BioDrugs

, Volume 17, Issue 6, pp 425–431 | Cite as

Tumour Necrosis Factor in Sarcoidosis and its Potential for Targeted Therapy

Therapy Review

Abstract

Tumour necrosis factor (TNF)-α is a potent cytokine involved in the inflammatory reactions of many acute and chronic diseases. Recently, agents that block TNFα either directly or indirectly have been successful in the treatment of a variety of immune-mediated inflammatory disorders including rheumatoid arthritis and Crohn’s disease. Sarcoidosis is an immune-mediated inflammatory disorder characterised by the formation of granulomas. TNFα is important in the initiation and perpetuation of inflammation in sarcoidosis, contributing to the initiation of granulomas and the progression of fibrosis, as well as to nongranulomatous inflammation. Various agents used to treat sarcoidosis affect TNF, including the most widely used drug class, corticosteroids, which are usually effective in blocking TNFα release from cells. Other agents that nonspecifically inhibit TNFα release include methotrexate, azathioprine and pentoxifylline. Specific TNF-antagonising biological agents such as infliximab and etanercept are being tested in patients with sarcoidosis, with mixed success. Infliximab has been shown to produce clinical improvement and reduce the requirement for corticosteroids in a small number of patients with sarcoidosis. However, as infliximab can be associated with reactivation of tuberculosis, which could be mistaken as worsening sarcoidosis, it should be used with caution in this patient group.

References

  1. 1.
    Carswell EA, Old LJ, Kassel RL, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975; 72: 3666–70PubMedCrossRefGoogle Scholar
  2. 2.
    Beutler B, Greenwald D, Hulmes JD, et al. Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 1985; 316: 552–4PubMedCrossRefGoogle Scholar
  3. 3.
    Bazzoni F, Beutler B. The tumor necrosis factor ligand and receptor families. N Engl J Med 1996; 334: 1717–25PubMedCrossRefGoogle Scholar
  4. 4.
    Granger GA, Williams TW. Lymphocyte cytotoxicity in vitro: activation and release of a cytotoxic factor. Nature 1968; 218: 1253–4PubMedCrossRefGoogle Scholar
  5. 5.
    De Togni P, Goellner J, Ruddle NH, et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 1994; 264: 703–7PubMedCrossRefGoogle Scholar
  6. 6.
    Spies T, Morton CC, Nedospasov SA, et al. Genes for the tumor necrosis factors alpha and beta are linked to the human major histocompatibility complex. Proc Natl Acad Sci U S A 1986; 83: 8699–702PubMedCrossRefGoogle Scholar
  7. 7.
    Beutler B, Milsark IW, Cerami AC. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 1985; 229: 869–71PubMedCrossRefGoogle Scholar
  8. 8.
    Ulich TR, del Castillo J, Keys M, et al. Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosis factor-alpha-induced changes in circulating numbers of neutrophils and lymphocytes. J Immunol 1987; 139: 3406–15PubMedGoogle Scholar
  9. 9.
    Ulich TR, del Castillo J, Ni RX, et al. Hematologie interactions of endotoxin, tumor necrosis factor alpha (TNF alpha), interleukin 1, and adrenal hormones and the hematologie effects of TNF alpha in Corynebacterium parvum-primed rats. J Leukoc Biol 1989; 45: 546–57PubMedGoogle Scholar
  10. 10.
    Abraham E, Anzueto A, Gutierrez G, et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock: NORASEPT II Study Group. Lancet 1998; 351: 929–33PubMedGoogle Scholar
  11. 11.
    Abraham E, Wunderink R, Silverman H, et al. Efficacy and safety of monoclonal antibody to human tumor necrosis factor alpha in patients with sepsis syndrome: a randomized, controlled, double-blind, multicenter clinical trial. TNF-alpha MAb Sepsis Study Group. JAMA 1995; 273: 934–41PubMedCrossRefGoogle Scholar
  12. 12.
    Fisher Jr CJ, Agosti JM, Opal SM, et al. Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med 1996; 334: 1697–702PubMedCrossRefGoogle Scholar
  13. 13.
    Geyer AS, Anhalt GJ, Nousari HC. Effectiveness of infliximab in the treatment of refractory perineal cutaneous Crohn disease. Arch Dermatol 2000; 136: 459–60PubMedCrossRefGoogle Scholar
  14. 14.
