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Urinary JCV-DNA Testing during Natalizumab Treatment May Increase Accuracy of PML Risk Stratification

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Abstract

The risk of progressive multifocal leukoencephalopathy (PML) in patients treated with natalizumab for multiple sclerosis (MS) is a serious concern. The presence of anti-JC virus antibodies is a risk factor for PML development, but 2.5 % of the patients result falsely-negative, while the prognostic relevance of testing JCV-DNA in biological fluids of treated patients is debated. Aim of this work was to evaluate the utility of testing JCV-DNA, together with anti-JCV antibodies, in biological samples of treated patients as a tool for PML risk stratification. 126 subjects from 5 MS Centers in Italy were included in the study. We performed a cross-sectional study in 63 patients testing JCV-DNA in blood, peripheral blood cells and urine. We longitudinally assessed the presence of JCV-DNA in a cohort of 33 subjects, one of which developed PML. We could test retrospectively serum samples from another PML case occurred during natalizumab therapy. Anti-JCV antibodies and urinary JCV-DNA were both tested in 73 patients. No changes in JCV-DNA status occurred during natalizumab treatment. The subject who developed PML in the longitudinal cohort had detectable JCV-DNA in urine at all time-points while serum or blood from both PML patients were always negative before the onset of disease and, in one case, after. Four subjects with JCV-DNA in urine and undetectable anti-JCV antibodies were retested for anti-JCV antibodies and three out of four resulted positive. In conclusion, testing JCV-DNA in urine is complementary to testing anti-JCV antibodies in identifying patients at risk of PML.

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References

  • Abstracts (2010) Mult Scler 16(10 suppl):S7–S352. doi:10.1177/1352458510383204

  • Chen Y, Bord E, Tompkins T, Miller J, Tan CS, Kinkel RP, Stein MC, Viscidi RP, Ngo LH, Koralnik IJ (2009) Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 361(11):1067–1074. doi:10.1056/NEJMoa0904267

    Article  PubMed  CAS  Google Scholar 

  • Chesters PM, Heritage J, McCance DJ (1983) Persistence of DNA sequences of BK virus and JC virus in normal human tissues and in diseased tissues. J Infect Dis 147(4):676–684

    Article  PubMed  CAS  Google Scholar 

  • Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, Nath A (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol 9(4):438–446. doi:10.1016/S1474-4422(10)70028-4

    Article  PubMed  CAS  Google Scholar 

  • Gorelik L, Lerner M, Bixler S, Crossman M, Schlain B, Simon K, Pace A, Cheung A, Chen LL, Berman M, Zein F, Wilson E, Yednock T, Sandrock A, Goelz SE, Subramanyam M (2010) Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 68(3):295–303. doi:10.1002/ana.22128

    Article  PubMed  Google Scholar 

  • Jilek S, Jaquiéry E, Hirsch HH, Lysandropoulos A, Canales M, Guignard L, Schluep M, Pantaleo G, Du Pasquier RA (2010) Immune responses to JC virus in patients with multiple sclerosis treated with natalizumab: a cross-sectional and longitudinal study. Lancet Neurol 9(3):264–272

    Article  PubMed  CAS  Google Scholar 

  • Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D (2005) Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med 353(4):375–381

    Article  PubMed  CAS  Google Scholar 

  • Militello V, Trevisan M, Squarzon L, Biasolo MA, Rugge M, Militello C, Palu G, Barzon L (2009) Investigation on the presence of polyomavirus, herpesvirus, and papillomavirus sequences in colorectal neoplasms and their association with cancer. Int J Cancer 124(10):2501–2503. doi:10.1002/ijc.24224

    Article  PubMed  CAS  Google Scholar 

  • Parallel Session 13 — Late Breaking News (2009) Mult Scler 15(9 suppl):S271–S277. doi:10.1177/1352458509107025

    Article  Google Scholar 

  • Rolla D, Giacomazzi CG, Gentile R, Ravetti JL, Cannella G, Varnier OE (2009) Kidney graft loss associated with JC polyomavirus nephropathy. J Nephrol 22(2):295–298

