The American Journal of Medicine
Volume 119, Issue 8 , Pages 639-646 , August 2006

Pulmonary Adverse Events of Anti-Tumor Necrosis Factor-α Antibody Therapy

  • Gökhan M. Mutlu, MD

      Affiliations

    • Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
    • Corresponding Author InformationRequests for reprints should be addressed to Gökhan M. Mutlu, MD, Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, 240 East Huron Street, McGaw Building, Room 2342, Chicago, IL 60611.
  • ,
  • Ece A. Mutlu, MD

      Affiliations

    • Departments of Gastroenterology and Nutrition, Rush University Medical College, Chicago, Ill
  • ,
  • Amy Bellmeyer, MS

      Affiliations

    • Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, Ill
  • ,
  • Israel Rubinstein, MD

      Affiliations

    • Pulmonary, Critical Care and Sleep Medicine, University of Illinois at Chicago and Jesse Brown Veterans Administration Medical Center, Chicago, Ill

References 

  1. Lipsky PE, van der Heijde DM, St Clair EW, et al. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343:1594–1602
  2. Maini R, St Clair EW, Breedveld F, et al. ATTRACT Study Group Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate (a randomised phase III trial). Lancet. 1999;354:1932–1939
  3. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med. 2001;345:1098–1104
  4. Papadakis KA, Targan SR. Tumor necrosis factor (biology and therapeutic inhibitors). Gastroenterology. 2000;119(4):1148–1157
  5. Beutler B, Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986;320:584–588
  6. Choy EH, Panayi GS. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Engl J Med. 2001;344:907–916
  7. Grell M, Douni E, Wajant H, et al. The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor. Cell. 1995;83:793–802
  8. Bean AG, Roach DR, Briscoe H, et al. Structural deficiencies in granuloma formation in TNF gene-targeted mice underlie the heightened susceptibility to aerosol Mycobacterium tuberculosis infection, which is not compensated for by lymphotoxin. J Immunol. 1999;162:3504–3511
  9. Pfeffer K, Matsuyama T, Kundig TM, et al. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell. 1993;73:457–467
  10. Atkinson YH, Marasco WA, Lopez AF, Vadas MA. Recombinant human tumor necrosis factor-alpha. Regulation of N-formylmethionylleucylphenylalanine receptor affinity and function on human neutrophils. J Clin Invest. 1988;81:759–765
  11. Klebanoff SJ, Vadas MA, Harlan JM, et al. Stimulation of neutrophils by tumor necrosis factor. J Immunol. 1986;136:4220–4225
  12. Shalaby MR, Aggarwal BB, Rinderknecht E, Svedersky LP, Finkle BS, Palladino MA. Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985;135:2069–2073
  13. Perussia B, Kobayashi M, Rossi ME, Anegon I, Trinchieri G. Immune interferon enhances functional properties of human granulocytes (role of Fc receptors and effect of lymphotoxin, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor). J Immunol. 1987;138:765–774
  14. Kindler V, Sappino AP, Grau GE, Piguet PF, Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989;56:731–740
  15. Balcewicz-Sablinska MK, Keane J, Kornfeld H, Remold HG. Pathogenic Mycobacterium tuberculosis evades apoptosis of host macrophages by release of TNF-R2, resulting in inactivation of TNF-alpha. J Immunol. 1998;161:2636–2641
  16. Keane J, Remold HG, Kornfeld H. Virulent Mycobacterium tuberculosis strains evade apoptosis of infected alveolar macrophages. J Immunol. 2000;164:2016–2020
  17. Bekker LG, Moreira AL, Bergtold A, Freeman S, Ryffel B, Kaplan G. Immunopathologic effects of tumor necrosis factor alpha in murine mycobacterial infection are dose dependent. Infect Immun. 2000;68:6954–6961
  18. Gardam MA, Keystone EC, Menzies R, et al. Anti-tumour necrosis factor agents and tuberculosis risk (mechanisms of action and clinical management). Lancet Infect Dis. 2003;3:148–155
  19. Kawakami K, Qureshi MH, Koguchi Y, et al. Role of TNF-alpha in the induction of fungicidal activity of mouse peritoneal exudate cells against Cryptococcus neoformans by IL-12 and IL-18. Cell Immunol. 1999;193:9–16
  20. Schaffner A, Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest. 1982;69:617–631
  21. Diamond RD, Krzesicki R, Jao W. Damage to pseudohyphal forms of Candida albicans by neutrophils in the absence of serum in vitro. J Clin Invest. 1978;61:349–359
  22. Mehrad B, Strieter RM, Standiford TJ. Role of TNF-alpha in pulmonary host defense in murine invasive aspergillosis. J Immunol. 1999;162:1633–1640
  23. Nagai H, Guo J, Choi H, Kurup V. Interferon-gamma and tumor necrosis factor-alpha protect mice from invasive aspergillosis. J Infect Dis. 1995;172:1554–1560