    Kavanaugh A, Clair EW, McCune WJ, et al. Chimeric anti-tumor necrosis factor-alpha monoclonal antibody treatment of patients with rheumatoid arthritis receiving methotrexate therapy. J Rheumatol 2000; 27: 841–50PubMedGoogle Scholar
  15. 15.
    Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130: 478–86PubMedGoogle Scholar
  16. 16.
    Crystal RG, Roberts WG, Hunninghake GW, et al. Pulmonary sarcoidosis: a disease characterized and perpetuated by activated lung T lymphocytes. Ann Intern Med 1981; 94: 73–94Google Scholar
  17. 17.
    Pinkston P, Bitterman PB, Crystal RG. Spontaneous release of interleukin-2 by lung lymphocytes in active pulmonary sarcoidosis. N Engl J Med 1983; 308: 793–800PubMedCrossRefGoogle Scholar
  18. 18.
    Ward K, O’Connors C, Odlun C, et al. Prognostic value of bronchoalveolar lavage in sarcoidosis: the critical influence of disease presentation. Thorax 1989; 44: 6–12PubMedCrossRefGoogle Scholar
  19. 19.
    Baughman RP, Lower EE. The effect of corticosteroid or methotrexate therapy on lung lymphocytes and macrophages in sarcoidosis. Am Rev Respir Dis 1990; 142: 1268–71PubMedGoogle Scholar
  20. 20.
    Ceuppens JL, Lacquet LM, Marien G, et al. Alveolar T-cell subsets in pulmonary sarcoidosis: correlation with disease activity and effect of steroid treatment. Am Rev Respir Dis 1984; 129: 563–8PubMedGoogle Scholar
  21. 21.
    Baumer I, Zissel G, Schlaak M, et al. Th1/Th2 cell distribution in pulmonary sarcoidosis. Am J Respir Cell Mol Biol 1997; 16: 171–7PubMedGoogle Scholar
  22. 22.
    Robinson BW, McLemore TL, Crystal RG. Gamma interferon is spontaneously released by alveolar macrophages and lung T lymphocytes in patients with pulmonary sarcoidosis. J Clin Invest 1985; 75: 1488–95PubMedCrossRefGoogle Scholar
  23. 23.
    Shigehara K, Shijubo N, Ohmichi M, et al. IL-12 and IL-18 are increased and stimulate IFN-gamma production in sarcoid lungs. J Immunol 2001; 166: 642–9PubMedGoogle Scholar
  24. 24.
    Moller DR, Forman JD, Liu MC, et al. Enhanced expression of IL-12 associated with Th1 cytokine profiles in active pulmonary sarcoidosis. J Immunol 1996; 156: 4952–60PubMedGoogle Scholar
  25. 25.
    Kunkel SL, Lukacs NW, Strieter RM, et al. Th1 and Th2 responses regulate experimental lung granuloma development. Sarcoidosis Vasc Diffuse Lung Dis 1996; 13: 120–8PubMedGoogle Scholar
  26. 26.
    Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med 2001; 344: 907–16PubMedCrossRefGoogle Scholar
  27. 27.
    Keffer J, Probert L, Cazlaris H, et al. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J 1991; 10: 4025–31PubMedGoogle Scholar
  28. 28.
    Wooley PH, Dutcher J, Widmer MB, et al. Influence of a recombinant human soluble tumor necrosis factor receptor FC fusion protein on type II collageninduced arthritis in mice. J Immunol 1993; 151: 6602–7PubMedGoogle Scholar
  29. 29.
    Baughman RP, Strohofer SA, Buchsbaum J, et al. Release of tumor necrosis factor by alveolar macrophages of patients with sarcoidosis. J Lab Clin Med 1990; 115: 36–42PubMedGoogle Scholar
  30. 30.
    Pueringer RJ, Schwartz DA, Dayton CS, et al. The relationship between alveolar macrophage TNF, IL-1, and PGE2 release, alveolitis, and disease severity in sarcoidosis. Chest 1993; 103: 832–8PubMedCrossRefGoogle Scholar
  31. 31.
    Bost TW, Riches DW, Schumacher B, et al. Alveolar macrophages from patients with beryllium disease and sarcoidosis express increased levels of mRNA for tumor necrosis factor-alpha and interleukin-6 but not interleukin-1 beta. Am J Respir Cell Mol Biol 1994; 10: 506–13PubMedGoogle Scholar
  32. 32.
