Drug Safety

, Volume 33, Issue 11, pp 969–983 | Cite as

Progressive Multif ocal Leukoencephalopathy and Newer Biological Agents

Review Article


Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease of the brain due to a polyoma virus, JC virus. Despite the ubiquity of this virus, PML is rare and almost always seen in association with an underlying immunosuppressive condition. In the last 30 years, AIDS has been the most common predisposing factor. The observation of PML attending the use of certain monoclonal antibody therapies and other pharmacological agents has raised concerns about the safety profile of these agents, but has also provided a window into the pathogenesis of PML. Certain agents, such as the monoclonal antibodies natalizumab, an α4b1 and α4β7 integrin inhibitor, and efalizumab, an antibody directed against CD11a, appear to uniquely predispose to PML. Prior to their introduction for multiple sclerosis and Crohn’s disease with respect to natalizumab, and psoriasis with respect to efalizumab, PML had never been observed with these disorders. PML occurring with other agents that currently carry US FDA-mandated ‘black-box’ warnings, such as rituximab, an antibody directed to CD20, or mycophenolate mofetil, a drug that inhibits T- and B-cell proliferation, typically occur in the background of underlying disorders that have already been identified as risks for PML. This review will focus on the available data regarding the risk for PML with monoclonal antibodies and other drugs. A biologically plausible explanation for the increased risk of PML will be proposed, as well as potential strategies for mitigating disease risk.



Dr Berger has received research funding from Bayer, EMD-Serono and Biogen, and speakers honoraria from Bayer, EMD Serono and Teva. He has served as a consultant to Asphelia, Astellas, Bayer, Biogen, Genentech, GlaxoSmithKline, Millenium and Pfizer. No funding was provided for the preparation of this review.


  1. 1.
    Valuck RJ, Libby AM, Sills MR, et al. Antidepressant treatment and risk of suicide attempt by adolescents with major depressive disorder: a propensity-adjusted retrospective cohort study. CNS Drugs 2004; 18(15): 1119–32PubMedCrossRefGoogle Scholar
  2. 2.
    Cheng AY, Fantus IG. Thiazolidinedione-induced congestive heart failure. Ann Pharmacother 2004 May; 38(5): 817–20PubMedCrossRefGoogle Scholar
  3. 3.
    Kleinschmidt-DeMasters BK, Tyler KL. Progressive multi-focal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 2005 Jul 28; 353(4): 369–74PubMedCrossRefGoogle Scholar
  4. 4.
    Langer-Gould A, Atlas SW, Green AJ, et al. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 2005 Jul 28; 353(4): 375–81PubMedCrossRefGoogle Scholar
  5. 5.
    Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 2005 Jul 28; 353(4): 362–8PubMedCrossRefGoogle Scholar
  6. 6.
    Sobell JM, Weinberg JM. Patient fatalities potentially associated with efalizumab use [letter]. J Drugs Dermatol 2009; 8: 215PubMedGoogle Scholar
  7. 7.
    Korman BD, Tyler KL, Korman NJ. Progressive multifocal leukoencephalopathy, efalizumab, and immunosuppression: a cautionary tale for dermatologists. Arch Dermatol 2009; 145: 937–42PubMedCrossRefGoogle Scholar
  8. 8.
    Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory therapies. Annu Rev Med 2009; 61: 35–47CrossRefGoogle Scholar
  9. 9.
    Garcia-Suarez J, de Miguel D, Krsnik I, et al. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol 2005 Dec; 80(4): 271–81PubMedCrossRefGoogle Scholar
  10. 10.
    Gonzalez H, Bolgert F, Camporo P, et al. Progressive multifocal leukoencephalitis (PML) in three patients treated with standard-dose fludarabine (FAMP). Hematol Cell Ther 1999 Aug; 41(4): 183–6PubMedCrossRefGoogle Scholar
  11. 11.
    Astrom KE, Mancall EL, Richardson Jr EP. Progressive multifocal leuko-encephalopathy: a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin’s disease. Brain 1958 Mar; 81(1): 93–111PubMedCrossRefGoogle Scholar
  12. 12.
    ZuRhein G, Chou S. Particles resembling papovavirions in human cerebral demyelinating disease. Science 1965; 148: 1477–9PubMedCrossRefGoogle Scholar
  13. 13.
    Padgett BL, Walker DL, ZuRhein GM, et al. Cultivation of papova-like virus from human brain with progressive multi-focal leucoencephalopathy. Lancet 1971; 1(7712): 1257–60PubMedCrossRefGoogle Scholar
  14. 14.
    Brown P, Tsai T, Gajdusek DC. Seroepidemiology of human papovaviruses: discovery of virgin populations and some unusual patterns of antibody prevalence among remote peoples of the world. Am J Epidemiol 1975 Oct; 102(4): 331–40PubMedGoogle Scholar
  15. 15.
    Walker D, Padgett B. The epidemiology of human polyomaviruses. In: Sever J, Madden D, editors. Polyomaviruses and human neurological disease. New York: Alan R. Liss, Inc., 1983: 99–106Google Scholar
  16. 16.
    Hamilton RS, Gravell M, Major EO. Comparison of antibody titers determined by hemagglutination inhibition and enzyme immunoassay for JC virus and BK virus. J Clin Microbiol 2000 Jan; 38(1): 105–9PubMedGoogle Scholar
  17. 17.
    Stolt A, Sasnauskas K, Koskela P, et al. Seroepidemiology of the human polyomaviruses. J Gen Virol 2003 Jun; 84(Pt 6): 1499–504PubMedCrossRefGoogle Scholar
  18. 18.
    Egli A, Infanti L, Dumoulin A, et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 2009 Mar 15; 199(6): 837–46PubMedCrossRefGoogle Scholar
  19. 19.
    Kean JM, Rao S, Wang M, et al. Seroepidemiology of human polyomaviruses. PLoS Pathog 2009 Mar; 5(3): e1000363PubMedCrossRefGoogle Scholar
  20. 20.
    Berger JR, Miller CS, Mootoor Y, et al. JC virus detection in bodily fluids: clues to transmission. Clin Infect Dis 2006 Jul 1;43(1): e9–12PubMedCrossRefGoogle Scholar
  21. 21.
    Koralnik IJ, Boden D, Mai VX, et al. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology 1999 Jan 15; 52(2): 253–60PubMedCrossRefGoogle Scholar
  22. 22.
    Chang H, Wang M, Tsai RT, et al. High incidence of JC viruria in JC-seropositive older individuals. J Neurovirol 2002 Oct; 8(5): 447–51PubMedCrossRefGoogle Scholar
  23. 23.
    Bofill-Mas S, Girones R. Excretion and transmission of JCV in human populations. J Neurovirol 2001 Aug; 7(4): 345–9PubMedCrossRefGoogle Scholar
  24. 24.
    Monaco MC, Jensen PN, Hou J, et al. Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection. J Virol 1998; 72(12): 9918–23PubMedGoogle Scholar
  25. 25.
    Sabath BF, Major EO. Traffic of JC virus from sites of initial infection to the brain: the path to progressive multifocal leukoencephalopathy. J Infect Dis 2002 Dec 1; 186 Suppl. 2: S180–6PubMedCrossRefGoogle Scholar
  26. 26.
    Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy. Neurol Clin 1984; 2(2): 299–313PubMedGoogle Scholar
  27. 27.
    Bernick C, Gregorios JB. Progressive multifocal leukoencephalopathy in a patient with acquired immune deficiency syndrome. Arch Neurol 1984 Jul; 41(7): 780–2PubMedCrossRefGoogle Scholar
  28. 28.
    Miller JR, Barrett RE, Britton CB, et al. Progressive multifocal leukoencephalopathy in a male homosexual with T-cell immune deficiency. N Engl J Med 1982; 307(23): 1436–8PubMedCrossRefGoogle Scholar
  29. 29.
    Snider WD, Simpson DM, Nielsen S, et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol 1983 Oct; 14(4): 403–18PubMedCrossRefGoogle Scholar
  30. 30.
    Power C, Gladden JG, Halliday W, et al. AIDS- and non-AIDS-related PML association with distinct p53 polymorphism. Neurology 2000 Feb 8; 54(3): 743–6PubMedCrossRefGoogle Scholar
  31. 31.
