
  • 50 Smith J L, Wilkinson A H, Hunsicker L G et al.. Increased frequency of posttransplant lymphomas in patients treated with cyclosporin, azathioprine, and prednisone.  Transplant Proc. 1989;  21(1 pt 3) 3199-3200
  • 51 Silman A J, Petrie J, Hazleman 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;  47 988-992
  • 52 Nero P, Rahman A, Isenberg D A. Does long-term treatment with azathioprine predispose to malignancy and death in patients with systemic lupus erythematosus?.  Ann Rheum Dis. 2004;  63 325-326
  • 53 Taylor L, Hughes R AC, McPehrson K. The risk of cancer from azathoprine as a treatment for multiple sclerosis.  Eur J Neurol. 2004;  11 111-142
  • 54 Fraser A G, Orchard T R, Robinson E M et al.. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine.  Aliment Pharmacol Ther. 2002;  16 1225-1232
  • 55 Matalon S T, Ornoy A, Lishner M. Review of the potential effects of three commonly used antineoplastic and immunosuppressive drugs (cyclophosphamide, azathioprine, doxorubicin on the embryo and placenta).  Reprod Toxicol. 2004;  18 219-230
  • 56 Polifka J E, Friedman J M. Teratogen update: azathioprine and 6-mercaptopurine.  Teratology. 2002;  65 240-261
  • 57 Norgard B, Pedersen L, Jacobsen J et al.. The risk of congenital abnormalities in children fathered by men treated with azathioprine or mercaptopurine before conception.  Aliment Pharmacol Ther. 2004;  19 679-685
  • 58 Janssen N M, Genta M S. The effects of immunosuppressive and anti-inflammatory medications on fertility, pregnancy, and lactation.  Arch Intern Med. 2000;  160 610-619
  • 59 Dean T, Dewey A, Bara A et al.. Azathioprine as an oral corticosteroid sparing agent for asthma.  Cochrane Database Syst Rev. 2004;  CD003270
  • 60 Esdaile J M, Joseph L, MacKenzie T et al.. The benefit of early treatment with immunosuppressive drugs in lupus nephritis.  J Rheumatol. 1994;  21 2046-2051
  • 61 Austin III H A, Klippel J H, Balow J E et al.. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs.  N Engl J Med. 1986;  314 614-619
  • 62 Ortiz Z, Shea B, Suarez Almazor M et al.. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2000: CD000951
  • 63 Ortiz Z, Shea B, Suarez-Almazor M E et al.. The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis: a metaanalysis of randomized controlled trials.  J Rheumatol. 1998;  25 36-43
  • 64 Fox D A, McCune W J. Immunosuppressive drug therapy of systemic lupus erythematosus.  Rheum Dis Clin North Am. 1994;  20 265-299
  • 65 Weinblatt M E. Methotrexate for chronic diseases in adults.  N Engl J Med. 1995;  332 330-331
  • 66 Chan E S, Cronstein B N. Molecular action of methotrexate in inflammatory diseases.  Arthritis Res. 2002;  4 266-273
  • 67 Genestier L, Paillot R, Fournel S et al.. Immunosuppressive properties of methotrexate: apoptosis and clonal deletion of activated peripheral T cells.  J Clin Invest. 1998;  102 322-328
  • 68 Rosengren S, Arfors K E, Proctor K G. Potentiation of leukotriene B4-mediated inflammatory response by the adenosine antagonist, 8-phenyl theophylline.  Int J Microcirc Clin Exp. 1991;  10 345-357
  • 69 Lewis J H, Schiff E. Methotrexate-induced chronic liver injury: guidelines for detection and prevention. The ACG Committee on FDA-related matters. American College of Gastroenterology.  Am J Gastroenterol. 1988;  83 1337-1345
  • 70 Weinblatt M E, Fraser P. Elevated mean corpuscular volume as a predictor of hematologic toxicity due to methotrexate therapy.  Arthritis Rheum. 1989;  32 1592-1596
  • 71 Hilsden R J, Urbanski S J, Swain M G. End-stage liver disease developing with the use of methotrexate in heterozygous alpha 1-antitrypsin deficiency.  Arthritis Rheum. 1995;  38 1014-1018
