Advances in Immunosuppressive Therapy

ABSTRACT

Despite the intense interest in biological agents, traditional immunosuppressive drugs remain the mainstays of treatment for systemic rheumatic diseases that involve the lung. Herewith, we review the mechanism of action, administration and clinical use of immunosuppressive drugs, including cyclophosphamide, chlorambucil, azathioprine, methotrexate, leflunomide, cyclosporine, and mycophenolate mofetil. Emphasis is placed on the use of sequential therapies, in which cyclophosphamide is used to induce a remission, and then drugs such as methotrexate or azathioprine are used to maintain the remission. In addition, new regimens that avoid the use of cyclophosphamide for severe forms of vasculitis such as Wegener's granulomatosis have been recently described. Finally, significant benefit has been found when interstitial lung disease due to scleroderma is treated with cyclophosphamide. This represents the first evidence that immunosuppressive drugs are efficacious in rheumatic disease-associated interstitial fibrosis and provides a rationale for developing therapeutic regimens that optimize efficacy and safety.

Cyclophosphamide - sequential therapy - Wegener's granulomatosis - mycophenolate mofetil

REFERENCES

• 1 Walters M T, Cawley M I. Combined suppressive drug treatment in severe refractory rheumatoid disease: an analysis of the relative effects of parenteral methylprednisolone, cyclophosphamide, and sodium aurothiomalate.  Ann Rheum Dis. 1988;  47 924-929
• 2 Cash J M, Klippel J H. Second-line drug therapy for rheumatoid arthritis.  N Engl J Med. 1994;  330 1368-1375
• 3 Takada K, Arefayene M, Desta Z et al.. Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis.  Arthritis Rheum. 2004;  50 2202-2210
• 4 Turk J L, Poulter L W. Selective depletion of lymphoid tissue by cyclophosphamide.  Clin Exp Immunol. 1972;  10 285-296
• 5 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
• 6 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
• 7 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
• 8 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
• 9 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
• 10 Wegener's Granulomatosis Etanercept Trial (WGET) Research Group . Etanercept plus standard therapy for Wegener's granulomatosis.  N Engl J Med. 2005;  352 351-361
• 11 McCarthy C J, Sheldon S, Ross C W et al.. Cytogenetic abnormalities and therapy-related myelodysplastic syndromes in rheumatic disease.  Arthritis Rheum. 1998;  41 1493-1496
• 12 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
• 13 Mark G J, Lehimgar-Zadeh A, Ragsdale B D. Cyclophosphamide pneumonitis.  Thorax. 1978;  33 89-93
• 14 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
• 15 Lynch III J P, Chavis A D. Chronic interstitial pulmonary disorders. In: Victor TC Clinical Pulmonary Disorders. Boston; Little, Brown 1992: 193-264
• 16 Myers J L. Diagnosis of drug reactions in the lung.  Monogr Pathol. 1993;  36 32-53
• 17 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
• 18 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
• 19 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
• 20 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
• 21 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
• 22 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 follow-up study.  Arthritis Rheum. 1995;  38 1120-1127
• 23 Ognenovski V M, Marder W, Somers E C et al.. Increased incidence of cervical intraepithelial neoplasia in women with systemic lupus erythematosus treated with intravenous cyclophosphamide.  J Rheumatol. 2004;  31 1763-1767
• 24 Lynch III J P, McCune W J. Immunosuppressive and cytotoxic pharmacotherapy for pulmonary disorders.  Am J Respir Crit Care Med. 1997;  155 395-420
• 25 Stone J H, Holbrook J T, Marriott M A et al.. Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial.  Arthritis Rheum. 2006;  54 1608-1618
• 26 Koyama H, Wada T, Nishizawa Y et al.. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer.  Cancer. 1977;  39(4) 1403-1409
• 27 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
• 28 Blumenfeld Z. Ovarian rescue/protection from chemotherapeutic agents.  J Soc Gynecol Investig. 2001;  8(1 Suppl Proceedings) S60-S64
• 29 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