    Bower JH, Hammack JE, McDonnell SK, et al. The neurologic complications of B-cell chronic lymphocytic leukemia. Neurology 1997 Feb; 48(2): 407–12PubMedCrossRefGoogle Scholar
  32. 32.
    Berger JR, Kaszovitz B, Post MJ, et al. Progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection: a review of the literature with a report of sixteen cases. Ann Intern Med 1987; 107(1): 78–87PubMedCrossRefGoogle Scholar
  33. 33.
    Kure K, Llena JF, Lyman WD, et al. Human immunodeficiency virus-1 infection of the nervous system: an autopsy study of 268 adult, pediatric, and fetal brains. Hum Pathol 1991; 22(7): 700–10PubMedCrossRefGoogle Scholar
  34. 34.
    Holman RC, Janssen RS, Buehler JW, et al. Epidemiology of progressive multifocal leukoencephalopathy in the United States: analysis of national mortality and AIDS surveillance data. Neurology 1991; 41(11): 1733–6PubMedCrossRefGoogle Scholar
  35. 35.
    Selik RM, Karon JM, Ward JW. Effect of the human immunodeficiency virus epidemic on mortality from opportunistic infections in the United States in 1993. J Infect Dis 1997 Sep; 176(3): 632–6PubMedCrossRefGoogle Scholar
  36. 36.
    Gray F, Chretien F, Vallat-Decouvelaere AV, et al. The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol 2003 May; 62(5): 429–40PubMedGoogle Scholar
  37. 37.
    Sacktor N. The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. J Neurovirol 2002 Dec; 8 Suppl. 2: 115–21CrossRefGoogle Scholar
  38. 38.
    Berger JR, Houff SA, Major EO. Monoclonal antibodies and progressive multifocal leukoencephalopathy. mAbs 2009; 1(6): 1–7Google Scholar
  39. 39.
    Caldarelli-Stefano R, Vago L, Omodeo-Zorini E, et al. Detection and typing of JC virus in autopsy brains and extraneural organs of AIDS patients and non-immunocompromised individuals. J Neurovirol 1999 Apr; 5(2): 125–33PubMedCrossRefGoogle Scholar
  40. 40.
    Jensen PN, Major EO. Viral variant nucleotide sequences help expose leukocytic positioning in the JC virus pathway to the CNS. J Leukoc Biol 1999 Apr; 65(4): 428–38PubMedGoogle Scholar
  41. 41.
    Perez-Liz G, Del Valle L, Gentilella A, et al. Detection of JC virus DNA fragments but not proteins in normal brain tissue. Ann Neurol 2008 Oct; 64(4): 379–87PubMedCrossRefGoogle Scholar
  42. 42.
    Delbue S, Branchetti E, Boldorini R, et al. Presence and expression of JCV early gene large T Antigen in the brains of immunocompromised and immunocompetent individuals. J Med Virol 2008 Dec; 80(12): 2147–52PubMedCrossRefGoogle Scholar
  43. 43.
    Houff SA, Major EO, Katz DA, et al. Involvement of JC virus-infected mononuclear cells from the bone marrow and spleen in the pathogenesis of progressive multifocal leukoencephalopathy. N Engl J Med 1988; 318(5): 301–5PubMedCrossRefGoogle Scholar
  44. 44.
    Major EO, Amemiya K, Elder G, et al. Glial cells of the human developing brain and B cells of the immune system share a common DNA binding factor for recognition of the regulatory sequences of the human polyomavirus, JCV. J Neurosci Res 1990; 27(4): 461–71PubMedCrossRefGoogle Scholar
  45. 45.
    Atwood W, Amemiya K, Traub R, et al. Interactions of the human polyomavirus, JCV, with human B lymphocytes. Virology 1992; 190: 716–23PubMedCrossRefGoogle Scholar
  46. 46.
    Monaco MC, Atwood WJ, Gravell M, et al. JC virus infection of hematopoietic progenitor cells, primary B lymphocytes, and tonsillar stromal cells: implications for viral latency. J Virol 1996 Oct; 70(10): 7004–12PubMedGoogle Scholar
  47. 47.
