American Journal of Ophthalmology
Volume 146, Issue 6 , Pages 802-812.e1 , December 2008

Long-term Risk of Malignancy Among Patients Treated With Immunosuppressive Agents for Ocular Inflammation: A Critical Assessment of the Evidence

  • John H. Kempen

      Affiliations

    • Ocular Inflammation Service, Scheie Eye Institute, The University of Pennsylvania, Philadelphia, Pennsylvania
    • Center for Preventive Ophthalmology and Biostatistics, Department of Ophthalmology, The University of Pennsylvania, Philadelphia, Pennsylvania
    • Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, The University of Pennsylvania, Philadelphia, Pennsylvania
    • Corresponding Author InformationInquiries to John H. Kempen, Center for Preventive Ophthalmology and Biostatistics, Department of Ophthalmology, University of Pennsylvania, 3535 Market St., Suite 700, Philadelphia, PA 19104
  • ,
  • Sapna Gangaputra

      Affiliations

    • Department of Ophthalmology, The Johns Hopkins University, Baltimore, Maryland
  • ,
  • Ebenezer Daniel

      Affiliations

    • Department of Ophthalmology, The Johns Hopkins University, Baltimore, Maryland
  • ,
  • Grace A. Levy-Clarke

      Affiliations

    • St Luke's Cataract and Laser Institute, Tarpon Springs, Florida
    • Laboratory of Immunology, National Eye Institute, Bethesda, Maryland
  • ,
  • Robert B. Nussenblatt

      Affiliations

    • Laboratory of Immunology, National Eye Institute, Bethesda, Maryland
  • ,
  • James T. Rosenbaum

      Affiliations

    • Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon
    • Department of Medicine, Oregon Health and Science University, Portland, Oregon
  • ,
  • Eric B. Suhler

      Affiliations

    • Department of Ophthalmology, Oregon Health and Science University, Portland, Oregon
    • Portland Veterans' Affairs Medical Center, Portland, Oregon
  • ,
  • Jennifer E. Thorne

      Affiliations

    • Department of Ophthalmology, The Johns Hopkins University, Baltimore, Maryland
    • Department of Epidemiology, The Johns Hopkins University, Baltimore, Maryland
  • ,
  • C. Stephen Foster

      Affiliations

    • Massachusetts Eye Research and Surgery Institute, Cambridge, Massachusetts
    • Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
  • ,
  • Douglas A. Jabs

      Affiliations

    • Department of Ophthalmology, The Johns Hopkins University, Baltimore, Maryland
    • Department of Epidemiology, The Johns Hopkins University, Baltimore, Maryland
    • Department of Ophthalmology, Mount Sinai School of Medicine, New York, New York
  • ,
  • Kathy J. Helzlsouer

      Affiliations

    • Department of Epidemiology, The Johns Hopkins University, Baltimore, Maryland
    • Center for Prevention and Research at Mercy, Mercy Medical Center, Baltimore, Maryland

,Accepted 29 April 2008.

