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Immunosuppressant Therapy for Idiopathic Pulmonary Fibrosis

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Idiopathic pulmonary fibrosis (IPF) is associated with progressive respiratory failure and is usually fatal. Corticosteroid therapy is effective in less than half of the patients in whom it is tried.

Recently, it has become apparent that immunosuppressant drugs, especially azathioprine and cyclophosphamide, have a role in the management of IPF patients. We review the indications, previous experience, proposed mechanism of action and apparent effectiveness of these drugs in patients with IPF. Both drugs appear to be more effective than corticosteroids alone in selected patients with IPF. Although not all patients respond to either therapy, the drugs seem to be indicated in patients with mild to moderate symptomatic disease. Factors associated with a better prognosis and response to therapy in pulmonary fibrosis include patients being less than 50 years old, having vital capacities > 50% of predicted, and the presence of an underlying collagen vascular disease. If monitored appropriately, the toxicity of these agents is minimal in most patients.

With the limited information now available, use of immunosuppressive agents should be considered in all patients with pulmonary fibrosis, especially those failing to respond to corticosteroid therapy.

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  1. 1.

    Campbell EJ, Harris B, Avioli LV. Idiopathic pulmonary fibrosis. Arch Intern Med 1981; 141: 771–4

  2. 2.

    Carrington CB, Gaensler EA, Coutu RE, et al. Natural history and treated course of usual and desquamative interstitial pneumonia. N Engl J Med 1978; 298: 801–9

  3. 3.

    Panos RJ, Morrenson R, Niccoli SA, et al. Clinical deterioration in patients with idiopathic pulmonary fibrosis: causes and assessment. Am J Med 1990; 88: 396–404

  4. 4.

    Schwartz DA, Van Fossen DS, Davis CS, et al. Determinants of progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149: 444–9

  5. 5.

    du Bois RM. Idiopathic pulmonary fibrosis. Annu Rev Med 1993; 44: 441–50

  6. 6.

    Schwartz DA, Helmers RA, Galvin JR, et al. Determinants of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1994; 149: 450–4

  7. 7.

    Rudd RM, Haslam PL, Turner-Warwick M. Cryptogenic fibrosing alveolitis: relationships of pulmonary physiology and bronchoalveolar lavage to response to treatment and prognosis. Am Rev Respir Dis 1981; 124: 1–8

  8. 8.

    Cherniack RM, Crystal RG, Kalica AR. NHLBI workshop summary. Current concepts in idiopathic pulmonary fibrosis: a road map for the future. Am Rev Respir Dis 1991; 143: 680–3

  9. 9.

    Crystal RG, Bitterman PB, Rennard SI, et al. Interstitial lung disease of unknown cause: disorders characterized by chronic inflammation of the lower respiratory tract. N Engl J Med 1984; 310: 154–66

  10. 10.

    Johnson ID, Bleasdale C, Hind CR, et al. Accuracy of diagnostic coding of hospital admissions for cryptogenic fibrosing alveolitis. Thorax 1991; 46: 589–91

  11. 11.

    Thurlbeck WM, Miller RR, Muller NL, et al. Diffuse diseases of the lung: a team approach. Philadelphia: BC Decker, 1991

  12. 12.

    Baughman RP, Shipley RT, Loudon RG, et al. Crackles in interstitial lung disease: comparison of sarcoidosis and fibrosing alveolitis. Chest 1991; 100: 96–101

  13. 13.

    Orens JR, Kazerooni EA, Martinez FJ, et al. The sensitivity of high-resolution CT in detecting idiopathic pulmonary fibrosis proved by open lung biopsy: a prospective study. Chest 1995; 108: 109–15

  14. 14.

    Muller NL. Computed tomography in chronic interstitial lung disease. Radiol Clin North Am 1991; 29: 1085–93

  15. 15.

    Tung KT, Wells AU, Rubens MB, et al. Accuracy of the typical computed tomographic appearances of fibrosing alveolitis. Thorax 1993; 48: 334–8

  16. 16.