    Tan CS, Dezube BJ, Bhargava P, et al. Detection of JC virus DNA and proteins in the bone marrow of HIV-positive and HIV-negative patients: implications for viral latency and neurotropic transformation. J Infect Dis 2009 Mar 15; 199(6): 881–8PubMedCrossRefGoogle Scholar
  48. 48.
    Andreoletti L, Dubois V, Lescieux A, et al. Human polyomavirus JC latency and reactivation status in blood of HIV-1-positive immunocompromised patients with and without progressive multifocal leukoencephalopathy. Aids 1999 Aug 20; 13(12): 1469–75PubMedCrossRefGoogle Scholar
  49. 49.
    Andreoletti L, Lescieux A, Lambert V, et al. Semiquantitative detection of JCV-DNA in peripheral blood leukocytes from HIV-1-infected patients with or without progressive multifocal leukoencephalopathy. J Med Virol 2002 Jan; 66(1): 1–7PubMedCrossRefGoogle Scholar
  50. 50.
    Delbue S, Guerini FR, Mancuso R, et al. JC virus viremia in interferon-beta-treated and untreated Italian multiple sclerosis patients and healthy controls. J Neurovirol 2007; 13(1): 73–7PubMedCrossRefGoogle Scholar
  51. 51.
    Dubois V, Dutronc H, Lafon ME, et al. Latency and reactivation of JC virus in peripheral blood of human immunodeficiency virus type 1-infected patients. J Clin Microbiol 1997 Sep; 35(9): 2288–92PubMedGoogle Scholar
  52. 52.
    Dubois V, Moret H, Lafon ME, et al. Prevalence of JC virus viraemia in HIV-infected patients with or without neurological disorders: a prospective study. J Neurovirol 1998; 4(5): 539–44PubMedCrossRefGoogle Scholar
  53. 53.
    Koralnik IJ, Schmitz JE, Lifton MA, et al. Detection of JC virus DNA in peripheral blood cell subpopulations of HIV-1-infected individuals. J Neurovirol 1999 Aug; 5(4): 430–5PubMedCrossRefGoogle Scholar
  54. 54.
    Tornatore C, Berger JR, Houff SA, et al. Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy. Ann Neurol 1992 Apr; 31(4): 454–62PubMedCrossRefGoogle Scholar
  55. 55.
    Tornatore C, Berger J, Winfield D, et al. Detection of JC viral genome in the lymphocytes of non-PML HIV positive patients: association with B cell lymphopenia [abstract]. Neurology 1992; 42 Suppl. 3:211Google Scholar
  56. 56.
    Fedele CG, Ciardi MR, Delia S, et al. Identical rearranged forms of JC polyomavirus transcriptional control region in plasma and cerebrospinal fluid of acquired immunodeficiency syndrome patients with progressive multifocal leukoencephalopathy. J Neurovirol 2003 Oct; 9(5): 551–8PubMedGoogle Scholar
  57. 57.
    Willoughby E, Price RW, Padgett BL, et al. Progressive multifocal leukoencephalopathy (PML): in vitro cell-mediated immune responses to mitogens and JC virus. Neurology 1980 Mar; 30(3): 256–62PubMedCrossRefGoogle Scholar
  58. 58.
    Weber F, Goldmann C, Kramer M, et al. Cellular and humoral immune response in progressive multifocal leukoencephalopathy. Ann Neurol 2001 May; 49(5): 636–42PubMedCrossRefGoogle Scholar
  59. 59.
    Weber T, Weber F, Petry H, et al. Immune response in progressive multifocal leukoencephalopathy: an overview. J Neurovirol 2001 Aug; 7(4): 311–7PubMedCrossRefGoogle Scholar
  60. 60.
    Du Pasquier RA, Clark KW, Smith PS, et al. JCV-specific cellular immune response correlates with a favorable clinical outcome in HIV-infected individuals with progressive multifocal leukoencephalopathy. J Neurovirol 2001 Aug; 7(4): 318–22PubMedCrossRefGoogle Scholar
  61. 61.
    Du Pasquier RA, Kuroda MJ, Zheng Y, et al. A prospective study demonstrates an association between JC virus-specific cytotoxic T lymphocytes and the early control of progressive multifocal leukoencephalopathy. Brain 2004 Sep; 127(Pt 9): 1970–8PubMedCrossRefGoogle Scholar
  62. 62.