• 30 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
• 31 Somers E C, Marder W, Christman G M et al.. Use of a gonadotropin-releasing hormone analog for protection against premature ovarian failure during cyclophosphamide therapy in women with severe lupus.  Arthritis Rheum. 2005;  52 2761-2767
• 32 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
• 33 Masala A, Faedda R, Alagna S et al.. Use of testosterone to prevent cyclophosphamide-induced azoospermia.  Ann Intern Med. 1997;  126 292-295
• 34 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
• 35 Bradley J D, Brandt K D, Katz B P. Infectious complications of cyclophosphamide treatment for vasculitis.  Arthritis Rheum. 1989;  32 45-53
• 36 de Groot K, Adu D, Savage C O. The value of pulse cyclophosphamide in ANCA-associated vasculitis: meta-analysis and critical review.  Nephrol Dial Transplant. 2001;  16 2018-2027
• 37 Mitrovic D, Popovic M, Stefanovic D et al.. Immunosuppressive therapy with cyclophosphamide pulse doses in Wegener's granulomatosis.  Transplant Proc. 2001;  33 2378-2379
• 38 Contreras G, Pardo V, Leclercq B et al.. Sequential therapies for proliferative lupus nephritis.  N Engl J Med. 2004;  350 971-980
• 39 Tashkin D P, Elashoff R, Clements P J et al.. Cyclophosphamide versus placebo in scleroderma lung disease.  N Engl J Med. 2006;  354 2655-2666
• 40 Flaherty K R, Martinez F J. Nonspecific interstitial pneumonia.  Semin Respir Crit Care Med. 2006;  27 652-658
• 41 Beretta L, Caronni M, Raimondi M et al.. Oral cyclophosphamide improves pulmonary function in scleroderma patients with fibrosing alveolitis: experience in one centre.  Clin Rheumatol. 2007;  26 168-172
• 42 Lunseth J H, Baker L A, Shifrin A. Chronic scleroderma with acute exacerbation during corticotropin therapy; report of a case with autopsy observations.  AMA Arch Intern Med. 1951;  88 783-792
• 43 Sharnoff J G, Carideo H L, Stein I D. Cortisone-treated scleroderma; report of a case with autopsy findings.  J Am Med Assoc. 1951;  145 1230-1232
• 44 Steen V D, Medsger Jr T A. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis.  Arthritis Rheum. 1998;  41 1613-1619
• 45 DeMarco P J, Weisman M H, Seibold J R et al.. Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial.  Arthritis Rheum. 2002;  46 2983-2989
• 46 Hoyles R K, Ellis R W, Wellsbury J et al.. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma.  Arthritis Rheum. 2006;  54 3962-3970
• 47 Yiannopoulos G, Pastromas V, Antonopoulos I et al.. Combination of intravenous pulses of cyclophosphamide and methylprednisolone in patients with systemic sclerosis and interstitial lung disease.  Rheumatol Int. 2007;  27 357-361
• 48 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
• 49 Burt R K, Traynor A E. SLE: hematopoietic stem cell transplantation for systemic lupus erythematosus.  Arthritis Res Ther. 2003;  5 207-209
• 50 Petri M, Jones R J, Brodsky R A. High-dose cyclophosphamide without stem cell transplantation in systemic lupus erythematosus.  Arthritis Rheum. 2003;  48 166-173
• 51 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
• 52 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
• 53 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
• 54 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
• 55 Metzler C, Fink C, Lamprecht P et al.. Maintenance of remission with leflunomide in Wegener's granulomatosis.  Rheumatology (Oxford). 2004;  43 315-320
• 56 Houssiau F A, Vasconcelos C, D'Cruz D et al.. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide.  Arthritis Rheum. 2002;  46 2121-2131
• 57 Ginzler E M, Dooley M A, Aranow C et al.. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis.  N Engl J Med. 2005;  353 2219-2228
• 58 Tessler H H, Jennings T. High-dose short-term chlorambucil for intractable sympathetic ophthalmia and Behçet's disease.  Br J Ophthalmol. 1990;  74 353-357
• 59 Furst D E, Clements P J, Hillis S et al.. Immunosuppression with chlorambucil, versus placebo, for scleroderma: results of a three-year, parallel, randomized, double-blind study.  Arthritis Rheum. 1989;  32 584-593
• 60 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
• 61 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
• 62 Kataria Y P. Chlorambucil in sarcoidosis.  Chest. 1980;  78 36-43