    Allen JN, Pacht ER, Gadek JE. Acute eosinophilic pneumonia as a reversible cause of noninfectious respiratory failure. N Engl J Med 1989; 321: 569–74

  17. 17.

    Baughman RP, Dohn MN, Loudon RG, et al. Bronchoscopy with bronchoalveolar lavage in tuberculosis and fungal infections. Chest 1991; 99: 92–7

  18. 18.

    Baughman RP, Dohn MN, Frame PT. The continued utility of bronchoalveolar lavage to diagnose opportunistic infection in AIDS patients. Am J Med 1994; 97: 515–22

  19. 19.

    Wall CP, Gaensler EA, Carrington CB, et al. Comparison of transbronchial and open lung biopsies in chronic infiltrative lung diseases. Am Rev Respir Dis 1981; 123: 280–5

  20. 20.

    Miller RR, Nelems B, Muller NL, et al. Lingular and right middle lobe biopsy in the assessment of diffuse lung disease. Ann Thorac Surg 1987; 44: 269–73

  21. 21.

    Bentzon N, Adamsen S, Jacobsen B, et al. Videothorascopic lung biopsy by a stapler technique. Eur J Surg 1994; 160: 543–6

  22. 22.

    Cormier Y, Belanger J, Laviolette M. Prognostic significance of bronchoalveolar lymphocytes in farmer’s lung. Am Rev Respir Dis 1987; 135: 692–5

  23. 23.

    Epler GR, Colby TV, McLoud T, et al. Bronchiolitis obliterans organizing pneumonia. N Engl J Med 1985; 312: 152–8

  24. 24.

    Baughman RP, Lower EE, Lynch JP. Treatment modalities for sarcoidosis. Clin Pulmon Med 1994; 1: 223–31

  25. 25.

    Winterbauer RH, Hammar RP, Hallman KO, et al. Diffuse interstitial pneumonitis: clinical pathologic correlations in 20 patients treated with prednisone/azathioprine. Am J Med 1978; 65: 661–72

  26. 26.

    Raghu G, DePaso WJ, 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: 291–6

  27. 27.

    Agusti C, Xaubet A, Agusti AG, et al. Clinical and functional assessment of patients with idiopathic pulmonary fibrosis: results of a 3 year follow-up. Eur Respir J 1994; 7: 643–50

  28. 28.

    Smith CM, Moser KM. Management of interstitial lung disease: state of the art. Chest 1989; 95: 676–8

  29. 29.

    Johnston ID, Gomm SA, Kalra S, et al. The management of cryptogenic fibrosing alveolitis in three regions of the United Kingdom. Eur Respir J 1993; 6: 891–3

  30. 30.

    DeVita VT, Hellman S, Rosenberg SA. Cancer: principles and ractice of oncology. 4th ed. Philadelphia: JB Lippincott, 1993

  31. 31.

    Hollander AA, van Saase JL, Kootte AM, et al. Beneficial effects of conversion from cyclosporine to azathioprine after kidney transplantation. Lancet 1995; 345: 610–4

  32. 32.

    Shapiro R, Jordan M, Scantlebury V, et al. A prospective, randomized trial of FK-506 in renal transplantation: a comparison between double- and triple-drug therapy. Clin Trans 1994; 8: 508–15

  33. 33.

    de Glas-Vos JW, Kreidiet RT, Weening JJ, et al. Treatment of proliferative lupus nephritis with methylprednisolone pulse therapy and oral azathioprine. Neth J Med 1995; 46: 4–14

  34. 34.

    Wilkens RF, Urowitz MB, Stablein DM, et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis: a controlled clinical trial. Arthritis Rheum 1992; 35: 849–56

  35. 35.

    Jeurissen ME, Boerbooms AM, van de Putte LB, et al. Methotrexate versus azathioprine in the treatment of rheumatoid arthritis: a forty-eight-week randomized, double-blind trial. Arthritis Rheum 1991; 34: 961–72

  36. 36.

    Johnson PJ, McFarlane IG, Williams R. Azathioprine for long-term maintenance of remission in autoimmune hepatitis. N Engl J Med 1995; 333: 958–63

  37. 37.

