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Medical Microbiology and Immunology

, Volume 204, Issue 5, pp 613–618 | Cite as

Increased frequency of JC-polyomavirus detection in rheumatoid arthritis patients treated with multiple biologics

  • Jens VerheyenEmail author
  • Kseniya Maizus
  • Eugen Feist
  • Zebulon Tolman
  • Elena Knops
  • Jasemine Saech
  • Lydia Spengler
  • Tim Waterboer
  • Gerd R. Burmester
  • Michael Pawlita
  • Herbert Pfister
  • Andrea Rubbert-Roth
Original Investigation

Abstract

Progressive multifocal leukoencephalopathy (PML) represents a rare but potentially fatal reactivation of JC-polyomavirus (JCPyV) recently also reported in patients with autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (RA) treated with rituximab. The aim of the present study was to analyse the pattern of JCPyV infections in patients with RA undergoing treatment with biologic agents. Urine and blood samples were analysed from 80 patients for antibody levels and/or the presence of JCPyV DNA. Genotyping of the control region and VP1 was performed for all JCPyV DNA-positive specimens. Viremia of JCPyV was only temporarily detected in two patients, and these viruses did not carry any mutations associated with the occurrence of PML. JCPyV DNA was prevalent in initial urine samples of 33 % of all patients. RA patients who have consecutively been treated with two or more biologic agents revealed significantly higher prevalence of JCPyV DNA in the urine compared to RA patients treated with their first biologic agent. The presence of JCPyV DNA in the urine closely correlated to JCPyV antibody positivity, and therefore, antibody titres were higher in RA patients who had consecutively received two or more biologic agents over time. Therefore, the overall number of biologic agents had an impact on the pattern of JCPyV detection in this study. Hence, JCPyV antibody screening might be useful as part of the PML risk stratification for RA patients in the future.

Keywords

Rheumatoid arthritis TNF-blocker Rituximab JC-polyomavirus 

Notes

Acknowledgments

This study was funded by grant FKZ 1369-401 from the German National Reference Center for Papillomaviruses and Polyomaviruses (German Federal Ministry of Health).

Conflict of interest

None.