  • 72 Cannon G W, Ward J R, Clegg D O et al.. Acute lung disease associated with low-dose pulse methotrexate therapy in patients with rheumatoid arthritis.  Arthritis Rheum. 1983;  26 1269-1274
  • 73 Imokawa S, Colby T V, Leslie K O et al.. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients.  Eur Respir J. 2000;  15 373-381
  • 74 Zisman D A, McCune W J, Tino G et al.. Drug-induced pneumonitis: the role of methotrexate.  Sarcoidosis Vasc Diffuse Lung Dis. 2001;  18 243-252
  • 75 Cottin V, Tebib J, Massonnet B et al.. Pulmonary function in patients receiving long-term low-dose methotrexate.  Chest. 1996;  109 933-938
  • 76 Carroll G J, Thomas R, Phatouros C C et al.. Incidence, prevalence and possible risk factors for pneumonitis in patients with rheumatoid arthritis receiving methotrexate.  J Rheumatol. 1994;  21 51-54
  • 77 Hargreaves M R, Mowat A G, Benson M K. Acute pneumonitis associated with low dose methotrexate treatment for rheumatoid arthritis: report of five cases and review of published reports.  Thorax. 1992;  47 628-633
  • 78 Padley S P, Adler B, Hansell D M et al.. High-resolution computed tomography of drug-induced lung disease.  Clin Radiol. 1992;  46 232-236
  • 79 Arakawa  H, Yamasaki  M, Kurihara Y et al.. Methotrexate-induced pulmonary injury: serial CT findings.  J Thorac Imaging. 2003;  18 231-236
  • 80 White D A, Rankin J A, Stover D E et al.. Methotrexate pneumonitis: bronchoalveolar lavage findings suggest an immunologic disorder.  Am Rev Respir Dis. 1989;  139 18-21
  • 81 Schnabel A, Richter C, Bauerfeind S et al.. Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis.  Thorax. 1997;  52 377-379
  • 82 Menke D M, Griesser H, Moder K G et al.. Lymphomas in patients with connective tissue disease: comparison of p53 protein expression and latent EBV infection in patients immunosuppressed and not immunosuppressed with methotrexate.  Am J Clin Pathol. 2000;  113 212-218
  • 83 Patsner B, Kenigsberg D. Successful treatment of persistent ectopic pregnancy with oral methotrexate therapy.  Fertil Steril. 1988;  50 982-983
  • 84 Hoffman G S, Leavitt R Y, Kerr G S et al.. Treatment of glucocorticoid-resistant or relapsing Takayasu arteritis with methotrexate.  Arthritis Rheum. 1994;  37 578-582
  • 85 Langford C A, Talar-Williams C, Barron K S et al.. A staged approach to the treatment of Wegener’s granulomatosis: induction of remission with glucocorticoids and daily cyclophosphamide switching to methotrexate for remission maintenance.  Arthritis Rheum. 1999;  42 2666-2673
  • 86 Langford C A, Talar-Williams C, Sneller M C. Use of methotrexate and glucocorticoids in the treatment of Wegener’s granulomatosis: long-term renal outcome in patients with glomerulonephritis.  Arthritis Rheum. 2000;  43 1836-1840
  • 87 Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults. Cochrane Database Syst Rev 2000: CD000391
  • 88 de Groot K, Muhler M, Reinhold-Keller E et al.. Induction of remission in Wegener’s granulomatosis with low dose methotrexate.  J Rheumatol. 1998;  25 492-495
  • 89 Baughman R P, Winget D B, Lower E E. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial.  Sarcoidosis Vasc Diffuse Lung Dis. 2000;  17 60-66
  • 90 Brazelton T R, Morris R E. Molecular mechanisms of action of new xenobiotic immunosuppressive drugs: tacrolimus (FK506), sirolimus (rapamycin), mycophenolate mofetil and leflunomide.  Curr Opin Immunol. 1996;  8 710-720
  • 91 Palmer G, Burger D, Mezin F et al.. The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes.  Arthritis Res Ther. 2004;  6 R181-R189