    Pearson DC, May GR, Fick GH, et al. Azathioprine and 6-mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med 1995; 123: 132–42

  38. 38.

    Weese WC, Levine BW, Kazemi H. Interstitial lung disease resistant to corticosteroid therapy: report of three cases treated with azathioprine or cyclophosphamide. Chest 1975; 67: 57–60

  39. 39.

    Cegla UH, Kroidl RF, Meier-Sydow J, et al. Therapy of the idiopathic fibrosis of the lung. Pneumonologie 1975; 152: 75–92

  40. 40.

    Meier-Sidow 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. Prax Pneumol 1979; 33: 680–8

  41. 41.

    Costabel U, Matthys H. Different therapies and factors influencing response to therapy in idiopathic diffuse fibrosing alveolitis. Respiration 1981; 42: 141–9

  42. 42.

    Brown CH, Turner-Warwick M. The treatment of cryptogenic fibrosing alveolitis with immunosuppressant drugs. Q J Med 1971; 40: 289–302

  43. 43.

    Isbister JP, Ralston M, Hayes JM, et al. Fulminant lupus pneumonitis with acute renal failure and RBC aplasia: successful management with plasmapheresis and immunosuppression. Arch Intern Med 1981; 141: 1081–3

  44. 44.

    Levey AS, Lan SP, Corwin HL, et al. Progression and remission of renal disease in the lupus nephritis collaborative study: results of treatment with prednisone and short-term oral cyclophosphamide. Ann Intern Med 1992; 116: 114–23

  45. 45.

    Boumpas DT, Austin HA, Vaughn EM, et al. Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis. Lancet 1992; 340: 741–5

  46. 46.

    Belmont HM, Storch M, Buyon J, et al. New York University/Hospital for joint disease experience with intravenous cyclophosphamide treatment: efficacy in steroid unresponsive lupus nephritis. Lupus 1995; 4: 104–8

  47. 47.

    Fauci AS, Wolff SM. Wegener’s granulomatosis: studies in eighteen patients and a review of the literature. Medicine 1973; 52: 535–61

  48. 48.

    Fauci AS, Haynes BF, 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

  49. 49.

    Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener’s granulomatosis: an analysis of 158 patients. Ann Intern Med 1992; 116: 488–98

  50. 50.

    Conn DL. Role of cyclophosphamide in treatment of polyarteritis nodosa? J Rheumatol 1991; 18: 489–90

  51. 51.

    Stewart KA, Mazanec DJ. Pulse intravenous cyclophosphamide for kidney disease in relapsing polychondritis. J Rheumatol 1992; 19: 498–500

  52. 52.

    Fukuda M, Kamiyama Y, Kawamura K, et al. The favorable effect of cyclophosphamide pulse therapy in the treatment of massive pulmonary hemorrhage in systemic lupus erythematosus. Eur J Pediatr 1994; 153: 167–70

  53. 53.

    Green H, Bootsma H, Postma DS, et al. Primary pulmonary hypertension in a patient with systemic lupus erythematosus: partial improvement with cyclophosphamide. J Rheumatol 1993; 20: 1055–7

  54. 54.

    Eiser AR, Shanies HM. Treatment of lupus interstitial lung disease with intravenous cyclophosphamide. Arthritis Rheum 1994; 37: 428–31

  55. 55.

    DePaso WJ, Winterbauer RH. Interstitial lung disease. Dis Mon 1991; 37: 61–133

  56. 56.

    Al-janadi M, Smith CD, Karsh J. Cyclophosphamide treatment of interstitial pulmonary fibrosis in polymyositis/dermatomyositis. J Rheumatol 1989; 16: 1592–6

  57. 57.

    Steen VD, Lanz Jr JK, Conte C, et al. Therapy for severe interstitial lung disease in systemic sclerosis: a retrospective study. Arthritis Rheum 1994; 37: 1290–6

  58. 58.

    Akeesson A, Scheja A, Lundin A, et al. Improved pulmonary function in systemic sclerosis after treatment with cyclophosphamide. Arthritis Rheum 1994; 37: 729–35

  59. 59.

    Silver RM, Warrick JH, Kinsella MB, et al. Cyclophosphamide and low-dose prednisone therapy in patients with systemic sclerosis (scleroderma) with interstitial lung disease. J Rheumatol 1993; 20: 838–44

  60. 60.

    Wells AU, Cullinan P, Hansell DM, et al. Fibrosing alveolitis associated with systemic sclerosis has a better prognosis than lone cryptogenic fibrosing alveolitis. Am J Respir Crit Care Med 1994; 149: 1583–90

  61. 61.

    Baughman RP, Lower EE. Use of intermittent, intravenous cyclophosphamide for idiopathic pulmonary fibrosis. Chest 1992; 102: 1090–4

  62. 62.

    Weiland J, Dorinsky P, Davis WB, et al. Use of cyclophosphamide in the treatment of idiopathic pulmonary fibrosis. Chest 1986; 89: 1505–15

  63. 63.

    Dayton CS, Schwartz DA, Helmers RA, et al. Outcome of subjects with idiopathic pulmonary fibrosis who fail corticosteroid therapy: implications for further studies. Chest 1993; 103: 69–73

  64. 64.

    van Oortegam K, Wallaert B, Marquette CH, et al. Determinants of response to immunosuppressive therapy in idiopathic pulmonary fibrosis. Eur Respir J 1994; 7: 1950–7

  65. 65.

    Baughman RP, Winget DB, Lower EE. The safety and efficacy of prolonged use of cyclophosphamide for idiopathic pulmonary fibrosis [abstract]. Eur Respir J 1994; 7: 102S

  66. 66.

    Johnson MA, Kwan S, Snell JC, et al. Randomized controlled trial comparing prednisolone alone with cyclophosphamide and low dose prednisone in combination in cryptogenic fibrosing alveolitis. Thorax 1989; 44: 280–8

  67. 67.

    Haslam PL, Turton CWG, Lukoszek A, et al. Bronchoalveolar lavage fluid cell counts in cryptogenic fibrosing alveolitis and their relations to therapy. Thorax 1980; 35: 328–39

  68. 68.

    Haslam PL, Poulter LW, Rossi GA, et al. The clinical role of BAL in idiopathic pulmonary fibrosis. Eur Respir J 1990; 3: 940–2, 961-9

  69. 69.

    Turner-Warwick M, Haslam PL. The value of serial bronchoalveolar lavages in assessing the clinical progress of patients with cryptogenic fibrosing alveolitis. Am Rev Respir Dis 1987; 135: 26–34

  70. 70.

    Watters LC, King TE, Schwarz MI, et al. A clinical, radiographic, and physiologic scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis. Am Rev Respir Dis 1986; 133: 97–103

  71. 71.

    Greene NB, Solinger AM, Baughman RP. Patients with collagen vascular disease and dyspnea: the value of gallium scanning and bronchoalveolar lavage in predicting response to steroid therapy and clinical outcome. Chest 1987; 91: 698–703

  72. 72.

    Peterson MW, Monick M, Hunninghake GW. Prognostic role of eosinophils in pulmonary fibrosis. Chest 1987; 92: 51–6

  73. 73.

    O’Donnell K, Keogh B, Cantin A, et al. Pharmacologie suppression of the neutrophil component of the alveolitis in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1987; 136: 288–92

  74. 74.

    Balow JE, Austin HA, Muenz LR, et al. Effect of treatment on the evolution of renal abnormalities in lupus nephritis. N Engl J Med 1984; 311: 491–5

  75. 75.

    Austin HA, Klippel JH, Balow JE, et al. Therapy of lupus nephritis: controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986; 314: 614–9

  76. 76.

    Steppat D, Gross WL. Stage adapted treatment of Wegener’s granulomatosis. Klin Wochenschr 1989; 67: 666–71

  77. 77.

    Chapman PT, O’Donnell JL. Respiratory failure in Wegener’s granulomatosis: response to pulse intravenous methylprednisolone and cyclophosphamide. J Rheumatol 1993; 20: 504–6

  78. 78.

    Hoffman GS, Leavitt RY, Fleischer TA, et al. Treatment of Wegener’s granulomatosis with intermittent high-dose intravenous cyclophosphamide. Am J Med 1990; 89: 403–10

  79. 79.

    Pizzo PA, Rubin M, Freifeld A, et al. The child with cancer and infection. I. Empiric therapy for fever and neutropenia, and preventive strategies. J Pediatr 1991; 119: 676–94

  80. 80.

    King J, Deboisblanc BP, Mason CM, et al. Effect of granulocyte colony-stimulating factor on acute lung injury in rat. Am J Respir Crit Care Med 1995; 151: 302–9

  81. 81.

    Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med 1996; 124: 477–84

  82. 82.

    Schoenike SE. Ifosfamide and mesna. Clin Pharm 1990; 9: 179–91

  83. 83.

    Anderson D, Bishop JB, Garner RC, et al. Cyclophosphamide: review of its mutagenicity for an assessment of potential germ cell risks. Mutat Res 1995; 330: 115–81

  84. 84.

    Casciato DA, Scott JL. Acute leukemia following prolonged cytotoxic agent therapy. Medicine 1979; 58: 32–47

  85. 85.

    Baker GL, Kahl LE, Zee BC, et al. Malignancy following treatment of rheumatoid arthritis with cyclophosphamide. Am J Med 1987; 83: 1–9

  86. 86.

    Turner-Warwick M, Lebowitz M, Burrows B, et al. Cryptogenic fibrosing alveolitis and lung cancer. Thorax 1980; 35: 496–9

  87. 87.

    Mizushima Y, Kobayashi M. Clinical characteristics of synchronous multiple lung cancer associated with idiopathic pulmonary fibrosis: a review of Japanese literature. Chest 1995; 108: 1272–7

  88. 88.

    McCune WJ, Vallance DK, Lynch JP. Immunosuppressive drug therapy. Curr Opin Rheumatol 1994; 6: 262–72

  89. 89.

    Moolman JA, Bardin PG, Rossouw DJ, et al. Cyclosporine as a treatment for interstitial lung disease of unknown aetiology. Thorax 1991; 46: 592–5

  90. 90.

    Venuta F, Rendina EA, Ciriaco P, et al. Efficacy of cyclosporine to reduce steroids in patients with idiopathic pulmonary fibrosis before lung transplantation. J Heart Lung Transplant 1993; 12: 909–14

  91. 91.

    Cohen DJ, Appel GB. Cyclosporine: nephrotoxic effects and guidelines for safe use in patients with rheumatoid arthritis. Semin Arthritis Rheum 1992; 21: 43S–8S

  92. 92.

    Kahan BD. Cyclosporine. N Engl J Med 1989; 321: 1725–38

  93. 93.

    Peters SG, McDougall JC, Douglas WW, et al. Colchicine in the treatment of pulmonary fibrosis. Chest 1993; 103: 101–4

  94. 94.

    Giri SN, Hyde DM, Hollinger MA. Effect of antibody to transforming growth factor beta on bleomycin induced accumulation of lung collagen in mice [see comments]. Thorax 1993; 48: 959–66

  95. 95.

    Hunninghake GW, Kalica AR. Approaches to the treatment of pulmonary fibrosis. Am J Respir Crit Care Med 1995; 151: 915–8

  96. 96.

    Raghu G. Interstitial lung disease: a diagnostic approach. Am J Respir Crit Care Med 1995; 151: 909–14

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Correspondence to Dr Robert P. Baughman.

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Baughman, R.P., Lower, E.E. Immunosuppressant Therapy for Idiopathic Pulmonary Fibrosis. Clin. Immunother. 6, 431–442 (1996). https://doi.org/10.1007/BF03259365

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  • Cyclophosphamide
  • Idiopathic Pulmonary Fibrosis
  • Pulmonary Fibrosis
  • Lupus Nephritis
  • Interstitial Lung Disease