Correspondence

Asymptomatic Reactivation of JC Virus in Patients Treated with Natalizumab

N Engl J Med 2009; 361:2487-2490December 17, 2009

Article

To the Editor:

Chen and colleagues (Sept. 10 issue)1 describe an increased prevalence of JC virus DNA in 19 patients with multiple sclerosis after 12 to 18 months of treatment with natalizumab. These findings contrast with results from other groups2-4 and large studies by Biogen Idec and Elan Pharmaceuticals5 (Table 1Table 1Recent Studies Assessing the Prevalence of JC Virus in Patients with Multiple Sclerosis Treated with Natalizumab.).

Data from one ongoing study showed no increase in the prevalence of JC virus in plasma, urine, or peripheral-blood mononuclear cells (PBMCs) after 12 months of natalizumab treatment2; another showed no increase in the presence of JC virus in serum for up to 30 months.3 A third study showed no increase over baseline in the presence of JC virus in urine or plasma over 15 months of therapy.4 In a safety study of natalizumab involving 1397 patients with a mean exposure of 22 months,5 JC virus was detected in plasma in 0.3% of patients; this is similar to the incidence in untreated adults. In a 48-week study involving patients treated with natalizumab, there was no increase in the frequency of JC virus in plasma or urine, and JC virus was not detected in PBMCs.5 In more than 2000 patients with multiple sclerosis who were treated for up to 2 years, natalizumab was not associated with an increased presence of JC virus. Possible reasons for this discrepancy with the study reported on by Chen et al. include study size and methodologic differences.

Leonid Gorelik, Ph.D.
Susan Goelz, Ph.D.
Alfred W. Sandrock, M.D., Ph.D.
Biogen Idec, Cambridge, MA
leonid.gorelik@biogenidec.com

Drs. Gorelik, Goelz, and Sandrock report being employees of and having equity interest in Biogen Idec. No other potential conflict of interest relevant to this letter was reported.

5 References

1. 1

   Chen Y, Bord E, Tompkins T, et al. Asymptomatic reactivation of JC virus in patients treated with natalizumab. N Engl J Med 2009;361:1067-1074
   Full Text | Web of Science | Medline

2. 2

   Jilek Terrase S, Lysandropoulos A, Jaquiery E, et al. Viral- and myelin-specific cellular immune response in MS patients treated with natalizumab: a cross-sectional and a longitudinal study. J Neuroviral 2009;15:Suppl 1:39-40
   Web of Science

3. 3

   Varnier OE, McDermott JL, Giacommazzi CG, et al. A non-invasive surveillance of JCV reactivation in blood and urine from natalizumab treated MS patients, blood donors and immunocompromised patients identifies five PML cases in HIV and congenital immunodeficiency patients. Presented at the 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Düsseldorf, Germany, September 9–12, 2009.
   

4. 4

   De Gascun C, Carr M, Lonergan RM, et al. Reactivation of latent viral infections in patients receiving natalizumab for the treatment of multiple sclerosis. J Neuroviral 2009;15:Suppl 1:22-23
   Web of Science

5. 5

   Rudick RA, Polman CH, O'Connor PW, et al. Evaluation of natalizumab treatment on the presence of JC virus in blood and urine from multiple sclerosis patients. Mult Scler 2009;15:Suppl:S274-S275
   CrossRef | Web of Science

To the Editor:

In contrast to the findings reported by Chen et al., in a large Irish cohort of 57 patients (41 women and 16 men) receiving natalizumab for multiple sclerosis and monitored since January 2007, we detected JC reactivation in urine samples from 1 of 52 patients (1.9%). This reactivation occurred after the first dose of natalizumab and cleared after the second dose; JC viremia (in plasma) did not occur. Conversely, BK reactivation in urine occurred in 12 of 54 patients (22.2%), and viruria preceded transient BK viremia in 2 patients.1

These contrasting findings in different cohorts of patients with multiple sclerosis raise the possibility of genetic predisposition or environmental factors as contributory factors leading to polyomavirus reactivation. Large collaborative international studies are warranted to determine whether polyomavirus reactivation after natalizumab therapy is a class effect of this new and promising drug family, which host factors may account for differential patterns of polyomavirus reactivation, and the clinical relevance of polyomavirus reactivation in the increasing numbers of patients receiving this class of drug.

Cillian F. De Gascun, M.B.
National Virus Reference Laboratory, Dublin, Ireland
cfbdeg@hotmail.com

Roisin M. Lonergan, M.B.
St. Vincent's University Hospital, Dublin, Ireland

William W. Hall, M.D., Ph.D.
National Virus Reference Laboratory, Dublin, Ireland

1 References

1. 1

   Lonergan RM, Carr MJ, De Gascun CF, et al. Reactivation of BK polyomavirus in patients with multiple sclerosis receiving natalizumab therapy. J Neurovirol 2009 August 9 (Epub ahead of print).
   