    PubMed  Google Scholar 

  • Rudick RA, O’Connor PW, Polman CH, Goodman AD, Ray SS, Griffith NM, Jurgensen SA, Gorelik L, Forrestal F, Sandrock AW, E Goelz S (2010) Assessment of JC virus DNA in blood and urine from natalizumab-treated patients. Ann Neurol 68(3):304–310. doi:10.1002/ana.22107

    Article  PubMed  Google Scholar 

  • Sadiq S, Puccio L, Brydon E (2010) JCV detection in multiple sclerosis patients treated with natalizumab. J Neurol 257(6):954–958. doi:10.1007/s00415-009-5444-4

    Article  PubMed  CAS  Google Scholar 

  • Sandrock A, Hotermans C, Richman S, Natarajan A, Lee S, Plavina T, Bloomgreen G, Subramanyam M, Bozic C (2011) Risk stratification for progressive multifocal leukoencephalopahty (PML) in MS patients: role of prior immunosuppressant use, natalizumab-treatment duration and anti-JCV antibody status. Neurology 76(9: S4):Poster P03-248

  • Tan CS, Chen Y, Viscidi RP, Kinkel RP, Stein MC, Koralnik IJ (2010) Discrepant findings in immune responses to JC virus in patients receiving natalizumab. Lancet Neurol 9(6):565–566

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was partially supported by Italian Ministry of Health, grant CCM 2009

A. Laroni work was supported by a grant from Fondazione Italiana Sclerosi Multipla, FISM 2009 (Prot. N. 297/09/F14)

Conflict of interest

Laroni A. received honoraria for speaking by Biogen-Dompé, received funding for travel from Bayer-Schering, Biogen-Dompé, Merck Serono, and Sanofi Aventis and a grant from Fondazione Italiana Sclerosi Multipla.

Giacomazzi C.G., declares no conflict of interest

Grimaldi L. served on a scientific advisory board for Merck Serono; has received funding for travel or speaker honoraria from Merck Serono, Biogen-Dompé, Sanofi- Aventis, Bayer Schering, and Solvay Pharmaceuticals, Inc.; has received institutional research support from Teva, Biogen Idec, Genzyme Corporation, Sanofi-Aventis, Merck Serono, Novartis, and Eisai Inc.; has received research support from Merck Serono, Biogen-Dompé, and Ministero della Salute

Gallo P. has been a member of scientific boards supported by Novartis, Biogen-Elan, Merck Serono, Sanofi-Aventis, and Bayer-Schering; has been a consultant for Biogen-Elan, Sanofi-Aventis, and Bayer-Schering; has given expert testimony for Biogen-Dompé Italy, Sanofi-Aventis, and Merck Serono; has received honoraria from Novartis Farma, Biogen-Elan, Sanofi-Aventis, Merck Serono, and Bayer-Schering; and has had travel/accommodations expenses covered or reimbursed by University of Padova, Novartis Farma, Sanofi-Aventis, Biogen-Dompé Italy, Merck Serono, and Bayer-Schering

Sormani MP. serves on a scientific advisory board for Biogen Idec; has received funding for travel and speaker honoraria from Merck Serono; has served as a consultant to Actelion Pharmaceuticals Ltd., Merck Serono and Biogen Idec; and serves on speakers’ bureaus for Teva Pharmaceutical Industries Ltd., Merck Serono, and Biogen Idec.

Bertolotto A has been on steering committees in clinical trials sponsored by Biogen Idec, Roche; has received speaker honoraria from Biogen Idec, Merck Serono, Teva, Bayer Schering, Sanofi-Aventis, and Novartis; has been a member of scientific boards supported by Allergan, Almirall; has received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis, and from the Italian Multiple Sclerosis Society.