• 63 Sinoway P A, Callen J P. Chlorambucil. An effective corticosteroid-sparing agent for patients with recalcitrant dermatomyositis.  Arthritis Rheum. 1993;  36 319-324
• 64 Steinberg A D. Chlorambucil in the treatment of patients with immune-mediated rheumatic diseases.  Arthritis Rheum. 1993;  36 325-328
• 65 Kaklamani V G, Kaklamanis P G. Treatment of Behçet's disease: an update.  Semin Arthritis Rheum. 2001;  30 299-312
• 66 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
• 67 Starzl T E, Marchioro T L, Dickinson T C et al.. Technique of renal homotransplantation: experience with 42 Cases.  Arch Surg. 1964;  89 87-104
• 68 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
• 69 American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines . Guidelines for the management of rheumatoid arthritis: 2002 Update.  Arthritis Rheum. 2002;  46 328-346
• 70 Benenson E, Fries J W, Heilig B et al.. High-dose azathioprine pulse therapy as a new treatment option in patients with active Wegener's granulomatosis and lupus nephritis refractory or intolerant to cyclophosphamide.  Clin Rheumatol. 2005;  24 251-257
• 71 Pickenpack A, Straub R H, Distler O et al.. Safety and efficacy of an intravenous loading dose of azathioprine for treatment of non-TPMT-deficient patients with rheumatic diseases.  Rheumatology (Oxford). 2000;  39 1435-1436
• 72 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
• 73 Sterneck M, Wiesner R, Ascher N et al.. Azathioprine hepatotoxicity after liver transplantation.  Hepatology. 1991;  14 806-810
• 74 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
• 75 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
• 76 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
• 77 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
• 78 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
• 79 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
• 80 Norgard B, Pedersen L, Fonager K et al.. Azathioprine, mercaptopurine and birth outcome: a population-based cohort study.  Aliment Pharmacol Ther. 2003;  17 827-834
• 81 Polifka J E, Friedman J M. Teratogen update: azathioprine and 6-mercaptopurine.  Teratology. 2002;  65 240-261
• 82 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
• 83 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
• 84 Du Vivier A, Munro D D, Verbov J. Treatment of psoriasis with azathioprine.  BMJ. 1974;  1 49-51
• 85 Calin A. A placebo controlled, crossover study of azathioprine in Reiter's syndrome.  Ann Rheum Dis. 1986;  45 653-655
• 86 Muller-Quernheim J, Kienast K, Held M et al.. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen.  Eur Respir J. 1999;  14 1117-1122
• 87 Pacheco Y, Marechal C, Marechal F et al.. Azathioprine treatment of chronic pulmonary sarcoidosis.  Sarcoidosis. 1985;  2 107-113
• 88 Raghu G, Depaso W J, Cain K et al.. Azathioprine combined with prednisone in the treatment of idiopathic pulmonary fibrosis: a prospective double-blind, randomized, placebo-controlled clinical trial.  Am Rev Respir Dis. 1991;  144 291-296
• 89 Yazici H, Pazarli H, Barnes C G et al.. A controlled trial of azathioprine in Behçet's syndrome.  N Engl J Med. 1990;  322 281-285
• 90 Lee J C, Gladman D D, Schentag C T et al.. The long-term use of azathioprine in patients with psoriatic arthritis.  J Clin Rheumatol. 2001;  7 160-165
• 91 Dean T, Dewey A, Bara A et al.. Azathioprine as an oral corticosteroid sparing agent for asthma.  Cochrane Database Syst Rev. 2004;  (1) CD003270
• 92 Esdaile J M, Joseph L, MacKenzie T et al.. The benefit of early treatment with immunosuppressive drugs in lupus nephritis.  J Rheumatol. 1995;  22 1211
• 93 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
• 94 Winterbauer R H, Hammar S P, Hallman K O et al.. Diffuse interstitial pneumonitis: clinicopathologic correlations in 20 patients treated with prednisone/azathioprine.  Am J Med. 1978;  65 661-672
• 95 Meier-Sydow J, Rust M, Kronenberger H et al.. Long-term follow-up of lung function parameters in patients with idiopathic pulmonary fibrosis treated with prednisone and azathioprine or d-penicillamine [in German].  Prax Klin Pneumol. 1979;  33(Suppl 1) 680-688
• 96 Weese W C, Levine B W, Kazemi H. Interstitial lung disease resistant to corticosteroid therapy: report of three cases treated with azathioprine or cyclophosphamide.  Chest. 1975;  67 57-60