To the Editor:

Chen and colleagues report subclinical reactivation of JC virus, the cause of progressive multifocal leukoencephalopathy (PML), in patients with multiple sclerosis treated with natalizumab. Natalizumab is known to interfere with the adhesion of hematopoietic progenitor cells in the bone marrow,1,2 a potential reservoir for JC virus.3 In two different protocols with different primer pairs and settings in a study involving 67 patients with multiple sclerosis treated with natalizumab, we used quantitative real-time polymerase chain reaction (PCR) to detect the presence of JC virus DNA in plasma, PBMCs, and magnetically separated CD34+ hematopoietic progenitor cells. PBMCs were obtained from EDTA blood samples by means of Ficoll–Paque density-gradient centrifugation (GE Healthcare). Total CD34+ cells were isolated by means of positive magnetic-bead–assisted cell separation according to the manufacturer's instructions (Miltenyi Biotec).

We were unable to detect JC virus DNA in any of the cellular samples (Table 1Table 1JC Viral Loads in Patients with Multiple Sclerosis Treated with Natalizumab.). There was only a transient DNA expression in two plasma samples. Thus, we were unable to reproduce the findings reported by Chen et al., although we applied the same PCR protocol.4 In addition, we could not detect JC virus DNA in CD34+ cells. We think that, on the basis of all published data, the pathogenesis of PML in patients treated with natalizumab remains elusive. Further studies in large and diverse populations with the use of standardized experimental protocols are warranted.

Clemens Warnke, M.D.
Ortwin Adams, M.D.
Bernd C. Kieseier, M.D.
Heinrich Heine University, Düsseldorf, Germany
bernd.kieseier@uni-duesseldorf.de

Dr. Kieseier reports receiving lecture fees, travel support, and grant support from Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis, and Teva. No other potential conflict of interest relevant to this letter was reported.

4 References

1. 1

   Bonig H, Wundes A, Chang KH, Lucas S, Papayannopoulou T. Increased numbers of circulating hematopoietic stem/progenitor cells are chronically maintained in patients treated with the CD49d blocking antibody natalizumab. Blood 2008;111:3439-3441
   CrossRef | Web of Science | Medline

2. 2

   Zohren F, Toutzaris D, Klarner V, Hartung HP, Kieseier B, Haas R. The monoclonal anti-VLA-4 antibody natalizumab mobilizes CD34+ hematopoietic progenitor cells in humans. Blood 2008;111:3893-3895
   CrossRef | Web of Science | Medline

3. 3

   Major EO. Reemergence of PML in natalizumab-treated patients -- new cases, same concerns. N Engl J Med 2009;361:1041-1043
   Full Text | Web of Science | Medline

4. 4

   Ryschkewitsch C, Jensen P, Hou J, Fahle G, Fischer S, Major EO. Comparison of PCR-southern hybridization and quantitative real-time PCR for the detection of JC and BK viral nucleotide sequences in urine and cerebrospinal fluid. J Virol Methods 2004;121:217-221
   CrossRef | Web of Science | Medline

Author/Editor Response

We indeed found a significant decrease in the magnitude of the JC virus–specific cellular immune response between 6 and 12 months of natalizumab treatment, followed by an increased incidence of viruria at 12 months and the appearance of viremia at 18 months. JC virus was more frequently detected in PBMCs than in plasma, and JC virus regulatory-region sequences in urine and blood samples from several patients showed characteristics that are usually detected in isolates from the central nervous system from patients with PML. BK viruria remained stable, and BK virus was not detected in any blood samples.

Our results highlight the need to focus on PBMCs rather than plasma and to extend investigations until at least 18 months of natalizumab therapy, which was not the case in any of the studies mentioned by Gorelik et al.; these studies had shorter follow-up or did not include PBMCs.

When detectable, the JC viral load in blood is low, ranging from 28 to 880 copies per microgram of DNA in PBMCs in our patients with multiple sclerosis. Population characteristics and differences in methods for harvesting PBMCs, extracting DNA, and setting up the PCR reaction may account for the variability in the level of JC virus detection in PBMCs in different laboratories. Nevertheless, other investigators have also detected JC virus DNA in the plasma and blood cells of patients with multiple sclerosis who have received natalizumab.1 However, JC virus is more abundant in urine, and the low frequency found by De Gascun et al. in the urine of Irish patients with multiple sclerosis who were treated with natalizumab2 is surprising, since the same group recently reported a 20.7% incidence of JC viruria among healthy Irish people.3

The data from Warnke et al. do not confirm Major's attractive hypothesis that CD34+ hematopoietic progenitor cells, released in the circulation early during natalizumab treatment, are infected with JC virus.4 Therefore, the phenotype of leukocytes harboring JC virus in this population remains undetermined.