  • 92 Bartlett R R, Brendel S, Zielinski T et al.. Leflunomide, an immunorestoring drug for the therapy of autoimmune disorders, especially rheumatoid arthritis.  Transplant Proc. 1996;  28 3074-3078
  • 93 John G T, Manivannan J, J Chandy S et al.. Leflunomide therapy for cytomegalovirus disease in renal allograft recipients. Transplantation 2004 77: 1460-1461
  • 94 Scott D L, Smolen J S, Kalden J R et al.. Treatment of active rheumatoid arthritis with leflunomide: two-year follow-up of a double-blind, placebo-controlled trial versus sulfasalazine.  Ann Rheum Dis. 2001;  60 913-923
  • 95 Siva C ES, Shepherd R, Cunningham F et al.. Leflunomide use during the first 33 months after food and drug administration approval: experience with a national cohort of 3,325 patients. Arthritis Rheum 2003 49: 745-751
  • 96 Cohen S B, Iqbal I. Leflunomide.  Int J Clin Pract. 2003;  57 115-120
  • 97 Strand V, Cohen S, Schiff M et al.. Treatment of active rheumatoid arthritis with leflunomide compared with placebo and methotrexate. Leflunomide Rheumatoid Arthritis Investigators Group.  Arch Intern Med. 1999;  159 2542-2550
  • 98 Smolen J S, Kalden J R, Scott D L et al.. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group.  Lancet. 1999;  353 259-266
  • 99 Baughman R P, Lower E E. Leflunomide for chronic sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2004;  21 43-48
  • 100 Sintchak M D, Nimmesgern E. The structure of inosine 5′-monophosphate dehydrogenase and the design of novel inhibitors.  Immunopharmacology. 2000;  47 163-184
  • 101 Allison A C, Eugui E M. Mycophenolate mofetil and its mechanisms of action.  Immunopharmacology. 2000;  47 85-118
  • 102 Senda M, DeLustro B, Eugui  E et al.. Mycophenolic acid, an inhibitor of IMP dehydrogenase that is also an immunosuppressive agent, suppresses the cytokine-induced nitric oxide production in mouse and rat vascular endothelial cells.  Transplantation. 1995;  60 1143-1148
  • 103 Allison A C, Eugui E M. The design and development of an immunosuppressive drug, mycophenolate mofetil.  Springer Semin Immunopathol. 1993;  14 353-380
  • 104 Penny M J, Boyd R A, Hall B M. Mycophenolate mofetil prevents the induction of active Heymann nephritis: association with Th2 cytokine inhibition.  J Am Soc Nephrol. 1998;  9 2272-2282
  • 105 Lipsky J J. Mycophenolate mofetil.  Lancet. 1996;  348 1357-1359
  • 106 Ginzler E M, Buyon J, Dooley M A et al.. A multicenter study of mycophenolate mofetil (MMF) vs. intravenous cyclophosphamide (IVC) as induction therapy for severe lupus nephritis (LN). Arthritis Rheum 2003 48: S647
  • 107 Riskalla M M, Somers E C, Fatica R A et al.. Tolerability of mycophenolate mofetil in patients with systemic lupus erythematosus.  J Rheumatol. 2003;  30 1508-1512
  • 108 Husain S, Singh N. The impact of novel immunosuppressive agents on infections in organ transplant recipients and the interactions of these agents with antimicrobials.  Clin Infect Dis. 2002;  35 53-61
  • 109 Kahan B D. Cyclosporine.  N Engl J Med. 1989;  321 1725-1738
  • 110 Wiederrecht G, Lam E, Hung S et al.. The mechanism of action of FK-506 and cyclosporin A.  Ann N Y Acad Sci. 1993;  696 9-19
  • 111 Schreiber S L, Crabtree G R. The mechanism of action of cyclosporin A and FK506.  Immunol Today. 1992;  13 136-142
  • 112 Wera S, Zheng L, Hooghe-Peters E L et al.. Cyclosporin A, rapamycin and FK506 decrease prolactin release from rat pituitary cells in primary culture.  Endocr Res. 1995;  21 623-633
