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Progressive multifocal leukoencephalopathy and natalizumab

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Abstract

Natalizumab (TYSABRI®), a specific α4-integrin antagonist, is approved as a second-line treatment of relapsing-remitting MS (RRMS) patients who fail therapy with interferons or as first-line treatment of patients with highly active relapsing-remitting disease. Since the market introduction of natalizumab as a monotherapy in July of 2006, 111 cases of PML have been reported in natalizumab-treated MS patients as of April 2011. This review focuses on the available data regarding risk stratification for PML under long-term natalizumab therapy, and summarizes the current approach for PML management, as a natalizumab treatment complication is not necessarily associated with a fatal outcome. There is a need for development of surrogate markers that would help to better define the risk of PML in individual patients.

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References

  1. Polman CH, O’Connor PW, Havrdova E et al (2006) A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 354:889–910

    Article  Google Scholar 

  2. Miller DH, Soon D, Fernando KT et al (2007) MRI outcomes in a placebo-controlled trial of natalizumab in relapsing MS. Neurology 68:1390–1401

    Article  PubMed  CAS  Google Scholar 

  3. Munschauer F, Giovannoni G, Lublin F et al (2008) Natalizumab significantly increases the cumulative probability of sustained improvement in physical disability. Mult Scler 14(Suppl 1):S168

    Google Scholar 

  4. Hutchinson M, Kappos L, Calabresi PA, For the AFFIRM and SENTINEL Investigators et al (2009) The efficacy of natalizumab in patients with relapsing multiple sclerosis: subgroup analyses of AFFIRM and SENTINEL. J Neurol 256:405–415

    Article  PubMed  CAS  Google Scholar 

  5. Havrdova E, Galetta S, Hutchinson M et al (2009) Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study. Lancet Neurol 8:254–260

    Article  PubMed  Google Scholar 

  6. Balcer L, Galetta S, Calabresi P et al (2007) Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Neurology 68:1299–1304

    Article  PubMed  CAS  Google Scholar 

  7. Rudick R, Miller D, Hass S et al (2007) Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann Neurol 62:335–346

    Article  PubMed  CAS  Google Scholar 

  8. Kleinschmidt-DeMasters BK, Tyler KL (2005) Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med 353:369–374

    Article  PubMed  CAS  Google Scholar 

  9. Langer-Gould A, Atlas SW, Green AJ et al (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353:375–381

    Article  PubMed  CAS  Google Scholar 

  10. Van Assche G, Van Ranst M, Sciot R et al (2005) Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn’s disease. N Engl J Med 353:362–368

    Article  PubMed  Google Scholar 

  11. Yousry T, Major E, Ryschkewitsch C et al (2006) Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 354:924–933

    Article  PubMed  CAS  Google Scholar 

  12. Rudick RA, Stuart WH, Calabresi PA et al (2006) Natalizumab plus interferon beta-1 for relapsing multiple sclerosis. N Eng J Med 354:911–923

    Article  CAS  Google Scholar 

  13. Clifford DB, De Luca A, Simpson DW et al (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons learned from 28 cases. Lancet Neurol 9:438–446

    Article  PubMed  CAS  Google Scholar 

  14. Schröder A, Lee DH, Hellwig K et al (2010) Successful management of natalizumab-associated progressive multifocal leukoencephalopathy and immune reconstitution syndrome in a patient with multiple sclerosis. Arch Neurol 67(11):1391–1394

    Article  PubMed  Google Scholar 

  15. Gorelik L, Lerner M, Bixler S et al (2010) Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 68:295–303

    Article  PubMed  Google Scholar 

  16. Weber T (2008) Progressive multifocal leukoencephalopathy. Neurol Clin 26:833–854

    Article  PubMed  Google Scholar 

  17. Bag AK, Curé JK, Chapman PR, Roberson GH, Shah R (2010) JC virus infection of the brain. AJNR Am J Neuroradiol 31(9):1564–1576

    Article  PubMed  CAS  Google Scholar 

  18. Calabrese LH, Molloy ES, Huang DR, Ransohoff RM (2007) Progressive multifocal leukoencephalopathy in rheumatic diseases. Arthritis Rheum 56:2116–2128

    Article  PubMed  Google Scholar 

  19. Carson KR, Focosi D, Major EO et al (2009) Monoclonal antibody-associated progressive multifocal leukoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: a Review from the Research on Adverse Drug Events and Reports (RADAR) Project. Lancet Oncol 10:816–824

    Article  PubMed  CAS  Google Scholar 

  20. Dang X, Koralnik IJ (2006) A granule cell neuron-associated JC virus variant has a unique deletion in the VP1 gene. J Gen Virol 87(Pt 9):2533–2537

    Article  PubMed  CAS  Google Scholar 

  21. Wüthrich C, Dang X, Westmoreland S, McKay J, Maheshwari A, Anderson MP, Ropper AH, Viscidi RP, Koralnik IJ (2009) Fulminant JC virus encephalopathy with productive infection of cortical pyramidal neurons. Ann Neurol 65(6):742–748

    Article  PubMed  Google Scholar 

  22. Lima MA, Drislane FW, Koralnik IJ (2006) Seizures and their outcome in progressive multifocal leukoencephalopathy. Neurology 66(2):262–264

    Article  PubMed  Google Scholar 

  23. Giancola ML, Rizzi EB, Lorenzini P et al (2008) Progressive multifocal leukoencephalopathy in HIV-infected patients in the era of HAART: radiological features at diagnosis and follow-up and correlation with clinical variables. AIDS Res Hum Retroviruses 24:155–162

    Article  PubMed  Google Scholar 

  24. Warnke C, Menge T, Hartung HP, Racke MK, Cravens PD, Bennett JL, Frohman EM, Greenberg BM, Zamvil SS, Gold R, Hemmer B, Kieseier BC, Stüve O (2010) Natalizumab and progressive multifocal leukoencephalopathy: what are the causal factors and can it be avoided? Arch Neurol 67(8):923–930 Review

    Article  PubMed  Google Scholar 

  25. Chen Y, Bord E, Tompkins T et al (2009) Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 361:1067–1074

    Article  PubMed  CAS  Google Scholar 

  26. Rinaldi L, Rinaldi F, Perini P, Calabrese M, Seppi D, Grossi P, Mattisi I, Barzon L, Mengoli C, Sanzari M, Palú G, Gallo P (2010) No evidence of JC virus reactivation in natalizumab-treated multiple sclerosis patients: an 18 month follow-up study. J Neurol Neurosurg Psychiatry 81(12):1345–1350

    Article  PubMed  Google Scholar 

  27. Zohren F, Toutzaris D, Klärner V, Hartung HP, Kieseier B, Haas R (2008) The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 111(7):3893–3895

    Article  PubMed  CAS  Google Scholar 

  28. Warnke C, Smolianov V, Dehmel T, Andrée M, Hengel H, Zohren F, Arendt G, Wiendl H, Haas R, Hartung HP, Adams O, Kieseier BC (2011) CD34+ progenitor cells mobilized by natalizumab are not a relevant reservoir for JC virus. Mult Scler 17(2):151–156

    Article  PubMed  Google Scholar 

  29. Haghikia A, Perrech M, Pula B, Ruhrmann S, Potthoff A, Brockmeyer NH, Goelz S, Wiendl H, Lindå H, Ziemssen T, Baranzini SE, Käll T-B, Bengel D, Olsson T, Gold R, Chan A (2011) Functional energetics of CD4+ -cellular immunity in monoclonal antibody-associated progressive multifocal leukoencephalopathy in autoimmune disorders. PLoS One 6(4):e18506

    Article  PubMed  CAS  Google Scholar 

  30. Clifford DB, Yiannoutsos C, Glicksman M et al (1999) HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology 52:623–625

    PubMed  CAS  Google Scholar 

  31. DeLuca A, Giancola ML, Annassari A et al (2000) The effect of potent antiretroviral therapy and JC virus load in cerebrospinal fluid on clinical outcome of patients with AIDS-associated progressive multifocal leukoencephalopathy. J Infect Dis 182:1077–1083

    Article  CAS  Google Scholar 

  32. Brickelmaier M, Lugovskoy A, Kartikeyan R, Reviriego-Mendoza MM, Allaire N, Simon K, Frisque RJ, Gorelik L (2009) Identification and characterization of mefloquine efficacy against JC virus in vitro. Antimicrob Agents Chemother 53(5):1840–1849

    Article  PubMed  CAS  Google Scholar 

  33. Hall CD, Dafni U, Simpson D et al (1998) AIDS Clinical Trials Group 243 Team. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. N Engl J Med 338:1345–1351

    Article  PubMed  CAS  Google Scholar 

  34. DeLuca A, Giancola ML, Ammassari A et al (2000) Cidofovir added to HAART improved virological and clinical outcome in AIDS-associated progressive multifocal leukoencephalopathy. AIDS 14:F117–F121

    Article  CAS  Google Scholar 

  35. DeLuca A, Giancola ML, Ammassari A et al (2001) Potent anti-retroviral therapy with or without cidofovir for AIDS-associated progressive multifocal leukoencephalopathy: extended follow-up of an observational study. J Neurovirol 7:364–368

    Article  CAS  Google Scholar 

  36. Przepiorka D, Jaeckle KA, Birdwell RR et al (1997) Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2. Bone Marrow Transplant 20:983–987

    Article  PubMed  CAS  Google Scholar 

  37. Re D, Bamborschke S, Feiden W et al (1999) Progressive multifocal leukoencephalopathy after autologous bone marrow transplantation and alpha-interferon immunotherapy. Bone Marrow Transplant 23:295–298

    Article  PubMed  CAS  Google Scholar 

  38. Huang SS, Skolasky RL, Dal Pan GJ et al (1998) Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study. J Neurovirol 4:324–332

    Article  PubMed  CAS  Google Scholar 

  39. Geschwind MD, Skolasky RI, Royal WS, McArthur JC (2001) The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS. J Neurovirol 7:353–357