In seven of the last eight cases of multiple sclerosis and PML reported as of July 24, 2009, the patients had received natalizumab for 24 to 35 months, therefore raising concern that the incidence of PML will increase with the number of natalizumab infusions received.5 Furthermore, an additional 10 cases were reported in the 3 months before October 23, 2009, which brings to 23 the total number of natalizumab-associated cases of PML in patients with multiple sclerosis. Thus, we agree that further international studies with comprehensive virologic, immunologic, and clinical approaches are needed to better understand the mechanisms by which natalizumab triggers JC virus reactivation and to mitigate the risk of PML among this patient population.

Chen S. Tan, M.D.
R. Philip Kinkel, M.D.
Igor J. Koralnik, M.D.
Beth Israel Deaconess Medical Center, Boston, MA
ikoralni@bidmc.harvard.edu

5 References

1. 1

   Perkins MRC, Monaco-Kushner MC, Himelfarb D, et al. JC virus-specific T-cell responses in natalizumab-treated individuals: immune targets and viremia. In: Program and abstracts of the 3rd meeting on HIV Infection and the Central Nervous System, Stresa, Italy, October 24–29, 2009:42.
   

2. 2

   Lonergan RM, Carr MJ, De Gascun CF, et al. Reactivation of BK polyomavirus in patients with multiple sclerosis receiving natalizumab therapy. J Neurovirol 2009 August 9 (Epub ahead of print).
   

3. 3

   Schaffer K, Sheehy N, Coughlan S, Bergin C, Hall WW. JC virus in the Irish population: significant increase of genotype 2 in immunocompromised individuals. J Neurovirol 2006;12:39-46
   CrossRef | Web of Science | Medline

4. 4

   Major EO. Reemergence of PML in natalizumab-treated patients -- new cases, same concerns. N Engl J Med 2009;361:1041-1043
   Full Text | Web of Science | Medline

5. 5

   FDA MedWatch. Safety alert for human medical products: natalizumab (marketed as Tysabri). Silver Spring, MD: Department of Health and Human Services, 2009. (Accessed November 23, 2009, at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm182667.htm.)
   

Citing Articles (10)

Citing Articles

1. 1

   Eleonora Tavazzi, Martyn K. White, Kamel Khalili. (2012) Progressive multifocal leukoencephalopathy: clinical and molecular aspects. Reviews in Medical Virology 22:1, 18-32
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2. 2

   Henrik Gensicke, David Leppert, Özgür Yaldizli, Raija L.P. Lindberg, Matthias Mehling, Ludwig Kappos, Jens Kuhle. (2012) Monoclonal Antibodies and Recombinant Immunoglobulins for the Treatment of Multiple Sclerosis. CNS Drugs 26:1, 11-37
   CrossRef

3. 3

   O. Fernández, J.A. García-Merino, R. Arroyo, J.C. Álvarez-Cermeño, T. Arbizu, G. Izquierdo, A. Saiz, J.Olascoaga, A. Rodríguez-Antigüedad, J.M. Prieto, C. Oreja-Guevara, M.A. Hernández, X. Montalbán. (2011) Consenso español sobre la utilización de natalizumab (Tysabri®) - 2011. Neurología
   CrossRef

4. 4

   C. Warnke, O. Adams, R. Gold, H.-P. Hartung, R. Hohlfeld, H. Wiendl, B.C. Kieseier. (2011) Progressive multifokale Leukenzephalopathie unter Natalizumab. Der Nervenarzt 82:4, 475-480
   CrossRef

5. 5

   Bruce J. Brew, Nicholas W. S. Davies, Paola Cinque, David B. Clifford, Avindra Nath. (2010) Progressive multifocal leukoencephalopathy and other forms of JC virus disease. Nature Reviews Neurology 6:12, 667-679
   CrossRef

6. 6

   Richard A. Rudick, Paul W. O'Connor, Chris H. Polman, Andrew D. Goodman, Soma S. Ray, Nancy M. Griffith, Stephanie A. Jurgensen, Leonid Gorelik, Fiona Forrestal, Alfred W. Sandrock, Susan E. Goelz. (2010) Assessment of JC virus DNA in blood and urine from natalizumab-treated patients. Annals of Neurology 68:3, 304-310
   CrossRef

7. 7

   (2010) Current awareness: Pharmacoepidemiology and drug safety. Pharmacoepidemiology and Drug Safety 19:6, i-xiii
   CrossRef

8. 8

   Mathias Buttmann. (2010) Treating multiple sclerosis with monoclonal antibodies: a 2010 update. Expert Review of Neurotherapeutics 10:5, 791-809
   CrossRef

9. 9

   Chen S Tan, Igor J Koralnik. (2010) Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. The Lancet Neurology 9:4, 425-437
   CrossRef

10. 10

    David B Clifford, Andrea DeLuca, David M Simpson, Gabriele Arendt, Gavin Giovannoni, Avindra Nath. (2010) Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. The Lancet Neurology 9:4, 438-446
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