References

  1. 1.
    Strangfeld A, Listing J, Herzer P, Liebhaber A, Rockwitz K, Richter C, Zink A (2009) Risk of herpes zoster in patients with rheumatoid arthritis treated with anti-TNF-alpha agents. JAMA 301(7):737–744. doi: 10.1001/jama.2009.146 CrossRefPubMedGoogle Scholar
  2. 2.
    Kappos L, Bates D, Edan G, Eraksoy M, Garcia-Merino A, Grigoriadis N, Hartung HP, Havrdova E, Hillert J, Hohlfeld R, Kremenchutzky M, Lyon-Caen O, Miller A, Pozzilli C, Ravnborg M, Saida T, Sindic C, Vass K, Clifford DB, Hauser S, Major EO, O’Connor PW, Weiner HL, Clanet M, Gold R, Hirsch HH, Radu EW, Sorensen PS, King J (2011) Natalizumab treatment for multiple sclerosis: updated recommendations for patient selection and monitoring. Lancet Neurol 10(8):745–758. doi: 10.1016/S1474-4422(11)70149-1 CrossRefPubMedGoogle Scholar
  3. 3.
    Clifford DB, Ances B, Costello C, Rosen-Schmidt S, Andersson M, Parks D, Perry A, Yerra R, Schmidt R, Alvarez E, Tyler KL (2011) Rituximab-associated progressive multifocal leukoencephalopathy in rheumatoid arthritis. Arch Neurol 68(9):1156–1164. doi: 10.1001/archneurol.2011.103 PubMedCentralCrossRefPubMedGoogle Scholar
  4. 4.
    Molloy ES, Calabrese LH (2009) Progressive multifocal leukoencephalopathy: a national estimate of frequency in systemic lupus erythematosus and other rheumatic diseases. Arthritis Rheum 60(12):3761–3765. doi: 10.1002/art.24966 CrossRefPubMedGoogle Scholar
  5. 5.
    Molloy ES, Calabrese LH (2012) Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies. Arthritis Rheum. doi: 10.1002/art.34468 PubMedGoogle Scholar
  6. 6.
    Antonsson A, Green AC, Mallitt KA, O’Rourke PK, Pawlita M, Waterboer T, Neale RE (2010) Prevalence and stability of antibodies to the BK and JC polyomaviruses: a long-term longitudinal study of Australians. J Gen Virol 91(Pt 7):1849–1853. doi: 10.1099/vir.0.020115-0 CrossRefPubMedGoogle Scholar
  7. 7.
    Egli A, Infanti L, Dumoulin A, Buser A, Samaridis J, Stebler C, Gosert R, Hirsch HH (2009) Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis 199(6):837–846CrossRefPubMedGoogle Scholar
  8. 8.
    Rinaldi L, Rinaldi F, Perini P, Calabrese M, Seppi D, Grossi P, Mattisi I, Barzon L, Mengoli C, Sanzari M, Palu 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 Psychiatr 81(12):1345–1350. doi: 10.1136/jnnp.2009.201079 CrossRefPubMedGoogle Scholar
  9. 9.
    Rudick RA, O’Connor PW, Polman CH, Goodman AD, Ray SS, Griffith NM, Jurgensen SA, Gorelik L, Forrestal F, Sandrock AW, EG 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 CrossRefPubMedGoogle Scholar
  10. 10.
    Gorelik L, Reid C, Testa M, Brickelmaier M, Bossolasco S, Pazzi A, Bestetti A, Carmillo P, Wilson E, McAuliffe M, Tonkin C, Carulli JP, Lugovskoy A, Lazzarin A, Sunyaev S, Simon K, Cinque P (2011) Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity. J Infect Dis 204(1):103–114. doi: 10.1093/infdis/jir198 PubMedCentralCrossRefPubMedGoogle Scholar
  11. 11.
    Gosert R, Kardas P, Major EO, Hirsch HH (2010) Rearranged JC virus noncoding control regions found in progressive multifocal leukoencephalopathy patient samples increase virus early gene expression and replication rate. J Virol 84(20):10448–10456. doi: 10.1128/JVI.00614-10 PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Kitamura T, Aso Y, Kuniyoshi N, Hara K, Yogo Y (1990) High incidence of urinary JC virus excretion in nonimmunosuppressed older patients. J Infect Dis 161(6):1128–1133CrossRefPubMedGoogle Scholar
  13. 13.
    Hirsch HH, Kardas P, Kranz D, Leboeuf C (2013) The human JC polyomavirus (JCPyV): virological background and clinical implications. APMIS 121(8):685–727. doi: 10.1111/apm.12128 CrossRefPubMedGoogle Scholar
  14. 14.
    Knowles WA, Pillay D, Johnson MA, Hand JF, Brown DW (1999) Prevalence of long-term BK and JC excretion in HIV-infected adults and lack of correlation with serological markers. J Med Virol 59(4):474–479CrossRefPubMedGoogle Scholar
  15. 15.
    Markowitz RB, Thompson HC, Mueller JF, Cohen JA, Dynan WS (1993) Incidence of BK virus and JC virus viruria in human immunodeficiency virus-infected and -uninfected subjects. J Infect Dis 167(1):13–20CrossRefPubMedGoogle Scholar
  16. 16.
    Wang M, Tsai RT, Ou WC, Lin CK, Tsay GJ, Chang H, Chang D (2000) Treatment with cytotoxic immunosuppression agents increases urinary excretion of JCV in patients with autoimmune disease. J Med Virol 62(4):505–510. doi: 10.1002/1096-9071(200012)62:4<505:AID-JMV16>3.0.CO;2-0 CrossRefPubMedGoogle Scholar
  17. 17.
    Bellizzi A, Anzivino E, Ferrari F, Di Nardo G, Colosimo MT, Fioriti D, Mischitelli M, Chiarini F, Cucchiara S, Pietropaolo V (2011) Polyomavirus JC reactivation and noncoding control region sequence analysis in pediatric Crohn’s disease patients treated with infliximab. J Neurovirol. doi: 10.1007/s13365-011-0036-3 PubMedGoogle Scholar