    Article  PubMed  CAS  Google Scholar 

  40. Nath A, Venkataramana A, Reich DS et al (2006) Progression of progressive multifocal leukoencephalopathy despite treatment with β-interferon. Neurology 66:149–150

    Article  PubMed  CAS  Google Scholar 

  41. Kunschner L, Scott TF (2005) Sustained recovery of progressive multifocal leukoencephalopathy after treatment with IL-2. Neurology 65:1510

    Article  PubMed  Google Scholar 

  42. Venkataramana A, Pardo CA, McArthur JC, Kerr DA, Irani DN, Griffin JW, Burger P, Reich DS, Calabresi PA, Nath A (2006) Immune reconstitution inflammatory syndrome in the CNS of HIV-infected patients. Neurology 67(3):383–388

    Article  PubMed  CAS  Google Scholar 

  43. Tan K, Roda R, Ostrow L et al (2009) PML-IRIS in HIV infection. Clinical manifestations and treatment with steroids. Neurology 72:1458–1464

    Article  PubMed  CAS  Google Scholar 

  44. Biogen Idec. Data on file

  45. Bozic C, Christiano LM, Hyde R et al (2010) Utilisation and safety of natalizumab in patients with relapsing multiple sclerosis. Mult Scler 16(suppl 10):S315

    Google Scholar 

  46. Stangel M, Sorensen PS, Petersen T et al (2009) Natalizumab utilization and safety in the TYGRIS program in the European Union and Canada. Mult Scler 15(suppl 2):S234

    Google Scholar 

  47. Khatri B, Man S, Giovannoni G et al (2009) Effect of plasma exchange in accelerating natalizumab clearance and restoring leukocyte function. Neurology 72:402–409

    Article  PubMed  CAS  Google Scholar 

  48. Wenning W, Haghikia A, Laubenberger M et al (2009) Treatment of progressive multifocal leukoencephalopathy associated with natalizumab. N Engl J Med 361:1075–1080

    Article  PubMed  CAS  Google Scholar 

  49. Ryschkewitsch CF, Jensen PN, Monaco MC, Major EO (2010) JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol 68(3):384–391

    Article  PubMed  Google Scholar 

  50. Carson KR, Evens AM, Richey EA, Habermann TM, Focosi D, Seymour JF, Laubach J, Bawn SD, Gordon LI, Winter JN, Furman RR, Vose JM, Zelenetz AD, Mamtani R, Raisch DW, Dorshimer GW, Rosen ST, Muro K, Gottardi-Littell NR, Talley RL, Sartor O, Green D, Major EO, Bennett CL (2009) 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 113(20):4834–4840

    Article  PubMed  CAS  Google Scholar 

  51. O’Connor PW, Goodman A, Kappos L et al (2009) Return of disease activity with cessation of natalizumab therapy in patients with multiple sclerosis. Mult Scler 15(suppl 2):S240–S243

    Google Scholar 

  52. Killestein J, Vennegoor A, Strijbis EM et al (2010) Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol 68:392–395

    Article  PubMed  Google Scholar 

  53. Clinicaltrials.gov Web site (2010) Trial NCT00746941. http://www.clinicaltrials.gov/ct2/show/NCT01071083?term=biogen+idec+restore&rank=1. Accessed 9 November 2010

  54. European Agency for the Evaluation of Medicinal Products (2010) TYSABRI® summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000603/WC500044686.pdf. Accessed 19 August 2010

  55. Kappos L, Bates D, Hartung HP et al (2007) Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring. Lancet Neurol 6:431–444

    Article  PubMed  Google Scholar 

  56. Kappos L, Radue EW, O’Connor P, Polman C, Hohlfeld R, Calabresi P, Selmaj K, Agoropoulou C, Leyk M, Zhang-Auberson L, Burtin P, FREEDOMS Study Group (2010) A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N Engl J Med 362(5):387–401

    Article  PubMed  CAS  Google Scholar 

  57. Kappos L, Bates D, Edan G et al (2011) Natalizumab in patients with multiple sclerosis: treatment recommendations. Lancet Neurol (in press)

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Acknowledgments

We thank Prof L. Kappos, Basel, for helpful discussions and comments. We thank Dr. Alexandra Schröder and Dr. Carsten Lukas for providing the MRI images.

Conflict of interest

RG and KH have received speaker’s and board honoraria, and grant support from BiogenIdec.

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Authors and Affiliations

  1. Department of Neurology, St. Josef Hospital, Ruhr University Bochum, Gudrunstrasse 56, 44791, Bochum, Germany

    Kerstin Hellwig & Ralf Gold

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  1. Kerstin Hellwig
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  2. Ralf Gold
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Correspondence to Ralf Gold.

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Hellwig, K., Gold, R. Progressive multifocal leukoencephalopathy and natalizumab. J Neurol 258, 1920–1928 (2011). https://doi.org/10.1007/s00415-011-6116-8

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  • DOI: https://doi.org/10.1007/s00415-011-6116-8

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