References 

  1. Gordon DM. Prednisone and prednisolone in ocular disease. Am J Ophthalmol. 1956;41:593–600
  2. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492–513
  3. Lindelof B, Sigurgeirsson B, Gabel H, Stern RS. Incidence of skin cancer in 5,356 patients following organ transplantation. Br J Dermatol. 2000;143:513–519
  4. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation. 1990;49:506–509
  5. McGregor JM, Berkhout RJ, Rozycka M, et al. p53 mutations implicate sunlight in post-transplant skin cancer irrespective of human papillomavirus status. Oncogene. 1997;15:1737–1740
  6. Iftner A, Klug SJ, Garbe C, et al. The prevalence of human papillomavirus genotypes in nonmelanoma skin cancers of nonimmunosuppressed individuals identifies high-risk genital types as possible risk factors. Cancer Res. 2003;63:7515–7519
  7. Blohme I, Larko O. Skin lesions in renal transplant patients after 10 to 23 years of immunosuppressive therapy. Acta Derm Venereol. 1990;70:491–494
  8. Snow AL, Martinez OM. Epstein-Barr virus: evasive maneuvers in the development of PTLD. Am J Transplant. 2007;7:271–277
  9. Preiksaitis JK, Keay S. Diagnosis and management of posttransplant lymphoproliferative disorder in solid-organ transplant recipients. Clin Infect Dis. 2001;33:S38–S46
  10. Starzl TE, Nalesnik MA, Porter KA, et al. Reversibility of lymphomas and lymphoproliferative lesions developing under cyclosporin-steroid therapy. Lancet. 1984;323:583–587
  11. Salloum E, Cooper DL, Howe G, et al. Spontaneous regression of lymphoproliferative disorders in patients treated with methotrexate for rheumatoid arthritis and other rheumatic diseases. J Clin Oncol. 1996;14:1943–1949
  12. Swinnen LJ, Mullen GM, Carr TJ, Costanzo MR, Fisher RI. Aggressive treatment for postcardiac transplant lymphoproliferation. Blood. 1995;86:3333–3340
  13. Birkeland SA, Hamilton-Dutoit S. Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se?. Transplantation. 2003;76:984–988
  14. Hunt SA. Malignancy in organ transplantation: heart. Transplant Proc. 2002;34:1874–1876
  15. Penn I. The effect of immunosuppression on pre-existing cancers. Transplantation. 1993;55:742–747
  16. Pedersen-Bjergaard J, Ersboll J, Hansen VL, et al. Carcinoma of the urinary bladder after treatment with cyclophosphamide for non-Hodgkin's lymphoma. N Engl J Med. 1988;318:1028–1032
  17. Radis CD, Kahl LE, Baker GL, 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
  18. Fairchild WV, Spence CR, Solomon HD, Gangai MP. The incidence of bladder cancer after cyclophosphamide therapy. J Urol. 1979;122:163–164
  19. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116:488–498
  20. Puri HC, Campbell RA. Cyclophosphamide and malignancy. Lancet. 1977;309:1306
  21. Tucker MA, Meadows AT, Boice JD, et al. Leukemia after therapy with alkylating agents for childhood cancer. J Natl Cancer Inst. 1987;78:459–464
  22. Baker GL, Kahl LE, Zee BC, Stolzer BL, Agarwal AK, Medsger TA. Malignancy following treatment of rheumatoid arthritis with cyclophosphamide (Long-term case-control follow-up study). Am J Med. 1987;83:1–9
  23. Baltus JA, Boersma JW, Hartman AP, Vandenbroucke JP. The occurrence of malignancies in patients with rheumatoid arthritis treated with cyclophosphamide: a controlled retrospective follow-up. Ann Rheum Dis. 1983;42:368–373
  24. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst. 1995;87:524–530
  25. Schmahl D, Habs M, Tacchi AM. Prevention of tumor formation in the bladder by sodium-2-mercaptoethane sulfonate (mesna) (Experimental studies and clinical consequences). Urologe A. 1984;23:291–296
  26. Chabner BA. Second neoplasm—a complication of cancer chemotherapy. N Engl J Med. 1977;297:213–215
  27. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124:477–484
  28. Shepherd JD, Pringle LE, Barnett MJ, Klingemann HG, Reece DE, Phillips GL. Mesna versus hyperhydration for the prevention of cyclophosphamide-induced hemorrhagic cystitis in bone marrow transplantation. J Clin Oncol. 1991;9:2016–2020
  29. Patapanian H, Graham S, Sambrook PN, et al. The oncogenicity of chlorambucil in rheumatoid arthritis. Br J Rheumatol. 1988;27:44–47
  30. Lerner HJ. Acute myelogenous leukemia in patients receiving chlorambucil as long-term adjuvant chemotherapy for stage II breast cancer. Cancer Treat Rep. 1978;62:1135–1138
  31. Boivin JF, Hutchison GB, Zauber AG, et al. Incidence of second cancers in patients treated for Hodgkin's disease. J Natl Cancer Inst. 1995;87:732–741
  32. Berk PD, Goldberg JD, Silverstein MN, et al. Increased incidence of acute leukemia in polycythemia vera associated with chlorambucil therapy. N Engl J Med. 1981;304:441–447
  33. Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature. 1999;397:530–534
  34. York LJ, Qualtiere LF. Cyclosporin abrogates virus-specific T-cell control of EBV-induced B-cell lymphoproliferation. Viral Immunol. 1990;3:127–136
  35. Birkeland SA, Bendtzen K, Moller B, Hamilton-Dutoit S, Andersen HK. Interleukin-10 and posttransplant lymphoproliferative disorder after kidney transplantation. Transplantation. 1999;67:876–881
  36. Palanduz S, Sever MS, Ozturk S, et al. Genotoxic potential of cyclosporin A in patients with renal transplantation. Cell Biol Toxicol. 1999;15:13–17
  37. Yuzawa K, Kondo I, Fukao K, Iwasaki Y, Hamaguchi H. Mutagenicity of cyclosporine (Induction of sister chromatid exchange in human cells). Transplantation. 1986;42:61–63
  38. Zwanenburg TS, Suter W, Matter BE. Absence of genotoxic potential for cyclosporine in experimental systems. Transplant Proc. 1988;20:931–933
  39. Dantal J, Hourmant M, Cantarovich D, et al. Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet. 1998;351:623–628
  40. McGeown MG, Douglas JF, Middleton D. One thousand renal transplants at Belfast City Hospital: post-graft neoplasia 1968–1999, comparing azathioprine only with cyclosporin-based regimes in a single center. Clin Transpl. 2000;193–202
  41. Van den Borne BE, Landewe RB, Houkes I, et al. No increased risk of malignancies and mortality in cyclosporin A–treated patients with rheumatoid arthritis. Arthritis Rheum. 1998;41:1930–1937
  42. Paul CF, Ho VC, McGeown C, et al. Risk of malignancies in psoriasis patients treated with cyclosporine: a 5-year cohort study. J Invest Dermatol. 2003;120:211–216
  43. Caillard S, Dharnidharka V, Agodoa L, Bohen E, Abbott K. Posttransplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression. Transplantation. 2005;80:1233–1243
  44. Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant. 2004;4:222–230
  45. Dharnidharka VR, Sullivan EK, Stablein DM, Tejani AH, Harmon WE. Risk factors for posttransplant lymphoproliferative disorder (PTLD) in pediatric kidney transplantation: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Transplantation. 2001;71:1065–1068
  46. Younes BS, McDiarmid SV, Martin MG, et al. The effect of immunosuppression on posttransplant lymphoproliferative disease in pediatric liver transplant patients. Transplantation. 2000;70:94–99
  47. Mithoefer AB, Supran S, Freeman RB. Risk factors associated with the development of skin cancer after liver transplantation. Liver Transpl. 2002;8:939–944
  48. Frezza EE, Fung JJ, van Thiel DH. Non-lymphoid cancer after liver transplantation. Hepatogastroenterology. 1997;44:1172–1181
  49. Jonas S, Rayes N, Neumann U, et al. De novo malignancies after liver transplantation using tacrolimus-based protocols or cyclosporine-based quadruple immunosuppression with an interleukin-2 receptor antibody or antithymocyte globulin. Cancer. 1997;80:1141–1150
  50. Yakupoglu YK, Buell JF, Woodle S, Kahan BD. Individualization of immunosuppressive therapy. III. Sirolimus associated with a reduced incidence of malignancy. Transplant Proc. 2006;38:358–361
  51. Huang S, Houghton PJ. Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs. 2002;3:295–304
  52. Brenneisen P, Wenk J, Wlaschek M, Krieg T, Scharffetter-Kochanek K. Activation of p70 ribosomal protein S6 kinase is an essential step in the DNA damage-dependent signaling pathway responsible for the ultraviolet B-mediated increase in interstitial collagenase (MMP-1) and stromelysin-1 (MMP-3) protein levels in human dermal fibroblasts. J Biol Chem. 2000;275:4336–4344
  53. Mathew T, Kreis H, Friend P. Two-year incidence of malignancy in sirolimus-treated renal transplant recipients: results from five multicenter studies. Clin Transplant. 2004;18:446–449
  54. Connell WR, Kamm MA, Dickson M, Balkwill AM, Ritchie JK, Lennard-Jones JE. Long-term neoplasia risk after azathioprine treatment in inflammatory bowel disease. Lancet. 1994;343:1249–1252
  55. Singh G, Fries JF, Spitz P, Williams CA. Toxic effects of azathioprine in rheumatoid arthritis (A national post-marketing perspective). Arthritis Rheum. 1989;32:837–843
  56. Castor CW, Bull FE. Review of United States data on neoplasms in rheumatoid arthritis. Am J Med. 1985;78:33–38
  57. Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther. 2002;16:1225–1232
  58. Hazleman BL. The comparative incidence of malignant disease in rheumatoid arthritics exposed to different treatment regimens. Ann Rheum Dis. 1982;41:12–17
  59. Confavreux C, Saddier P, Grimaud J, Moreau T, Adeleine P, Aimard G. Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control study. Neurology. 1996;46:1607–1612
  60. Kwon JH, Farrell RJ. The risk of lymphoma in the treatment of inflammatory bowel disease with immunosuppressive agents. Crit Rev Oncol Hematol. 2005;56:169–178
  61. Jensen P, Moller B, Hansen S. Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol. 2000;42:307
  62. Bailin PL, Tindall JP, Roenigk HH, Hogan MD. Is methotrexate therapy for psoriasis carcinogenic? (A modified retrospective-prospective analysis). JAMA. 1975;232:359–362
  63. Nyfors A, Jensen H. Frequency of malignant neoplasms in 248 long-term methotrexate-treated psoriatics (A preliminary study). Dermatologica. 1983;167:260–261
  64. Rustin GJ, Newlands ES, Lutz JM, et al. Combination but not single-agent methotrexate chemotherapy for gestational trophoblastic tumors increases the incidence of second tumors. J Clin Oncol. 1996;14:2769–2773
  65. Alarcon GS, Tracy IC, Strand GM, Singh K, Macaluso M. Survival and drug discontinuation analyses in a large cohort of methotrexate treated rheumatoid arthritis patients. Ann Rheum Dis. 1995;54:708–712
  66. Tishler M, Caspi D, Yaron M. Long-term experience with low-dose methotrexate in rheumatoid arthritis. Rheumatol Int. 1993;13:103–106
  67. Georgescu L, Quinn GC, Schwartzman S, Paget SA. Lymphoma in patients with rheumatoid arthritis: association with the disease state or methotrexate treatment. Semin Arthritis Rheum. 1997;26:794–804
  68. Wolfe F, Michaud K. The effect of methotrexate and anti–tumor necrosis factor therapy on the risk of lymphoma in rheumatoid arthritis in 19,562 patients during 89,710 person-years of observation. Arthritis Rheum. 2007;56:1433–1439
  69. O'Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25:1186–1191
  70. David KM, Morris JA, Steffen BJ, Chi-Burris KS, Gotz VP, Gordon RD. Mycophenolate mofetil vs. azathioprine is associated with decreased acute rejection, late acute rejection, and risk for cardiovascular death in renal transplant recipients with pre-transplant diabetes. Clin Transplant. 2005;19:279–285
  71. Wang K, Zhang H, Li Y, et al. Safety of mycophenolate mofetil versus azathioprine in renal transplantation: a systematic review. Transplant Proc. 2004;36:2068–2070
  72. Leckel K, Beecken WD, Jonas D, et al. The immunosuppressive drug mycophenolate mofetil impairs the adhesion capacity of gastrointestinal tumour cells. Clin Exp Immunol. 2003;134:238–245