    Ziegenhagen MW, Benner UK, Zissel G, et al. Sarcoidosis: TNF-alpha release from alveolar macrophages and serum level of sIL-2R are prognostic markers. Am J Respir Crit Care Med1997; 156: 1586–92PubMedGoogle Scholar
  33. 33.
    Wilson AG, Symons JA, McDowell TL, et al. Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 1997; 94: 3195–9PubMedCrossRefGoogle Scholar
  34. 34.
    Yamaguchi E, Itoh A, Hizawa N, et al. The gene polymorphism of tumor necrosis factor-beta, but not that of tumor necrosis factor-alpha, is associated with the prognosis of sarcoidosis. Chest 2001; 119: 753–61PubMedCrossRefGoogle Scholar
  35. 35.
    Grutters JC, Sato H, Pantelidis P, et al. Increased frequency of the uncommon tumor necrosis factor −857T allele in British and Dutch patients with sarcoidosis. Am J Respir Crit Care Med 2002; 165: 1119–24PubMedGoogle Scholar
  36. 36.
    Baughman RP, Lower EE, Pierson G, et al. Spontaneous hydrogen peroxide release from alveolar macrophages of patients with active sarcoidosis: comparison with cigarette smokers. J Lab Clin Med 1988; 111: 399–404PubMedGoogle Scholar
  37. 37.
    Black RA, Rauch CT, Kozlosky CJ, et al. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 1997; 385: 729–33PubMedCrossRefGoogle Scholar
  38. 38.
    McGeehan GM, Becherer JD, Bast Jr RC, et al. Regulation of tumour necrosis factor-alpha processing by a metalloproteinase inhibitor. Nature 1994; 370: 558–61PubMedCrossRefGoogle Scholar
  39. 39.
    Chen G, Goeddel DV. TNF-R1 signaling: a beautiful pathway. Science 2002; 296: 1634–5PubMedCrossRefGoogle Scholar
  40. 40.
    Scheinman RI, Cogswell PC, Lofquist AK, et al. Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science 1995; 270: 283–6PubMedCrossRefGoogle Scholar
  41. 41.
    Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor beta isoform: expression, biochemical properties, and putative function. J Biol Chem 1996; 271: 9550–9PubMedCrossRefGoogle Scholar
  42. 42.
    Webster JC, Oakley RH, Jewell CM, et al. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci U S A 2001; 98: 6865–70PubMedCrossRefGoogle Scholar
  43. 43.
    Ziegenhagen MW, Rothe E, Zissel G, et al. Chronic sarcoidosis with persistent TNF release. Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 185–90PubMedGoogle Scholar
  44. 44.
    Corral LG, Muller GW, Moreira AL, et al. Selection of novel analogs of thalidomide with enhanced tumor necrosis factor alpha inhibitory activity. Mol Med 1996; 2: 506–15PubMedGoogle Scholar
  45. 45.
    Strieter RM, Remick DG, Ward PA, et al. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem Biophys Res Commun 1988; 155: 1230–6PubMedCrossRefGoogle Scholar
  46. 46.
    Katakami Y, Nakao Y, Koizumi T, et al. Regulation of tumour necrosis factor production by mouse peritoneal macrophages: the role of cellular cyclic AMP. Immunology 1988; 64: 719–24PubMedGoogle Scholar
  47. 47.
    Hunninghake GW, Costabel U, Ando M, et al. ATS/ERS/WASOG statement on sarcoidosis: American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 149–73Google Scholar
  48. 48.
    Pinkston P, Saltini C, Muller-Quernheim J, et al. Corticosteroid therapy suppresses spontaneous interleukin 2 release and spontaneous proliferation of lung T lymphocytes of patients with active pulmonary sarcoidosis. J Immunol 1987; 139: 755–60PubMedGoogle Scholar
  49. 49.
    Martinet Y, Pinkston P, Saltini C, et al. Evaluation of the in vitro and in vivo effects of cyclosporine on the lung T-lymphocyte alveolitis of active pulmonary sarcoidosis. Am Rev Respir Dis 1996; 138: 1242–8Google Scholar
  50. 50.