    O’Hara BA, Atwood WJ. Interferon beta1-a and selective anti-5HT(2a) receptor antagonists inhibit infection of human glial cells by JC virus. Virus Res 2008 Mar; 132(1-2): 97–103PubMedCrossRefGoogle Scholar
  63. 63.
    Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 2006 Mar 2; 354(9): 924–33PubMedCrossRefGoogle Scholar
  64. 64.
    Biogen Idec. PML incidence [online]. Available from URL: https://medinfobiogenideccom/medinfo/download?doc=Tysabri&type=monup&Continue=Continue 2010 [Accessed 2010 Apr 9]
  65. 65.
    Whiteman ML, Post MJ, Berger JR, et al. Progressive multifocal leukoencephalopathy in 47 HIV-seropositive patients: neuroimaging with clinical and pathologic correlation. Radiology 1993; 187(1): 233–40PubMedGoogle Scholar
  66. 66.
    Biogen Idec. Medical information services letter, 20 August 2010. Cambridge (MA): Biogen Idec., 2010Google Scholar
  67. 67.
    Du Pasquier RA, Schmitz JE, Jean-Jacques J, et al. Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals. J Virol 2004 Sep; 78(18): 10206–10PubMedCrossRefGoogle Scholar
  68. 68.
    Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy and natalizumab: unforeseen consequences. N Engl J Med 2005 Jul 28; 353(4): 414–6PubMedCrossRefGoogle Scholar
  69. 69.
    del Pilar Martin M, Cravens PD, Winger R, et al. Decrease in the numbers of dendritic cells and CD4+ T cells in cerebral perivascular spaces due to natalizumab. Arch Neurol 2008 Dec; 65(12): 1596–603PubMedCrossRefGoogle Scholar
  70. 70.
    Marzocchetti A, Lima M, Tompkins T, et al. Efficient in vitro expansion of JC virus-specific CD8(+) T-cell responses by JCV peptide-stimulated dendritic cells from patients with progressive multifocal leukoencephalopathy. Virology 2009 Jan 20; 383(2): 173–7PubMedCrossRefGoogle Scholar
  71. 71.
    Krumbholz M, Meinl I, Kumpfel T, et al. Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis. Neurology 2008 Oct 21; 71(17): 1350–4PubMedCrossRefGoogle Scholar
  72. 72.
    Houff SA, Berger JR. The bone marrow, B cells, and JC virus. J Neurovirol 2008 Oct; 14(5): 341–3PubMedCrossRefGoogle Scholar
  73. 73.
    Lindberg RL, Achtnichts L, Hoffmann F, et al. Natalizumab alters transcriptional expression profiles of blood cell subpopulations of multiple sclerosis patients. J Neuroimmunol 2008 Feb; 194(1–2): 153–64PubMedCrossRefGoogle Scholar
  74. 74.
    Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009 Sep 10; 361(11): 1067–74PubMedCrossRefGoogle Scholar
  75. 75.
    Gorelik L, Goelz S, Sandrock AW. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009 Dec 17; 361(25): 2487–8; author reply 2489–90PubMedCrossRefGoogle Scholar
  76. 76.
    Jilek S, Jaquiery E, Hirsch HH, et al. Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study. Lancet Neurol 2010 Mar; 9(3): 264–72PubMedCrossRefGoogle Scholar
  77. 77.
    Leonardi CL. Current concepts and review of efalizumab in the treatment of psoriasis. Dermatol Clin 2004 Oct; 22(4): 427–35, ixPubMedCrossRefGoogle Scholar
  78. 78.
    Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate to severe plaque psoriasis: a randomized controlled trial. JAMA 2003 Dec 17; 290(23): 3073–80PubMedCrossRefGoogle Scholar
  79. 79.
    Leonardi C, Menter A, Hamilton T, et al. Efalizumab: results of a 3-year continuous dosing study for the long-term control of psoriasis. Br J Dermatol 2008 May; 158(5): 1107–16PubMedCrossRefGoogle Scholar
  80. 80.
    Lub M, van Kooyk Y, Figdor CG. Ins and outs of LFA-1. Immunol Today 1995 Oct; 16(10): 479–83PubMedCrossRefGoogle Scholar
  81. 81.