  18. 18.
    Arkema EV, van Vollenhoven RF, Askling J (2012) Incidence of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis: a national population-based study. Ann Rheum Dis. doi: 10.1136/annrheumdis-2012-201638 Google Scholar
  19. 19.
    Sundsfjord A, Osei A, Rosenqvist H, Van Ghelue M, Silsand Y, Haga HJ, Rekvig OP, Moens U (1999) BK and JC viruses in patients with systemic lupus erythematosus: prevalent and persistent BK viruria, sequence stability of the viral regulatory regions, and nondetectable viremia. J Infect Dis 180(1):1–9. doi: 10.1086/314830 CrossRefPubMedGoogle Scholar
  20. 20.
    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 CrossRefPubMedGoogle Scholar
  21. 21.
    Verheyen J, Kaiser R, Bozic M, Timmen-Wego M, Maier BK, Kessler HH (2012) Extraction of viral nucleic acids: comparison of five automated nucleic acid extraction platforms. J Clin Virol 54(3):255–259. doi: 10.1016/j.jcv.2012.03.008 CrossRefPubMedGoogle Scholar
  22. 22.
    Warnke C, Pawlita M, Dehmel T, Posevitz-Fejfar A, Hartung HP, Wiendl H, Kieseier BC, Adams O (2013) An assay to quantify species-specific anti-JC virus antibody levels in MS patients. Mult Scler 19(9):1137–1144. doi: 10.1177/1352458513475489 CrossRefPubMedGoogle Scholar
  23. 23.
    Lee P, Plavina T, Castro A, Berman M, Jaiswal D, Rivas S, Schlain B, Subramanyam M (2013) A second-generation ELISA (STRATIFY JCV DxSelect) for detection of JC virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol 57(2):141–146. doi: 10.1016/j.jcv.2013.02.002 CrossRefPubMedGoogle Scholar
  24. 24.
    Warnke C, von Geldern G, Markwerth P, Dehmel T, Hoepner R, Gold R, Pawlita M, Kumpfel T, Maurer M, Stangel M, Wegner F, Hohlfeld R, Straeten V, Limmroth V, Weber T, Hermsen D, Kleinschnitz C, Hartung HP, Wattjes MP, Svenningson A, Major E, Olsson T, Kieseier BC, Adams O (2014) Cerebrospinal fluid JC virus antibody index for diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 76(6):792–801. doi: 10.1002/ana.24153 CrossRefPubMedGoogle Scholar
  25. 25.
    Kardas P, Sadeghi M, Weissbach FH, Chen T, Hedman L, Auvinen E, Hedman K, Hirsch HH (2014) Inter- and intralaboratory comparison of JC polyomavirus antibody testing using two different virus-like particle-based assays. Clin Vaccine Immunol 21(11):1581–1588. doi: 10.1128/cvi.00489-14 PubMedCentralCrossRefPubMedGoogle Scholar
  26. 26.
    Pastrana DV, Wieland U, Silling S, Buck CB, Pfister H (2012) Positive correlation between Merkel cell polyomavirus viral load and capsid-specific antibody titer. Med Microbiol Immunol 201(1):17–23. doi: 10.1007/s00430-011-0200-7 PubMedCentralCrossRefPubMedGoogle Scholar
  27. 27.
    Du Pasquier RA, Schmitz JE, Jean-Jacques J, Zheng Y, Gordon J, Khalili K, Letvin NL, Koralnik IJ (2004) Detection of JC virus-specific cytotoxic T lymphocytes in healthy individuals. J Virol 78(18):10206–10210. doi: 10.1128/jvi.78.18.10206-10210.2004 PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Perkins MR, Ryschkewitsch C, Liebner JC, Monaco MC, Himelfarb D, Ireland S, Roque A, Edward HL, Jensen PN, Remington G, Abraham T, Abraham J, Greenberg B, Kaufman C, LaGanke C, Monson NL, Xu X, Frohman E, Major EO, Douek DC (2012) Changes in JC virus-specific T cell responses during natalizumab treatment and in natalizumab-associated progressive multifocal leukoencephalopathy. PLoS Pathog 8(11):e1003014. doi: 10.1371/journal.ppat.1003014 PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Weist BJ, Schmueck M, Fuehrer H, Sattler A, Reinke P, Babel N (2014) The role of CD4(+) T cells in BKV-specific T cell immunity. Med Microbiol Immunol 203(6):395–408. doi: 10.1007/s00430-014-0348-z CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Jens Verheyen
    • 1
    • 2
    Email author
  • Kseniya Maizus
    • 3
  • Eugen Feist
    • 4
  • Zebulon Tolman
    • 1
  • Elena Knops
    • 1
  • Jasemine Saech
    • 3
  • Lydia Spengler
    • 4
  • Tim Waterboer
    • 5
  • Gerd R. Burmester
    • 4
  • Michael Pawlita
    • 5
  • Herbert Pfister
    • 1
  • Andrea Rubbert-Roth
    • 3
  1. 1.Institute of Virology, National Reference Center for Papilloma- and PolyomavirusesUniversity of CologneCologneGermany
  2. 2.Institute of Virology, University HospitalUniversity Duisburg-EssenEssenGermany
  3. 3.Department of Medicine IUniversity of CologneCologneGermany
  4. 4.Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin BerlinFree University and Humboldt University of BerlinBerlinGermany
  5. 5.Infection and Cancer Program, Division of Genome Modifications and CarcinogenesisGerman Cancer Research Center (DKFZ)HeidelbergGermany

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