    Wyser CP, van Schalkwyk EM, Alheit B, et al. Treatment of progressive pulmonary sarcoidosis with cyclosporin A: a randomized controlled trial. Am J Respir Crit Care Med 1997; 156: 1571–6Google Scholar
  51. 51.
    Gottlieb JE, Israel HL, Steiner RM, et al. Outcome in sarcoidosis: the relationship of relapse to corticosteroid therapy. Chest 1997; 111: 623–31PubMedCrossRefGoogle Scholar
  52. 52.
    Baughman RP, Shipley R, Eisentrout CE. Predictive value of gallium scan, angiotensin-converting enzyme level, and bronchoalveolar lavage in two-year follow-up of pulmonary sarcoidosis. Lung 1987; 165: 371–7PubMedCrossRefGoogle Scholar
  53. 53.
    Rizzato G, Montemurro L, Colombo P. The late follow-up of chronic sarcoid patients previously treated with corticosteroids. Sarcoidosis 1998; 15: 52–8Google Scholar
  54. 54.
    Hunninghake GW, Gilbert S, Pueringer R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care Med 1994; 149: 893–8PubMedGoogle Scholar
  55. 55.
    Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: results of a double blind, randomized trial. Sarcoidosis 2000; 17: 60–6Google Scholar
  56. 56.
    Baughman RP, Lower EE. A clinical approach to the use of methotrexate for sarcoidosis. Thorax 1999; 54: 742–6PubMedCrossRefGoogle Scholar
  57. 57.
    Lower EE, Baughman RP. Prolonged use of methotrexate for sarcoidosis. Arch Intern Med 1995; 155: 846–51Google Scholar
  58. 58.
    Gedalia A, Molina JF, Ellis GS, et al. Low-dose methotrexate therapy for childhood sarcoidosis. J Pediatr 1997; 130: 25–9PubMedCrossRefGoogle Scholar
  59. 59.
    Lower EE, Broderick JP, Brott TG, et al. Diagnosis and management of neurologic sarcoidosis. Arch Intern Med 1997; 157: 1864–8PubMedCrossRefGoogle Scholar
  60. 60.
    Muller-Quernheim J, Kienast K, Held M, et al. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J 1999; 14: 1117–22PubMedCrossRefGoogle Scholar
  61. 61.
    Lewis SJ, Ainslie GM, Bateman ED. Efficacy of azathioprine as second-line treatment in pulmonary sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999; 16: 87–92PubMedGoogle Scholar
  62. 62.
    Baughman RP, Ohmichi M, Lower EE. Combination therapy for sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18: 133–7PubMedGoogle Scholar
  63. 63.
    Spatafora M, Chiappara G, Merendino AM, et al. Theophylline suppresses the release of tumour necrosis factor-alpha by blood monocytes and alveolar macrophages. Eur Respir J 1994; 7: 223–8PubMedCrossRefGoogle Scholar
  64. 64.
    Marques LJ, Zheng L, Poulakis N, et al. Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. Am J Respir Crit Care Med 1999; 159:508–11PubMedGoogle Scholar
  65. 65.
    Zabel P, Entzian P, Dalhoff K, et al. Pentoxifylline in treatment of sarcoidosis. Am J Respir Crit Care Med 1997; 155: 1665–9PubMedGoogle Scholar
  66. 66.
    Carlesimo M, Giustini S, Rossi A, et al. Treatment of cutaneous and pulmonary sarcoidosis with thalidomide. J Am Acad Dermatol 1995; 32: 866–9PubMedCrossRefGoogle Scholar
  67. 67.
    Baughman RP, Judson MA, Teirstein AS, et al. Thalidomide for chronic sarcoidosis. Chest 2002; 122: 227–32PubMedCrossRefGoogle Scholar
  68. 68.
    Lee JB, Koblenzer PS. Disfiguring cutaneous manifestation of sarcoidosis treated with thalidomide: a case report. J Am Acad Dermatol 1998; 39: 835–8PubMedCrossRefGoogle Scholar
  69. 69.
    Rousseau L, Beylot-Barry M, Doutre MS, et al. Cutaneous sarcoidosis successfully treated with low doses of thalidomide. Arch Dermatol 1998; 134: 1045–6PubMedCrossRefGoogle Scholar
  70. 70.