  24. Roilides E, Dimitriadou-Georgiadou A, Sein T, Kadiltsoglou I, Walsh TJ. Tumor necrosis factor alpha enhances antifungal activities of polymorphonuclear and mononuclear phagocytes against Aspergillus fumigatus. Infect Immun. 1998;66:5999–6003
  25. Louie A, Baltch AL, Smith RP, et al. Tumor necrosis factor alpha has a protective role in a murine model of systemic candidiasis. Infect Immun. 1994;62:2761–2772
  26. Steinshamn S, Bemelmans MH, van Tits LJ, Bergh K, Buurman WA, Waage A. TNF receptors in murine Candida albicans infection (evidence for an important role of TNF receptor p55 in antifungal defense). J Immunol. 1996;157:2155–2159
  27. Aguirre K, Havell EA, Gibson GW, Johnson LL. Role of tumor necrosis factor and gamma interferon in acquired resistance to Cryptococcus neoformans in the central nervous system of mice. Infect Immun. 1995;63:1725–1731
  28. Scallon B, Cai A, Solowski N, et al. Binding and functional comparisons of two types of tumor necrosis factor antagonists. J Pharmacol Exp Ther. 2002;301:418–426
  29. Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol. 1993;30:1443–1453
  30. Scallon BJ, Moore MA, Trinh H, Knight DM, Ghrayeb J. Chimeric anti-TNF-alpha monoclonal antibody cA2 binds recombinant transmembrane TNF-alpha and activates immune effector functions. Cytokine. 1995;7:251–259
  31. Lugering A, Schmidt M, Lugering N, Pauels HG, Domschke W, Kucharzik T. Infliximab induces apoptosis in monocytes from patients with chronic active Crohn’s disease by using a caspase-dependent pathway. Gastroenterology. 2001;121:1145–1157
  32. Lucas R, Tacchini-Cottier F, Guler R, et al. A role for lymphotoxin beta receptor in host defense against Mycobacterium bovis BCG infection. Eur J Immunol. 1999;29:4002–4010
  33. Infliximab (Remicade) for Crohn’s disease. Med Lett Drugs Ther. 1999;41:19–20
  34. Amiri P, Locksley RM, Parslow TG, et al. Tumour necrosis factor alpha restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature. 1992;356:604–607
  35. Piguet PF, Collart MA, Grau GE, Sappino AP, Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature. 1990;344:245–247
  36. Miyazaki Y, Araki K, Vesin C, et al. Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. J Clin Invest. 1995;96:250–259
  37. Baughman RP, Lower EE. Infliximab for refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2001;18:70–74
  38. Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med. 2001;135:27–31
  39. Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest. 2003;124:177–185
  40. Stone JH, Uhlfelder ML, Hellmann DB, Crook S, Bedocs NM, Hoffman GS. Etanercept combined with conventional treatment in Wegener’s granulomatosis (a six-month open-label trial to evaluate safety). Arthritis Rheum. 2001;44:1149–1154
  41. Deguchi Y, Shibata N, Kishimoto S. Enhanced expression of the tumour necrosis factor/cachectin gene in peripheral blood mononuclear cells from patients with systemic vasculitis. Clin Exp Immunol. 1990;81:311–314
  42. The Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J Med. 2005;352:351–361
  43. Piguet PF, Vesin C. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur Respir J. 1994;7:515–518
  44. Vassallo R, Matteson E, Thomas CF. Clinical response of rheumatoid arthritis-associated pulmonary fibrosis to tumor necrosis factor-alpha inhibition. Chest. 2002;122:1093–1096
  45. Bargagli E, Galeazzi M, Rottoli P. Infliximab treatment in a patient with rheumatoid arthritis and pulmonary fibrosis. Eur Respir J. 2004;24:708
  46. Alrashid AI, Brown RD, Mihalov ML, Sekosan M, Pastika BJ, Venu RP. Crohn’s disease involving the lung (resolution with infliximab). Dig Dis Sci. 2001;46:1736–1739
  47. Keane J, Gershon SK, Braun MM. Tuberculosis and treatment with infliximab. N Engl J Med. 2002;346:623–626
  48. Myers A, Clark J, Foster H. Tuberculosis and treatment with infliximab. N Engl J Med. 2002;346:623–626
  49. van der Klooster JM, Bosman RJ, Oudemans-van Straaten HM, van der Spoel JI, Wester JP, Zandstra DF. Disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex infection in a patient with infliximab and methotrexate. Intensive Care Med. 2003;29:2327–2329
  50. Mayordomo L, Marenco JL, Gomez-Mateos J, Rejon E. Pulmonary miliary tuberculosis in a patient with anti-TNF-alpha treatment. Scand J Rheumatol. 2002;31:44–45
  51. Uthman I, Sharara A. The usefulness of PPD testing in inflammatory bowel disease patients before infliximab therapy. Clin Gastroenterol Hepatol. 2004;2:xxii
  52. Centers for Disease Control and Prevention (CDC). Reported Tuberculosis in the United States, 1999. Atlanta, GA: US Department of Health and Human Services, CDC; 2000;
  53. Centers for Disease Control and Prevention (CDC). Reported Tuberculosis in the United States, 2000. Atlanta, GA: US Department of Health and Human Services, CDC; 2001;
  54. Wolfe F, Michaud K, Anderson J, Urbansky K. Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy. Arthritis Rheum. 2004;50:372–379
  55. Wallis RS, Broder MS, Wong JY, Hanson ME, Beenhouwer DO. Granulomatous infectious diseases associated with tumor necrosis factor antagonists. Clin Infect Dis. 2004;38:1261–1265
  56. Wallis RS, Broder M, Wong J, Beenhouwer D. Reply to Schaible TF. Clin Infect Dis. 2004;39:1256
  57. Warris A, Bjorneklett A, Gaustad P. Invasive pulmonary aspergillosis associated with infliximab therapy. N Engl J Med. 2001;344:1099–1100
  58. Zhang Z, Correa H, Begue RE. Tuberculosis and treatment with infliximab. N Engl J Med. 2002;346:623–626
  59. Nakelchik M, Mangino JE. Reactivation of histoplasmosis after treatment with infliximab. Am J Med. 2002;112:78
  60. Hage CA, Wood KL, Winer-Muram HT, Wilson SJ, Sarosi G, Knox KS. Pulmonary cryptococcosis after initiation of anti-tumor necrosis factor-alpha therapy. Chest. 2003;124:2395–2397
  61. True DG, Penmetcha M, Peckham SJ. Disseminated cryptococcal infection in rheumatoid arthritis treated with methotrexate and infliximab. J Rheumatol. 2002;29:1561–1563
  62. Lassoued S, Sire S, Farny M, Billey T, Lassoued K. Pulmonary aspergillosis in a patient with rheumatoid arthritis treated by etanercept. Clin Exp Rheumatol. 2004;22:267–268
  63. Kaiser MJ, Bozonnat MC, Jorgensen C, Daures JP, Sany J. Effect of etanercept on tenosynovitis and nodules in rheumatoid arthritis. Arthritis Rheum. 2002;46:559–560
  64. Kekow J, Welte T, Kellner U, Pap T. Development of rheumatoid nodules during anti-tumor necrosis factor alpha therapy with etanercept. Arthritis Rheum. 2002;46:843–844
  65. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum. 2002;47:445–449
  66. Hubscher O, Re R, Iotti R. Pulmonary rheumatoid nodules in an etanercept-treated patient. Arthritis Rheum. 2003;48:2077–2078
  67. Ostor AJ, Crisp AJ, Somerville MF, Scott DG. Fatal exacerbation of rheumatoid arthritis associated fibrosing alveolitis in patients given infliximab. BMJ. 2004;329:1266
  68. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab (a randomised controlled multicentre trial). Lancet. 2002;359:1187–1193
  69. Peno-Green L, Lluberas G, Kingsley T, Brantley S. Lung injury linked to etanercept therapy. Chest. 2002;122:1858–1860
  70. Courtney PA, Alderdice J, Whitehead EM. Comment on methotrexate pneumonitis after initiation of infliximab therapy for rheumatoid arthritis. Arthritis Rheum. 2003;49:617
  71. Yousem SA, Dacic S. Pulmonary lymphohistiocytic reactions temporally related to etanercept therapy. Mod Pathol. 2004;18:651–655
  72. Vavricka SR, Wettstein T, Speich R, Gaspert A, Bachli EB. Pulmonary granulomas after tumour necrosis factor alpha antagonist therapy. Thorax. 2003;58:278–279
  73. Mazurek GH, Villarino ME Centers for Disease Control and Prevention. Guidelines for using the QuantiFERON-TB test for diagnosing latent Mycobacterium tuberculosis infection. MMWR Recomm Rep. 2003;52:15–18
  74. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement Am J Respir Crit Care Med. 2000;161:S221–S247
  75. Wang L, Turner MO, Elwood RK, Schulzer M, FitzGerald JM. A meta-analysis of the effect of Bacille Calmette Guerin vaccination on tuberculin skin test measurements. Thorax. 2002;57:804–809
  76. Hernandez-Cruz B, Ponce-de-Leon-Rosales S, Sifuentes-Osornio J, Ponce-de-Leon-Garduno A, Diaz-Jouanen E. Tuberculosis prophylaxis in patients with steroid treatment and systemic rheumatic diseases. A case-control study. Clin Exp Rheumatol. 1999;17:81–87
  77. Wagner TE, Huseby ES, Huseby JS. Exacerbation of Mycobacterium tuberculosis enteritis masquerading as Crohn’s disease after treatment with a tumor necrosis factor-alpha inhibitor. Am J Med. 2002;112:67–69
  78. Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med. 2001;345:189–200
  79. International Union Against Tuberculosis Committee on Prophylaxis. Efficacy of various durations of isoniazid preventive therapy for tuberculosis (five years of follow-up in the IUAT trial). Bull World Health Organ. 1982;60:555–564

 This work was supported in part by the American Lung Association, and the American Lung Association of Metropolitan Chicago (G.M.M.), National Institute of Diabetes & Digestive & Kidney Diseases (E.A.M.), National Institute on Aging and Veterans Administration (I.R.).

PII: S0002-9343(06)00153-7

doi: 10.1016/j.amjmed.2006.01.015

The American Journal of Medicine
Volume 119, Issue 8 , Pages 639-646 , August 2006