  73. Engl T, Makarevic J, Relja B, et al. Mycophenolate mofetil modulates adhesion receptors of the beta1 integrin family on tumor cells: impact on tumor recurrence and malignancy. BMC Cancer. 2005;5:4
  74. Vegso G, Sebestyen A, Paku S, et al. Antiproliferative and apoptotic effects of mycophenolic acid in human B-cell non-Hodgkin lymphomas. Leuk Res. 2007;31:1003–1008
  75. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA. 2006;295:2275–2285
  76. Bongartz T, Matteson EL, Montori VM, Sutton AJ, Sweeting M, Buchan I. Author reply: Anti-TNF Antibody Therapy in Rheumatoid Arthritis and the Risk of Serious Infections and Malignancies. JAMA. 2006;296:2203–2204
  77. Okada SK, Siegel JN. Risk of serious infections and malignancies with anti-TNF antibody therapy in rheumatoid arthritis. JAMA. 2006;296:2201–2202
  78. Stone JH, Holbrook JT, Marriott MA, et al. Solid malignancies among patients in the Wegener's Granulomatosis Etanercept Trial. Arthritis Rheum. 2006;54:1608–1618
  79. Setoguchi S, Solomon DH, Weinblatt ME, et al. Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2757–2764
  80. Fleischmann RM, Tesser J, Schiff MH, et al. Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:1006–1012
  81. Lebwohl M, Blum R, Berkowitz E, et al. No evidence for increased risk of cutaneous squamous cell carcinoma in patients with rheumatoid arthritis receiving etanercept for up to 5 years. Arch Dermatol. 2005;141:861–864
  82. Jacobsson LT, Turesson C, Nilsson JA, et al. Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66:670–675
  83. Askling J, Fored CM, Brandt L, et al. Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists. Ann Rheum Dis. 2005;64:1421–1426
  84. Askling J, Fored CM, Baecklund E, et al. Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists. Ann Rheum Dis. 2005;64:1414–1420
  85. Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: analyses from a large US observational study. Arthritis Rheum. 2007;56:2886–2895
  86. Carmona L, Descalzo MA, Perez-Pampin E, et al. All-cause and cause-specific mortality in rheumatoid arthritis are not greater than expected when treated with tumour necrosis factor antagonists. Ann Rheum Dis. 2007;66:880–885
  87. Geborek P, Bladstrom A, Turesson C, et al. Tumour necrosis factor blockers do not increase overall tumour risk in patients with rheumatoid arthritis, but may be associated with an increased risk of lymphomas. Ann Rheum Dis. 2005;64:699–703
  88. Biancone L, Orlando A, Kohn A, et al. Infliximab and newly diagnosed neoplasia in Crohn's disease: a multicentre matched pair study. Gut. 2006;55:228–233
  89. Webster AC, Playford EG, Higgins G, Chapman JR, Craig JC. Interleukin 2 receptor antagonists for renal transplant recipients: a meta-analysis of randomized trials. Transplantation. 2004;77:166–176
  90. Waldmann TA. Daclizumab (anti-Tac, Zenapax) in the treatment of leukemia/lymphoma. Oncogene. 2007;26:3699–3703
  91. Lane L, Tamesis R, Rodriguez A, et al. Systemic immunosuppressive therapy and the occurrence of malignancy in patients with ocular inflammatory disease. Ophthalmology. 1995;102:1530–1535
  92. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med. 1999;340:115–126
  93. Beauparlant P, Papp K, Haraoui B. The incidence of cancer associated with the treatment of rheumatoid arthritis. Semin Arthritis Rheum. 1999;29:148–158
  94. Harper DM, Franco EL, Wheeler CM, et al. Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet. 2006;367:1247–1255
  95. Wolfe F, Michaud K. Lymphoma in rheumatoid arthritis: the effect of methotrexate and anti–tumor necrosis factor therapy in 18,572 patients. Arthritis Rheum. 2004;50:1740–1751
  96. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359:1173–1177

PII: S0002-9394(08)00337-1

doi: 10.1016/j.ajo.2008.04.035

American Journal of Ophthalmology
Volume 146, Issue 6 , Pages 802-812.e1 , December 2008