    Tramontana JM, Utaipat U, Molloy A, et al. Thalidomide treatment reduces tumor necrosis factor alpha production and enhances weight gain in patients with pulmonary tuberculosis. Mol Med 1995; 1: 384–97PubMedGoogle Scholar
  71. 71.
    Tavares JL, Wangoo A, Dilworth P, et al. Thalidomide reduces tumour necrosis factor-alpha production by human alveolar macrophages. Respir Med 1997; 91: 31–9PubMedCrossRefGoogle Scholar
  72. 72.
    Moller DR, Wysocka M, Greenlee BM, et al. Inhibition of IL-12 production by thalidomide. J Immunol 1997; 159: 5157–61PubMedGoogle Scholar
  73. 73.
    Sheskin J, Convit J. Results of a double blind study of the influence of thalidomide on the lepra reaction. Int J Lepr Other Mycobact Dis 1969; 37: 135–46PubMedGoogle Scholar
  74. 74.
    Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med 1999; 341: 1565–71PubMedCrossRefGoogle Scholar
  75. 75.
    Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor-alpha neutralizing agent. N Engl J Med 2001; 345: 1098–104PubMedCrossRefGoogle Scholar
  76. 76.
    Lofberg R. Treatment of fistulas in Crohn’s disease with infliximab. Gut 1999; 45: 642–3PubMedCrossRefGoogle Scholar
  77. 77.
    Lovell DJ, Giannini EH, Reiff A, et al. Etanercept in children with polyarticular juvenile rheumatoid arthritis: Pediatrie Rheumatology Collaborative Study Group. N Engl J Med 2000; 342: 763–9PubMedCrossRefGoogle Scholar
  78. 78.
    Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354: 1932–9PubMedCrossRefGoogle Scholar
  79. 79.
    Sandborn WJ, Hanauer SB. Antitumor necrosis factor therapy for inflammatory bowel disease: a review of agents, pharmacology, clinical results, and safety. Inflamm Bowel Dis 1999; 5: 119–33PubMedCrossRefGoogle Scholar
  80. 80.
    Rutgeerts P, D’Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn’s disease. Gastroenterology 1999; 117: 761–9PubMedCrossRefGoogle Scholar
  81. 81.
    Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2001; 18: 70–4PubMedGoogle Scholar
  82. 82.
    Yee AMF, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis-alpha therapy. Ann Intern Med 2001; 135: 27–31PubMedGoogle Scholar
  83. 83.
    Alabi OF, Lower EE, Baughman RP. Use of infliximab in refractory sarcoidosis [abstract]. Am J Respir Crit Care Med 2001; 163: A557Google Scholar
  84. 84.
    Baughman RP, Bradley DA, Raymond LA, et al. Double blind randomized trial of a tumor necrosis factor receptor antagonist (etanercept) for treatment of chronic ocular sarcoidosis [abstract]. Am J Respir Crit Care Med 2002; 165: A495Google Scholar
  85. 85.
    Smith JR, Levinson RD, Holland GN, et al. Differential efficacy of tumor necrosis factor inhibition in the management of inflammatory eye disease and associated rheumatic disease. Arthritis Rheum 2001; 45: 252–7PubMedCrossRefGoogle Scholar
  86. 86.
    Sfikakis PP, Theodossiadis PG, Katsiari CG, et al. Effect of infliximab on sight-threatening panuveitis in Behcet’s disease. Lancet 2001; 358: 295–6PubMedCrossRefGoogle Scholar
  87. 87.
    LaDuca JR, Gaspari AA. Targeting tumor necrosis factor alpha: new drugs used to modulate inflammatory diseases. Dermatol Clin 2001; 19(4): 617–35PubMedCrossRefGoogle Scholar
  88. 88.
    Maini RN, Taylor PC. Anti-cytokine therapy for rheumatoid arthritis. Ann Rev Med 2000; 51: 207–29PubMedCrossRefGoogle Scholar
  89. 89.
    Baughman RP, Lower EE. Can persistent tumor necrosis factor release lead to refractory sarcoidosis? Sarcoidosis Vasc Diffuse Lung Dis 2002; 19: 164–6PubMedGoogle Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Interstitial Lung Disease and Sarcoidosis ClinicUniversity of Cincinnati Medical CenterCincinnatiUSA
  2. 2.Henry Ford HospitalCase Western Reserve UniversityDetroitUSA
  3. 3.University of CincinnatiCincinnatiUSA

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