Gandoglia I., has received funding for travel by Sanofi Aventis

McDermott JL declares no conflict of interest

Martini I., declares no conflict of interest

Vitello G. declares no conflict of interest

Rinaldi F. received honoraria for speaking by Biogen-Dompé, received funding for travel fom Biogen-Dompé, Sanofi Aventis and Novartis

Barzon L., declares no conflict of interest

Militello V. declares no conflict of interest

Pizzorno M. declares no conflict of interest

Bandini F. declares no conflict of interest

Capello E. received honoraria for speaking by Biogen-Dompé and Innogenetics; received funding for travel fom Biogen-Dompé, Merck Serono, Sanofi-Aventis and Novartis

Palù G, declares no conflict of interest

Uccelli A., received financial support honoraria for consultation, speaking or both at meeting for Biogen Idec, Biogen-Dompé, Genetech, Roche, Allergan, Merck Serono, Bayer-Schering, Novartis and Sanofi-Aventis. He also received financial support for research form Fondazione Italiana Sclerosi Multipla, Fondazione CARIGE, Fondazione CARIPLO, the Italian Ministry of Health (Ricerca Finalizzata), the Italian Ministry of the University and Scientific Research (MIUR), the “Regione Liguria” (Limonte Project) and Merck Serono.

Mancardi G.L. received financial support for research, honoraria for consultation, speaking or both at meeting for Bayer-Schering, Biogen-Idec, Sanofi-Aventis and Merck Serono, the Fondazione Italiana Sclerosi Multipla (FISM), the Italian Ministry of Health (Ricerca Finalizzata), the Italian Ministry of the University and Scientific Research (MIUR) and the Fondazione CARIGE.

Varnier O.E. reports no disclosures. Received financial support for research from Biogen-Idec and the Italian Ministry of Health

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Authors and Affiliations

  1. Department of Neuroscience, Ophthalmology and Genetics, University of Genova, Via De Toni 5, 16132, Genoa, Italy

    A. Laroni, I. Gandoglia, E. Capello, A. Uccelli & G. L. Mancardi

  2. Laboratory of Microbiology and Virology, Department of Surgery and Diagnostics (DICS), University of Genova, Genoa, Italy

    C. G. Giacomazzi, I. Martini & O. E. Varnier

  3. Division of Neurology, Fondazione Istituto San Raffaele “G. Giglio”, Cefalù, Palermo, Italy

    L. Grimaldi & G. Vitello

  4. Multiple Sclerosis Centre, Neurology Unit, Department of Neurosciences, University of Padova, Padua, Italy

    P. Gallo & F. Rinaldi

  5. Biostatistics Unit, Department of Health Sciences, University of Genova, Genoa, Italy

    M. P. Sormani

  6. Neurology 2, Regional Reference Center for Multiple Sclerosis, University Hospital San Luigi Gonzaga, Orbassano, Torino, Italy

    A. Bertolotto

  7. Laboratory of Microbiology and Virology, San Martino Hospital, Genoa, Italy

    J. L. McDermott

  8. Department of Histology, Microbiology and Medical Biotechnologies, University of Padova, Padua, Italy

    L. Barzon, V. Militello & G. Palù

  9. Division of Neurology, San Paolo Hospital, Savona, Italy

    M. Pizzorno & F. Bandini

Authors
  1. A. Laroni
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  2. C. G. Giacomazzi
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  3. L. Grimaldi
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  4. P. Gallo
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  5. M. P. Sormani
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  6. A. Bertolotto
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  7. J. L. McDermott
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  8. I. Gandoglia
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  9. I. Martini
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  10. G. Vitello
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  11. F. Rinaldi
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  12. L. Barzon
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  13. V. Militello
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  14. M. Pizzorno
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  15. F. Bandini
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  16. E. Capello
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  17. G. Palù
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  18. A. Uccelli
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  19. G. L. Mancardi
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  20. O. E. Varnier
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Corresponding author

Correspondence to G. L. Mancardi.

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Laroni, A., Giacomazzi, C.G., Grimaldi, L. et al. Urinary JCV-DNA Testing during Natalizumab Treatment May Increase Accuracy of PML Risk Stratification. J Neuroimmune Pharmacol 7, 665–672 (2012). https://doi.org/10.1007/s11481-012-9366-z

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  • DOI: https://doi.org/10.1007/s11481-012-9366-z

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