• 97 Dheda K, Lalloo U G, Cassim B et al.. Experience with azathioprine in systemic sclerosis associated with interstitial lung disease.  Clin Rheumatol. 2004;  23 306-309
• 98 Khanna D, Wu H, Park G et al.. Association of tumor necrosis factor alpha polymorphism, but not the shared epitope, with increased radiographic progression in a seropositive rheumatoid arthritis inception cohort.  Arthritis Rheum. 2006;  54 1105-1116
• 99 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;  (2) CD000951
• 100 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 meta-analysis of randomized controlled trials.  J Rheumatol. 1998;  25 36-43
• 101 Fox D A, McCune W J. Immunosuppressive drug therapy of systemic lupus erythematosus.  Rheum Dis Clin North Am. 1994;  20 265-299
• 102 Weinblatt M E. Methotrexate for chronic diseases in adults.  N Engl J Med. 1995;  332 330-331
• 103 Chan E S, Cronstein B N. Molecular action of methotrexate in inflammatory diseases.  Arthritis Res. 2002;  4 266-273
• 104 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
• 105 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
• 106 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
• 107 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
• 108 Mielants H, Veys E M, Van der Straeten C et al.. The efficacy and toxicity of a constant low dose of methotrexate as a treatment for intractable rheumatoid arthritis: an open prospective study.  J Rheumatol. 1991;  18 978-983
• 109 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
• 110 Kremer J M, Alarcon G S, Lightfoot Jr R W et al.. Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity. American College of Rheumatology.  Arthritis Rheum. 1994;  37 316-328
• 111 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
• 112 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
• 113 Kremer J M, Alarcon G S, Weinblatt M E et al.. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis: a multicenter study with literature review.  Arthritis Rheum. 1997;  40 1829-1837
• 114 Cottin V, Tebib J, Massonnet B et al.. Pulmonary function in patients receiving long-term low-dose methotrexate.  Chest. 1996;  109 933-938
• 115 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
• 116 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
• 117 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
• 118 Arakawa H, Yamasaki M, Kurihara Y et al.. Methotrexate-induced pulmonary injury: serial CT findings.  J Thorac Imaging. 2003;  18 231-236
• 119 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
• 120 Schnabel A, Richter C, Bauerfeind S et al.. Bronchoalveolar lavage cell profile in methotrexate induced pneumonitis.  Thorax. 1997;  52 377-379
• 121 Gridley G, McLaughlin J K, Ekbom A et al.. Incidence of cancer among patients with rheumatoid arthritis.  J Natl Cancer Inst. 1993;  85 307-311
• 122 Symmons D P. Neoplasms of the immune system in rheumatoid arthritis.  Am J Med. 1985;  78(1A) 22-28
• 123 Prior P. Cancer and rheumatoid arthritis: epidemiologic considerations.  Am J Med. 1985;  78(1A) 15-21
• 124 Thomas E, Brewster D H, Black R J et al.. Risk of malignancy among patients with rheumatic conditions.  Int J Cancer. 2000;  88 497-502
• 125 Ellman M H, Hurwitz H, Thomas C et al.. Lymphoma developing in a patient with rheumatoid arthritis taking low dose weekly methotrexate.  J Rheumatol. 1991;  18 1741-1743
• 126 Mariette X, Cazals-Hatem D, Warszawki J et al.. Lymphomas in rheumatoid arthritis patients treated with methotrexate: a 3-year prospective study in France.  Blood. 2002;  99 3909-3915
• 127 Balandraud N, Roudier J, Roudier C. What are the links between Epstein-Barr virus, lymphoma, and tumor necrosis factor antagonism in rheumatoid arthritis?.  Semin Arthritis Rheum. 2005;  34(5 Suppl 1) 31-33
• 128 Kingsmore S F, Hall B D, Allen N B et al.. Association of methotrexate, rheumatoid arthritis and lymphoma: report of 2 cases and literature review.  J Rheumatol. 1992;  19 1462-1465
• 129 Hoshida Y, Aozasa K. Malignancies in organ transplant recipients.  Pathol Int. 2004;  54 649-658
• 130 Nalesnik M A, Jaffe R, Starzl T E et al.. The pathology of posttransplant lymphoproliferative disorders occurring in the setting of cyclosporine A-prednisone immunosuppression.  Am J Pathol. 1988;  133 173-192
• 131 Hoshida Y, Xu J X, Fujita S et al.. Lymphoproliferative disorders in rheumatoid arthritis: clinicopathological analysis of 76 cases in relation to methotrexate medication.  J Rheumatol. 2007;  34 322-331
• 132 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
• 133 Patsner B, Kenigsberg D. Successful treatment of persistent ectopic pregnancy with oral methotrexate therapy.  Fertil Steril. 1988;  50 982-983
• 134 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
• 135 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
• 136 Davies H, Olson L, Gibson P. Methotrexate as a steroid sparing agent for asthma in adults.  Cochrane Database Syst Rev. 2000;  (2) CD000391
• 137 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
• 138 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
• 139 Douglas W W, Tazelaar H D, Hartman T E et al.. Polymyositis-dermatomyositis-associated interstitial lung disease.  Am J Respir Crit Care Med. 2001;  164 1182-1185
• 140 Briemberg H R, Amato A A. Dermatomyositis and polymyositis.  Curr Treat Options Neurol. 2003;  5 349-356
• 141 Hochberg M C, Feldman D, Stevens M B et al.. Antibody to Jo-1 in polymyositis/dermatomyositis: association with interstitial pulmonary disease.  J Rheumatol. 1984;  11 663-665
• 142 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
• 143 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
• 144 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
• 145 John G T, Manivannan J, Chandy S et al.. Leflunomide therapy for cytomegalovirus disease in renal allograft recipients.  Transplantation. 2004;  77 1460-1461
• 146 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
• 147 Ginzler E MAC, 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).  N Engl J Med. 2005;  353 2219-2228
• 148 Siva C, Eisen S A, Shepherd R 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
• 149 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
• 150 McCurry J. Japan deaths spark concerns over arthritis drug.  Lancet. 2004;  363 461
• 151 Sakai F, Noma S, Kurihara Y et al.. Leflunomide-related lung injury in patients with rheumatoid arthritis: imaging features.  Mod Rheumatol. 2005;  15 173-179
• 152 Savage R L, Highton J, Boyd I W et al.. Pneumonitis associated with leflunomide: a profile of New Zealand and Australian reports.  Intern Med J. 2006;  36 162-169
• 153 Suissa S, Hudson M, Ernst P. Leflunomide use and the risk of interstitial lung disease in rheumatoid arthritis.  Arthritis Rheum. 2006;  54 1435-1439
• 154 Cohen S B, Iqbal I. Leflunomide.  Int J Clin Pract. 2003;  57 115-120
• 155 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
• 156 Baughman R P, Lower E E. Leflunomide for chronic sarcoidosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2004;  21 43-48
• 157 Sintchak M D, Nimmesgern E. The structure of inosine 5′-monophosphate dehydrogenase and the design of novel inhibitors.  Immunopharmacology. 2000;  47 163-184
• 158 Allison A C, Eugui E M. Mycophenolate mofetil and its mechanisms of action.  Immunopharmacology. 2000;  47 85-118
• 159 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
• 160 Allison A C, Eugui E M. The design and development of an immunosuppressive drug, mycophenolate mofetil.  Springer Semin Immunopathol. 1993;  14 353-380
• 161 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
• 162 Lipsky J J. Mycophenolate mofetil.  Lancet. 1996;  348 1357-1359
• 163 McCune W J, Riskalla M M. Mycophenolate mofetil: a magic bullet for lupus?.  J Rheumatol. 2005;  32 967-970
• 164 McCune W J. Mycophenolate mofetil for lupus nephritis.  N Engl J Med. 2005;  353 2282-2284
• 165 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
• 166 Ginzler E M, Aranow C. Mycophenolate mofetil in lupus nephritis.  Lupus. 2005;  14 59-64
• 167 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
• 168 Chan T M, Li F K, Tang C S et al.. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. Hong Kong-Guangzhou Nephrology Study Group.  N Engl J Med. 2000;  343 1156-1162
• 169 Moore R A, Derry S. Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis.  Arthritis Res Ther. 2006;  8 R182
• 170 Joy M S, Hogan S L, Jennette J C et al.. A pilot study using mycophenolate mofetil in relapsing or resistant ANCA small vessel vasculitis.  Nephrol Dial Transplant. 2005;  20 2725-2732
• 171 Nowack R, Gobel U, Klooker P et al.. Mycophenolate mofetil for maintenance therapy of Wegener's granulomatosis and microscopic polyangiitis: a pilot study in 11 patients with renal involvement.  J Am Soc Nephrol. 1999;  10 1965-1971
• 172 Liossis S N, Bounas A, Andonopoulos A P. Mycophenolate mofetil as first-line treatment improves clinically evident early scleroderma lung disease.  Rheumatology (Oxford). 2006;  45 1005-1008
• 173 Kahan B D. Cyclosporine.  N Engl J Med. 1989;  321 1725-1738
• 174 Miranda J M, Alvarez-Nemegyei J, Saavedra M A et al.. A randomized, double-blind, multicenter, controlled clinical trial of cyclosporine plus chloroquine vs. cyclosporine plus placebo in early-onset rheumatoid arthritis.  Arch Med Res. 2004;  35 36-42
• 175 Kvien T K, Zeidler H K, Hannonen P et al.. Long term efficacy and safety of cyclosporin versus parenteral gold in early rheumatoid arthritis: a three year study of radiographic progression, renal function, and arterial hypertension.  Ann Rheum Dis. 2002;  61 511-516
• 176 Schiff M H, Whelton A. Renal toxicity associated with disease-modifying antirheumatic drugs used for the treatment of rheumatoid arthritis.  Semin Arthritis Rheum. 2000;  30 196-208
• 177 Proudman S M, Conaghan P G, Richardson C et al.. 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. 2000;  43 1809-1819
• 178 Yocum D E. The role of T-cells in rheumatoid arthritis and the use of immunomodulating drugs.  Drugs Today (Barc). 1999;  35 295-307
• 179 van den Borne B E, Landewé R B, Goei Thè H S et al.. Cyclosporin A therapy in rheumatoid arthritis: only strict application of the guidelines for safe use can prevent irreversible renal function loss.  Rheumatology (Oxford). 1999;  38 254-259
• 180 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
• 181 Schreiber S L, Crabtree G R. The mechanism of action of cyclosporin A and FK506.  Immunol Today. 1992;  13 136-142
• 182 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
• 183 Timmerman L A, Clipstone N A, Ho S N et al.. Rapid shuttling of NF-AT in discrimination of Ca2 + signals and immunosuppression.  Nature. 1996;  383 837-840
• 184 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
• 185 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
• 186 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
• 187 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
• 188 Kopp J B, Klotman P E. Cellular and molecular mechanisms of cyclosporin nephrotoxicity.  J Am Soc Nephrol. 1990;  1 162-179
• 189 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
• 190 Miura K, Nakatani T, Asai T et al.. Role of hypomagnesemia in chronic cyclosporine nephropathy.  Transplantation. 2002;  73 340-347
• 191 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
• 192 Moyer T P, Post G R, Sterioff S et al.. Cyclosporine nephrotoxicity is minimized by adjusting dosage on the basis of drug concentration in blood.  Mayo Clin Proc. 1988;  63 241-247
• 193 Kahan B D, Welsh M, Urbauer D L et al.. Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care costs.  J Am Soc Nephrol. 2000;  11 1122-1131
• 194 Dawidson I, Ar'Rajab A, Lu C et al.. Cyclosporine blood levels predict the likelihood of rejection and toxicity after simultaneous pancreas-kidney transplantation.  Transplant Proc. 1995;  27 1324-1326
• 195 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
• 196 Arellano F, Krupp P. Malignancies in rheumatoid arthritis patients treated with cyclosporin A.  Br J Rheumatol. 1993;  32(Suppl 1) 72-75
• 197 Feutren G. The optimal use of cyclosporin A in autoimmune diseases.  J Autoimmun. 1992;  5(Suppl A) 183-195
• 198 Kitridou R C. The mother in systemic lupus erythematosus. In: Wallace DJ, Hahn BH, Quasimorio FP Jr, et al. Dubois' Lupus Erythematosus. Baltimore; Williams & Williams 1997: 967-1002
• 199 Sajjadi H, Soheilian M, Ahmadieh H et al.. Low dose cyclosporin-A therapy in Behçet's disease.  J Ocul Pharmacol. 1994;  10 553-560
• 200 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
• 201 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
• 202 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
• 203 Landewé R B, Goei Thè 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
• 204 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
• 205 Evans D J, Cullinan P, Geddes D M. Cyclosporin as an oral corticosteroid sparing agent in stable asthma.  Cochrane Database Syst Rev. 2001;  (2) CD002993