Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Sorting out the risks in progressive multifocal leukoencephalopathy

Abstract

Progressive multifocal leukoencephalopathy (PML) is a rare, opportunistic infection of the central nervous system, caused by reactivation of the ubiquitous JC virus. PML is a devastating disease that is frequently fatal, and although survival rates have improved, patients who survive PML often experience considerable neurological deficits. PML was associated with a variety of immunosuppressive therapies in the past decade, but attribution of causality is difficult owing to the presence of confounding factors and to an inadequate understanding of the underlying pathogenesis of this disease. This uncertainty has hindered efforts for shared decision-making between physicians and their patients and, in some cases, discouraged the use of potentially beneficial therapies. We propose a categorization of immunosuppressive agents according to their risk of PML to support a better-informed decision-making process when evaluating the risks and benefits of these therapies.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Infection with JC virus is at first asymptomatic and presumably occurs at an early age by oral route.

References

  1. 1

    Berger, J. R. et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 80, 1430–1438 (2013).

    Article  Google Scholar 

  2. 2

    Berger, J. R. & Houff, S. Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab. Neurol. Res. 28, 299–305 (2006).

    CAS  Article  Google Scholar 

  3. 3

    Kleinschmidt-DeMasters, B. K. & Tyler, K. L. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon β-1a for multiple sclerosis. N. Engl. J. Med. 353, 369–374 (2005).

    CAS  Article  Google Scholar 

  4. 4

    Langer-Gould, A., Atlas, S. W., Green, A. J., Bollen, A. W. & Pelletier, D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N. Engl. J. Med. 353, 375–381 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Van Assche, G. et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N. Engl. J. Med. 353, 362–368 (2005).

    CAS  Article  Google Scholar 

  6. 6

    Calabrese, L. H., Molloy, E. S., Huang, D. & Ransohoff, R. M. Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease. Arthritis Rheum. 56, 2116–2128 (2007).

    Article  Google Scholar 

  7. 7

    Molloy, E. S. & Calabrese, L. H. Progressive multifocal leukoencephalopathy in patients with rheumatic diseases: are patients with systemic lupus erythematosus at particular risk? Autoimmun. Rev. 8, 144–146 (2008).

    CAS  Article  Google Scholar 

  8. 8

    Berger, J. R. The basis for modeling progressive multifocal leukoencephalopathy pathogenesis. Curr. Opin. Neurol. 24, 262–267 (2011).

    CAS  Article  Google Scholar 

  9. 9

    Molloy, E. S. & Calabrese, L. H. Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum. 60, 3761–3765 (2009).

    Article  Google Scholar 

  10. 10

    Calabrese, L. H. & Molloy, E. S. Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risks of biological immunosuppressive therapies. Ann. Rheum. Dis. 67 (Suppl. 3), iii64–iii65 (2008).

    PubMed  Google Scholar 

  11. 11

    Molloy, E. S. & Calabrese, L. H. Therapy: Targeted but not trouble-free: efalizumab and PML. Nat. Rev. Rheumatol. 5, 418–419 (2009).

    CAS  Article  Google Scholar 

  12. 12

    US Department of Health & Human Services. FDA Drug Safety and Availability [online], (2010).

  13. 13

    US Department of Health & Human Services. FDA Drug Safety and Availability [online], (2006).

  14. 14

    US Department of Health & Human Services. FDA Drug Safety and Availability [online], (2008).

  15. 15

    Neff, R. T. et al. Progressive multifocal leukoencephalopathy and use of mycophenolate mofetil after kidney transplantation. Transplantation 86, 1474–1478 (2008).

    Article  Google Scholar 

  16. 16

    Clifford, D. B. et al. Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch. Neurol. 68, 1156–1164 (2011).

    Article  Google Scholar 

  17. 17

    Molloy, E. S. & Calabrese, L. H. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. 64, 3043–3051 (2012).

    CAS  Article  Google Scholar 

  18. 18

    Fredericks, C., Kvam, K., Bear, J., Crabtree, G. & Josephson, S. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus 23, 711–713 (2014).

    CAS  Article  Google Scholar 

  19. 19

    Padgett, B. L., Walker, D. L., ZuRhein, G. M., Eckroade, R. J. & Dessel, B. H. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet 1, 1257–1260 (1971).