  • 113 Timmerman L A, Clipstone N A, Ho S N et al.. Rapid shuttling of NF-AT in discrimination of Ca2+ signals and immunosuppression nuclear factor of activated T cells is associated with a mast cell interleukin 4 transcription complex.  Nature. 1996;  383 837-840
  • 114 Kim W U, Cho M L, Kim S I et al.. Divergent effect of cyclosporine on Th1/Th2 type cytokines in patients with severe, refractory rheumatoid arthritis.  J Rheumatol. 2000;  27 324-331
  • 115 Faulds D, Goa K L, Benfield P. Cyclosporin: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders.  Drugs. 1993;  45 953-1040
  • 116 Feutren G, Mihatsch M J. Risk factors for cyclosporine-induced nephropathy in patients with autoimmune diseases. International Kidney Biopsy Registry of Cyclosporine in Autoimmune Diseases.  N Engl J Med. 1992;  326 1654-1660
  • 117 Palestine A G, Austin III H A, Balow J E et al.. Renal histopathologic alterations in patients treated with cyclosporine for uveitis.  N Engl J Med. 1986;  314 1293-1298
  • 118 Kopp J B, Klotman P E. Cellular and molecular mechanisms of cyclosporin nephrotoxicity.  J Am Soc Nephrol. 1990;  1 162-179
  • 119 Keown P, Niese D. Cyclosporine microemulsion increases drug exposure and reduces acute rejection without incremental toxicity in de novo renal transplantation. International Sandimmun Neoral Study Group.  Kidney Int. 1998;  54 938-944
  • 120 Miura K, Nakatani T, Asai T et al.. Role of hypomagnesemia in chronic cyclosporine nephropathy.  Transplantation. 2002;  73 340-347
  • 121 Foley R J, Hamner R W, Weinman E J. Serum potassium concentrations in cyclosporine- and azathioprine-treated renal transplant patients.  Nephron. 1985;  40 280-285
  • 122 Burke Jr J F, Pirsch J D, Ramos E L et al.. Long-term efficacy and safety of cyclosporine in renal-transplant recipients.  N Engl J Med. 1994;  331 358-363
  • 123 Arellano F, Krupp P. Malignancies in rheumatoid arthritis patients treated with cyclosporin A.  Br J Rheumatol. 1993;  32(suppl 1) 72-75
  • 124 Feutren G. The optimal use of cyclosporin A in autoimmune diseases.  J Autoimmun. 1992;  5(suppl A) 183-195
  • 125 Kitridou R C, Goodwin T M. The fetus in systemic lupus erythematosus. In: Wallace DJ, Hahn BH Lupus Erythematosus. 6th ed Baltimore, MD; Williams & Wilkins 1997: 1023-1040
  • 126 Sajjadi H, Soheilian M, Ahmadieh H et al.. Low-dose cyclosporin-A therapy in Behçet’s disease.  J Ocul Pharmacol. 1994;  10 553-560
  • 127 Lebwohl M, Ellis C, Gottlieb A et al. Cyclosporine consensus conference: with emphasis on the treatment of psoriasis.  J Am Acad Dermatol. 1998;  39 464-475
  • 128 Wagner S A, Peter R U, Adam O et al.. Therapeutic efficacy of oral low-dose cyclosporin A in severe psoriatic arthritis.  Dermatology. 1993;  186 62-67
  • 129 Hallegua D, Wallace D J, Metzger A L et al.. Cyclosporine for lupus membranous nephritis: experience with ten patients and review of the literature.  Lupus. 2000;  9 241-251
  • 130 Landewe R B, Goei The H S, van Rijthoven A W et al.. A randomized, double-blind, 24-week controlled study of low-dose cyclosporine versus chloroquine for early rheumatoid arthritis.  Arthritis Rheum. 1994;  37 637-643
  • 131 Mobini N, Padilla Jr T, Ahmed A R. Long-term remission in selected patients with pemphigus vulgaris treated with cyclosporine.  J Am Acad Dermatol. 1997;  36(2 pt 1) 264-266
  • 132 Evans D J, Cullinan  P, Geddes D M. Cyclosporin as an oral corticosteroid sparing agent in stable asthma. Cochrane Database Syst Rev 2001: CD002993

W. Joseph McCuneM.D. 

Department of Internal Medicine, Division of Rheumatology, University of Michigan Health System

1500 E. Medical Center Dr., Rm. 3918 Taubman Center

Box 0358, Ann Arbor, MI 48109-0358

Email: jmccune@umich.edu