    Lebwohl M, Tyring SK, Hamilton TK, et al. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 2003 Nov 20; 349(21): 2004–13PubMedCrossRefGoogle Scholar
  82. 82.
    Benjamin RJ, Qin SX, Wise MP, et al. Mechanisms of monoclonal antibody-facilitated tolerance induction: a possible role for the CD4 (L3T4) and CD11a (LFA-1) molecules in self-non-self discrimination. Eur J Immunol 1988 Jul; 18(7): 1079–88PubMedCrossRefGoogle Scholar
  83. 83.
    Cavazzana-Calvo M, Sarnacki S, Haddad E, et al. Prevention of bone marrow and cardiac graft rejection in an H-2 haplotype disparate mouse combination by an anti-LFA-1 antibody. Transplantation 1995 Jun 15; 59(11): 1576–82PubMedGoogle Scholar
  84. 84.
    Waldmann H, Cobbold SP, Qin S, et al. Tolerance induction in the adult using monoclonal antibodies to CD4, CD8, and CD11a (LFA-1). Cold Spring Harb Symp Quant Biol 1989; 54 Pt 2: 885–92CrossRefGoogle Scholar
  85. 85.
    Guttman-Yassky E, Vugmeyster Y, Lowes MA, et al. Blockade of CD11a by efalizumab in psoriasis patients induces a unique state of T-cell hyporesponsiveness. J Invest Dermatol 2008 May; 128(5): 1182–91PubMedCrossRefGoogle Scholar
  86. 86.
    Krueger JG, Ochs HD, Patel P, et al. Effect of therapeutic integrin (CD11a) blockade with efalizumab on immune responses to model antigens in humans: results of a randomized, single blind study. J Invest Dermatol 2008 Nov; 128(11): 2615–24PubMedCrossRefGoogle Scholar
  87. 87.
    Vugmeyster Y, Kikuchi T, Lowes MA, et al. Efalizumab (anti-CD11a)-induced increase in peripheral blood leukocytes in psoriasis patients is preferentially mediated by altered trafficking of memory CD8+ T cells into lesional skin. Clin Immunol 2004 Oct; 113(1): 38–46PubMedCrossRefGoogle Scholar
  88. 88.
    Lowes MA, Chamian F, Abello MV, et al. Increase in TNF-alpha and inducible nitric oxide synthase-expressing dendritic cells in psoriasis and reduction with efalizumab (anti-CD 11a). Proc Natl Acad Sci U S A 2005 Dec 27; 102(52): 19057–62PubMedCrossRefGoogle Scholar
  89. 89.
    Langley RG, Carey WP, Rafal ES, et al. Incidence of infection during efalizumab therapy for psoriasis: analysis of the clinical trial experience. Clin Ther 2005 Sep; 27(9): 1317–28PubMedCrossRefGoogle Scholar
  90. 90.
    Cree B. Emerging monoclonal antibody therapies for multiple sclerosis. Neurologist 2006 Jul; 12(4): 171–8PubMedCrossRefGoogle Scholar
  91. 91.
    Gurcan HM, Keskin DB, Stern JN, et al. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009 Jan; 9(1): 10–25PubMedCrossRefGoogle Scholar
  92. 92.
    Carson KR, Evens AM, Richey EA, et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009 May 14; 113(20): 4834–40PubMedCrossRefGoogle Scholar
  93. 93.
    Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 2008 Feb 14; 358(7): 676–88PubMedCrossRefGoogle Scholar
  94. 94.
    Gever J. Third PML case reported with rituximab. Med-Page Today 2009 [online]. Available from URL: http://www.medpagetoday.com/ProductAlert/Prescriptions/16607 [Accessed 2009 Dec 25]
  95. 95.
    Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk? Autoimmun Rev 2008 Dec; 8(2): 144–6PubMedCrossRefGoogle Scholar
  96. 96.
    Marzocchetti A, Wuthrich C, Tan CS, et al. Rearrangement of the JC virus regulatory region sequence in the bone marrow of a patient with rheumatoid arthritis and progressive multifocal leukoencephalopathy. J Neurovirol 2008 Oct; 14(5): 455–8PubMedCrossRefGoogle Scholar
  97. 97.
    Nived O, Bengtsson AA, Jonsen A, et al. Progressive multifocal leukoencephalopathy: the importance of early diagnosis illustrated in four cases. Lupus 2008 Nov; 17(11): 1036–41PubMedCrossRefGoogle Scholar
  98. 98.
    Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum 2009 Dec; 60(12): 3761–5PubMedCrossRefGoogle Scholar
  99. 99.
    Corti P, Peters C, Balduzzi A, et al. Reconstitution of lymphocyte subpopulations in children with inherited metabolic storage diseases after haematopoietic cell transplantation. Br J Haematol 2005 Jul; 130(2): 249–55PubMedCrossRefGoogle Scholar
  100. 100.
    Leandro MJ, Cambridge G, Ehrenstein MR, et al. Reconstitution of peripheral blood B cells after depletion with rituximab in patients with rheumatoid arthritis. Arthritis Rheum 2006 Feb; 54(2): 613–20PubMedCrossRefGoogle Scholar
  101. 101.
    Anolik JH, Friedberg JW, Zheng B, et al. B cell reconstitution after rituximab treatment of lymphoma recapitulates B cell ontogeny. Clin Immunol 2007 Feb; 122(2): 139–45PubMedCrossRefGoogle Scholar
  102. 102.
    Cross AH, Stark JL, Lauber J, et al. Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients. J Neuroimmunol 2006 Nov; 180(1-2): 63–70PubMedCrossRefGoogle Scholar
  103. 103.
    McFarland HF. The B cell: old player, new position on the team. N Engl J Med 2008 Feb 14; 358(7): 664–5PubMedCrossRefGoogle Scholar
  104. 104.
    Ransom JT. Mechanism of action of mycophenolate mofetil. Ther Drug Monit 1995 Dec; 17(6): 681–4PubMedCrossRefGoogle Scholar
  105. 105.
    Villarroel MC, Hidalgo M, Jimeno A. Mycophenolate mofetil: an update. Drugs Today (Barc) 2009 Jul; 45(7): 521–32Google Scholar
  106. 106.
    Heatwole C, Ciafaloni E. Mycophenolate mofetil for myasthenia gravis: a clear and present controversy. Neuropsychiatr Dis Treat 2008 Dec; 4(6): 1203–9PubMedCrossRefGoogle Scholar
  107. 107.
    Neff RT, Hurst FP, Falta EM, et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation 2008 Nov 27; 86(10): 1474–8PubMedCrossRefGoogle Scholar
  108. 108.
    Lefevre G, Queyrel V, Maurage CA, et al. Effective immune restoration after immunosuppressant discontinuation in a lupus patient presenting progressive multifocal leukoencephalopathy. J Neurol Sci 2009 Dec 15; 287(1-2): 246–9PubMedCrossRefGoogle Scholar
  109. 109.
    Berger JR, Scott G, Albrecht J, et al. Progressive multifocal leukoencephalopathy in HIV-1-infected children. Aids 1992; 6(8): 837–41PubMedCrossRefGoogle Scholar
  110. 110.
    Khanna N, Wolbers M, Mueller NJ, et al. JC virus-specific immune responses in human immunodeficiency virus type 1 patients with progressive multifocal leukoencephalopathy. J Virol 2009 May; 83(9): 4404–11PubMedCrossRefGoogle Scholar
  111. 111.
    Khoury S, Weiner H, You X, et al. Pilot study to measure ATP expression in lymphcytes of MS paties undergoing various therapies using the Cylex ImmuKnow assay. 61st Annual Meeting of the American Academy of Neurology; 2009 Apr 25–May 2; Seattle (WA), P09.103Google Scholar
  112. 112.
    Linda H, von Heijne A, Major EO, et al. Progressive multifocal leukoencephalopathy after natalizumab monotherapy. N Engl J Med 2009 Sep 10; 361(11): 1081–7PubMedCrossRefGoogle Scholar
  113. 113.
    Clifford DB, De Luca A, Simpson DM, et al. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 2010 Apr; 9(4): 438–46PubMedCrossRefGoogle Scholar
  114. 114.
    Boster A, Hreha S, Berger JR, et al. Progressive multifocal leukoencephalopathy and relapsing-remitting multiple sclerosis: a comparative study. Arch Neurol 2009 May; 66(5): 593–9PubMedCrossRefGoogle Scholar
  115. 115.
    Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science 2004 Nov 19; 306(5700): 1380–3PubMedCrossRefGoogle Scholar
  116. 116.
    Nukuzuma S, Nakamichi K, Nukuzuma C, et al. Inhibitory effect of serotonin antagonists on JC virus propagation in a carrier culture of human neuroblastoma cells. Microbiol Immunol 2009 Sep; 53(9): 496–501PubMedCrossRefGoogle Scholar
  117. 117.
    Altschuler EL, Kast RE. The atypical antipsychotic agents ziprasidone [correction of zisprasidone], risperdone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. Med Hypotheses 2005; 65(3): 585–6PubMedCrossRefGoogle Scholar
  118. 118.
    Lanzafame M, Ferrari S, Lattuada E, et al. Mirtazapine in an HIV-1 infected patient with progressive multifocal leukoencephalopathy. Infez Med 2009 Mar; 17(1): 35–7PubMedGoogle Scholar
  119. 119.
    Chapagain ML, Verma S, Mercier F, et al. Polyomavirus JC infects human brain microvascular endothelial cells independent of serotonin receptor 2A. Virology 2007 Jul 20; 364(1): 55–63PubMedCrossRefGoogle Scholar
  120. 120.
    Rudick RA, Sandrock A. Natalizumab: alpha4-integrin antagonist selective adhesion molecule inhibitors for MS. Expert Rev Neurother 2004 Jul; 4(4): 571–80PubMedCrossRefGoogle Scholar
  121. 121.
    Tubridy N, Behan PO, Capildeo R, et al. The effect of anti-alpha4 integrin antibody on brain lesion activity in MS. The UK Antegren Study Group. Neurology 1999 Aug 11; 53(3): 466–72PubMedCrossRefGoogle Scholar
  122. 122.
    Stuve O, Marra CM, Bar-Or A, et al. Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol 2006 Oct; 63(10): 1383–7PubMedCrossRefGoogle Scholar
  123. 123.
    Khatri BO, Man S, Giovannoni G, et al. Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 2009 Feb 3; 72(5): 402–9PubMedCrossRefGoogle Scholar
  124. 124.
    Wenning W, Haghikia A, Laubenberger J, et al. Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 2009 Sep 10; 361(11): 1075–80PubMedCrossRefGoogle Scholar
  125. 125.
    Brickelmaier M, Lugovskoy A, Kartikeyan R, et al. Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 2009 May; 53(5): 1840–9PubMedCrossRefGoogle Scholar
  126. 126.
    Hou J, Major EO. The efficacy of nucleoside analogs against JC virus multiplication in a persistently infected human fetal brain cell line. J Neurovirol 1998; 4(4): 451–6PubMedCrossRefGoogle Scholar
  127. 127.
    Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med 1998; 338(19): 1345–51PubMedCrossRefGoogle Scholar
  128. 128.
    Venkataramana A, Pardo CA, McArthur JC, et al. Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients. Neurology 2006 Aug 8; 67(3): 383–8PubMedCrossRefGoogle Scholar
  129. 129.
    Tan K, Roda R, Ostrow L, et al. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology 2009 Apr 28; 72(17): 1458–648PubMedCrossRefGoogle Scholar
  130. 130.
    Vendrely A, Bienvenu B, Gasnault J, et al. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol (Berl) 2005 Apr; 109(4): 449–55CrossRefGoogle Scholar
  131. 131.
    BiogenIdec. TYSABRI: PML management strategies in multiple sclerosis [online]. Available from URL: https://medinfobiogenideccom/medinfo/pdf/secure/pmlres/SRM_TYS_PML_Management_in_MS_20100104pdf?Continue=Continue 2010 [Accessed 2010 Apr 9]
  132. 132.
    Menter A. The status of biologic therapies in the treatment of moderate to severe psoriasis. Cutis 2009 Oct; 84 (4 Suppl.): 14–24PubMedGoogle Scholar

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© Adis Data Information BV 2010

Authors and Affiliations

  1. 1.Department of Neurologyiversity of Kentucky College of MedicineLexingtonUSA

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