    CAS  Article  Google Scholar 

  20. 20

    Berger, J. R. & Khalili, K. The pathogenesis of progressive multifocal leukoencephalopathy. Discov. Med. 12, 495–503 (2012).

    Google Scholar 

  21. 21

    Egli, A. et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J. Infect. Dis. 199, 837–46 (2009).

    CAS  Article  Google Scholar 

  22. 22

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

    Article  Google Scholar 

  23. 23

    Monaco, M. C., Jensen, P. N., Hou, J., Durham, L. C. & Major, E. O. Detection of JC virus DNA in human tonsil tissue: evidence for site of initial viral infection. J. Virol. 72, 9918–9923 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24

    Houff, S. & Berger, J. R. The bone marrow, B cells and JC virus. J. Neurovirol. 14, 341–343 (2008).

    Article  Google Scholar 

  25. 25

    Houff, S. A. 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. 318, 301–305 (1988).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

    Marzocchetti, A. 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 383, 173–177 (2009).

    CAS  Article  Google Scholar 

  28. 28

    Biogen Idec. Medical Information [online], (2014).

  29. 29

    Major, E. O. & Douek, D. C. Risk factors for rare diseases can be risky to define: PML and natalizumab. Neurology 81, 858–859 (2013).

    Article  Google Scholar 

  30. 30

    Zaheer, F. & Berger, J. R. Treatment-related progressive multifocal leukoencephalopathy: current understanding and future steps. Ther. Adv. Drug Saf. 3, 227–239 (2012).

    Article  Google Scholar 

  31. 31

    Vinhas de Souza, M. et al. Drug-induced PML: a global agenda for a global challenge. Clin. Pharmacol. Ther. 91, 747–750 (2012).

    CAS  Article  Google Scholar 

  32. 32

    Molloy, E. S. PML and rheumatology: the contribution of disease and drugs. Cleve. Clin. J. Med. 78 (Suppl. 2), S28–S32 (2011).

    Article  Google Scholar 

  33. 33

    Gheuens, S., Pierone, G., Peeters, P. & Koralnik, I. J. Progressive multifocal leukoencephalopathy in individuals with minimal or occult immunosuppression. J. Neurol. Neurosurg. Psychiatry 81, 247–254 (2010).

    Article  Google Scholar 

  34. 34

    Reuben, D. B. & Tinetti, M. E. Goal-oriented patient care—an alternative health outcomes paradigm. N. Engl. J. Med. 366, 777–779 (2012).

    CAS  Article  Google Scholar 

  35. 35

    European Commission. A guideline on summary of product characteristics [online], (2009).

  36. 36

    Frohman, E. M. et al. JC virus in CD34+ and CD19+ cells in patients with multiple sclerosis treated with natalizumab. JAMA Neurol. 71, 596–602 (2014).

    Article  Google Scholar 

  37. 37

    Major, E. O., Frohman, E. & Douek, D. JC viremia in natalizumab-treated patients with multiple sclerosis. N. Engl. J. Med. 368, 2240–2241 (2013).

    CAS  Article  Google Scholar 

  38. 38

    Berger, J. R. et al. JC virus antibody status underestimates infection rates. Ann. Neurol. 74, 84–90 (2013).

    Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Contributions

All authors contributed equally to researching data for the article, discussions of the content, writing the article and editing the manuscript before submission.

Corresponding author

Correspondence to Leonard H. Calabrese.

Ethics declarations

Competing interests

L.H.C. has served as consultant to Genentech, GlaxoSmithKline and Pfizer in the area of progressive multifocal leukoencephalopathy (PML). E.M. has obtained research support from Roche, has served on advisory boards for Bristol-Myers Squibb, Pfizer and MSD, and received payment for developing educational materials relating to PML from GlaxoSmithKline. J.B. serves on the PML Adjudication Committees of Amgen, Astra Zeneca, Bristol-Myers Squibb, Eisai, Janssen, Millennium, Parexel, Pfizer, Roche and Takeda; he is a consultant to Genentech, Genzyme, Incyte, Inhibikase Therapeutics, Johnson & Johnson and Novartis. He has received grants from the PML Consortium, Biogen Idec and Novartis.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Calabrese, L., Molloy, E. & Berger, J. Sorting out the risks in progressive multifocal leukoencephalopathy. Nat Rev Rheumatol 11, 119–123 (2015). https://doi.org/10.1038/nrrheum.2014.167

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing