567728
research-article2015
MSJ0010.1177/1352458514567728Multiple Sclerosis JournalA Vennegoor
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Longitudinal JCV serology in multiple sclerosis patients preceding natalizumab-associated progressive multifocal leukoencephalopathy
Multiple Sclerosis Journal 1–4 DOI: 10.1177/ 1352458514567728 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Anke Vennegoor, Johannis A van Rossum, Chris H Polman, Mike P Wattjes and Joep Killestein
Abstract: The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MS patients treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. We here describe extensive longitudinal serum anti-JCV antibody indexes of four MS patients who developed PML. Anti-JCV antibodies were measured using the STRATIFY JCV™DxSelect™ test. All four patients had rather stable high anti-JCV antibody indexes in all samples obtained before developing PML. Possibly caused by reaching the saturation level of the assay, no increase in anti-JCV antibody indexes was seen just before the diagnosis of PML. This study confirms that high serum anti-JCV antibody indexes precede natalizumab-associated PML. Keywords: Multiple sclerosis, natalizumab, John Cunningham Virus (JCV), progressive multifocal leukoencephalopathy (PML) Date received: 5 August 2014; accepted: 11 December 2014 Introduction Progressive multifocal leukoencephalopathy (PML), which is caused by a reactivation of the John Cunningham Virus (JCV) is a serious complication in multiple sclerosis (MS) patients treated with natalizumab. Anti-JCV antibodies are associated with a higher risk of PML.1,2 It is hypothesized that this risk of developing PML is higher in patients with high anti-JCV antibody indexes in pre-PML samples.2-5 However, in studies presented so far, only very limited longitudinal samples were available. We here report four MS patients who developed PML during natalizumab treatment in whom extensive pre-PML samples were available. Methods Patients and materials All relapsing–remitting (RR) MS patients treated with natalizumab in the MS Centre Amsterdam, The Netherlands, were sampled before natalizumab initiation and at three-monthly intervals. If applicable, samples were also taken at the time PML-immune
reconstitution inflammatory syndrome (IRIS) was established and during plasmapheresis (PLEX) treatment. All serum samples were stored at –80ºC until shipped in one batch and assayed under masked conditions for clinical data at Unilabs, Denmark. Anti-JCV antibodies were measured using the two-step second-generation JCV antibody ELISA (STRATIFY JCV™DxSelect™), as previously described.3,6 After the first step, serum was classified as negative (index 0.40). The second step, a confirmation test using pre-incubated samples with in-solution JC viruslike particles, was only performed in serum, which showed an intermediate response. In the case of the percentage inhibition being ≤45%, serum was considered definitive negative, and if the percentage inhibition was >45%, it was considered definitive positive. Analytical sensitivities in monoclonal antibody equivalents are 60 ng/ml. We received quantitative results expressed as index values. Four patients developed natalizumab-associated PML. The diagnosis was confirmed in three patients by detection of JCV DNA by quantitative polymerase chain
Correspondence to: A Vennegoor MS Centre, Department of Neurology, VU University Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. [email protected] Anke Vennegoor Johannis A van Rossum Chris H Polman Joep Killestein Department of Neurology, MS Centre Amsterdam, VU Medical Centre, The Netherlands Mike P Wattjes Department of Radiology, MS Centre Amsterdam, VU Medical Centre, The Netherlands
http://msj.sagepub.com 1
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Multiple Sclerosis Journal reaction (qPCR) in the cerebrospinal fluid (CSF). In the other patient, MRI lesions were characteristic for PML, but no JCV DNA was detected by qPCR in the CSF. PML diagnosis was further confirmed by clinical and MRI follow-up demonstrating a PML-IRIS five weeks after PLEX (for further details on PML diagnosis, see Wattjes et al.7). This study was approved by the local institutional board (reference 2014.256). Informed consent was obtained from all participants. Statistical analysis Since the anti-JCV antibody index was not normally distributed, log-transformation was performed. Subsequently, generalized estimating equations were used to investigate the association between anti-JCV antibody indexes and the presence of PML. Results are reported with their 95% confidence interval (CI). For continuous paired data, the Wilcoxon signed rank test was applied. The statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 20.0 (SPSS, Inc., Chicago, IL, USA), with a statistical significance level of 0.05. Results In this group of 193 consecutive patients with RRMS who were treated with natalizumab, four patients developed PML. The mean age at first sample collection was 34.8 years old in the PML patients and 36.3 years in the non-PML patients. Two patients with PML (50%) were women versus 131 (69%) in the non-PML patients. None of the PML patients used prior immunosuppressive medication. In the four patients with PML serum anti-JCV antibody indexes were already high at baseline and subsequently in all available samples until PML diagnosis. (Figure 1(a) to (d)). From three patients, pre-natalizumab anti-JCV antibody indexes were available and already showed high indexes before start of treatment. The median anti-JCV antibody index before and during natalizumab therapy in these four patients was 3.04 with a range of 2.04–3.59. In all four patients, the antiJCV antibody indexes had been relatively stable for years. Importantly, no meaningful increase was seen in the samples at the time of the diagnosis of PML compared with the baseline sample (median 3.05 vs. 3.16, p=0.72) or compared with the sample before diagnosis was made (median 3.05 vs. 2.78, p=0.07). From the 189 RRMS patients treated with natalizumab therapy who did not develop PML, we
obtained 669 serum samples, in which we measured the anti-JCV antibody index. These samples were obtained before and after the initiation of natalizumab treatment. Of the 176 patients in whom at least two samples were available, one of which after the start of natalizumab, 79 patients (44.9%) tested seronegative and 97 patients (55.1%) seropositive at the first moment of testing. The median index in the natalizumab treated MS patients who were positive at baseline and stayed positive or had no follow-up sample, but did not develop PML, was 2.105 with a range of 0.260-3.941. The patients who developed PML had a 1.82 times (95% CI 1.51–2.19, p 3.0), the explanation might be that high indexes technically cannot increase by reaching the saturation level of the assay.5 Until now, known risk factors for PML have been treatment duration with natalizumab for more than two years, prior immunosuppressive therapy, and positive JCV status in serum. The duration of treatment of the four PML patients varied between 14 and 78 (mean 53) infusions. None of them had used immunosuppressive medication prior to natalizumab. In this study we have shown that patients who developed natalizumab-associated PML had a consistently high anti-JCV antibody index which was even 1.82 times higher than in the JCV positive patients not developing PML. These findings confirm that the height of anti-JCV antibody indexes in serum may have additional prognostic value for the risk of developing PML, as was suggested in previous studies in which limited longitudinal samples were obtained.2-5
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A Vennegoor, JA van Rossum et al.
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Figure 1. Longitudinal anti-JCV antibody indexes of four natalizumab-associated progressive multifocal leukoencephalopathy (PML) patients. In all PML patients a relatively stable anti-John Cunningham Virus (JCV) antibody index is seen. In patient (c), a minor increase in index is seen just before diagnosing the PML. After the diagnosis, plasmapheresis (PLEX) is started immediately. At the moment PLEX is started, there is a decrease of the anti-JCV antibody index, which increases again after the PLEX is stopped. In this patient (c), multiple samples before initiation of natalizumab show that already more than a year before start of treatment a high anti-JCV antibody index is seen, which does not show a further increase after start of the natalizumab. : Start natalizumab. : Diagnosis of PML. : Median anti-JCV antibody index in MS patients without PML. : Intravenous methylprednisolone 1000 mg for three days.
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Multiple Sclerosis Journal In particular, Plavina et al. recently published that higher anti-JCV antibody index, that is, > 1.5, is associated with a higher PML risk.5 In addition, we here confirm that anti-JCV antibody indexes decreased during PLEX, which was also described by Subramanyam et al.8 Furthermore, in line with data published by Ryschkewitsch and colleagues earlier,9 we also found that anti-JCV antibodies increased after the PLEX treatment was discontinued. In conclusion, we here show that natalizumab-associated PML can be associated with rather stable high anti-JCV antibody indexes in pre-PML samples obtained long before PML diagnosis was established. Possibly caused by reaching the saturation level of the assay, an increase of the anti-JCV antibody index in pre-PML samples, as previously suggested, has not been observed in our patients. Our findings are in line with the recently published findings of Plavina et al.5 suggesting that higher anti-JCV antibody indexes are associated with a higher risk of PML.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880. 2. Warnke C, Ramanujam R, Plavina T, et al. Changes to anti-JCV antibody levels in a Swedish national MS cohort. J Neurol Neurosurg Psychiatry 2013; 84: 1199–1205. 3. Outteryck O, Zéphir H, Salleron J, et al. JC-virus seroconversion in multiple sclerosis patients receiving natalizumab. Mult Scler 2014; 20: 822–829.
Acknowledgement The STRATIFY JCV™DxSelect™ test and shipping of the samples are financially supported by Biogen Idec.
4. Trampe AK, Hemmelmann C, Stroet A, et al. Anti-JC virus antibodies in a large German natalizumabtreated multiple sclerosis cohort. Neurology 2012; 78: 1736–1742.
Conflict of interest AV has received speaking fees from TEVA. VU Medical Centre has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. JAR: VU Medical Centre has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. CHP has accepted consulting fees or speaking fees from Actelion, Biogen-Idec, Bayer Schering, Teva, Merck-Serono, Novartis, GlaxoSmithKline, UCB, Roche, and Antisense Therapeutics. He has received grant support from Biogen Idec, Bayer Schering, GlaxoSmithKline, Novartis, UCB, Merck-Serono, and Teva. MPW has received speaking fees from Janssen-Cilag, BayerSchering and Biogen-Idec; VU Medical Centre has received financial support for research activities from UCB, Merck-Serono, and Novartis. JK has received consulting fees from Merck-Serono, Biogen Idec, Teva, Genzyme and Novartis; VU Medical Centre has received financial support for research activities from
5. Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JCV antibody levels in serum of plasma further define risk of natalizumab-associated PML. Ann Neurol. Epub ahead of print 1 October 2014. 6. Lee P, Plavina T, Castro A, et al. A secondgeneration ELISA (STRATIFY JCV ™ DxSelect™) for detection of JCV virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol 2013; 57: 141–146. 7. Wattjes MP, Vennegoor A, Mostert J, et al. Diagnosis of asymptomatic natalizumab-associated PML: Are we between a rock and a hard place? J Neurol. Epub ahead of print 6 April 2014. 8. Subramanyam M, Plavina T, Khatri BO, et al. The effect of plasma exchange on serum anti-JC virus antibodies. Mult Scler 2013; 19: 912–919. 9. Ryschkewitsch CF, Jensen PN, Monaco MC, et al. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol 2010; 68: 384–391.
4 http://msj.sagepub.com
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research-article2015
MSJ0010.1177/1352458514567728Multiple Sclerosis JournalA Vennegoor
MULTIPLE SCLEROSIS MSJ JOURNAL
Short Report
Longitudinal JCV serology in multiple sclerosis patients preceding natalizumab-associated progressive multifocal leukoencephalopathy
Multiple Sclerosis Journal 1–4 DOI: 10.1177/ 1352458514567728 © The Author(s), 2015. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Anke Vennegoor, Johannis A van Rossum, Chris H Polman, Mike P Wattjes and Joep Killestein
Abstract: The presence of anti-John Cunningham Virus (JCV) antibodies is a risk factor for the development of progressive multifocal leukoencephalopathy (PML) in MS patients treated with natalizumab. It has been suggested that an increase in serum anti-JCV antibody index precedes the development of PML. We here describe extensive longitudinal serum anti-JCV antibody indexes of four MS patients who developed PML. Anti-JCV antibodies were measured using the STRATIFY JCV™DxSelect™ test. All four patients had rather stable high anti-JCV antibody indexes in all samples obtained before developing PML. Possibly caused by reaching the saturation level of the assay, no increase in anti-JCV antibody indexes was seen just before the diagnosis of PML. This study confirms that high serum anti-JCV antibody indexes precede natalizumab-associated PML. Keywords: Multiple sclerosis, natalizumab, John Cunningham Virus (JCV), progressive multifocal leukoencephalopathy (PML) Date received: 5 August 2014; accepted: 11 December 2014 Introduction Progressive multifocal leukoencephalopathy (PML), which is caused by a reactivation of the John Cunningham Virus (JCV) is a serious complication in multiple sclerosis (MS) patients treated with natalizumab. Anti-JCV antibodies are associated with a higher risk of PML.1,2 It is hypothesized that this risk of developing PML is higher in patients with high anti-JCV antibody indexes in pre-PML samples.2-5 However, in studies presented so far, only very limited longitudinal samples were available. We here report four MS patients who developed PML during natalizumab treatment in whom extensive pre-PML samples were available. Methods Patients and materials All relapsing–remitting (RR) MS patients treated with natalizumab in the MS Centre Amsterdam, The Netherlands, were sampled before natalizumab initiation and at three-monthly intervals. If applicable, samples were also taken at the time PML-immune
reconstitution inflammatory syndrome (IRIS) was established and during plasmapheresis (PLEX) treatment. All serum samples were stored at –80ºC until shipped in one batch and assayed under masked conditions for clinical data at Unilabs, Denmark. Anti-JCV antibodies were measured using the two-step second-generation JCV antibody ELISA (STRATIFY JCV™DxSelect™), as previously described.3,6 After the first step, serum was classified as negative (index 0.40). The second step, a confirmation test using pre-incubated samples with in-solution JC viruslike particles, was only performed in serum, which showed an intermediate response. In the case of the percentage inhibition being ≤45%, serum was considered definitive negative, and if the percentage inhibition was >45%, it was considered definitive positive. Analytical sensitivities in monoclonal antibody equivalents are 60 ng/ml. We received quantitative results expressed as index values. Four patients developed natalizumab-associated PML. The diagnosis was confirmed in three patients by detection of JCV DNA by quantitative polymerase chain
Correspondence to: A Vennegoor MS Centre, Department of Neurology, VU University Medical Centre, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands. [email protected] Anke Vennegoor Johannis A van Rossum Chris H Polman Joep Killestein Department of Neurology, MS Centre Amsterdam, VU Medical Centre, The Netherlands Mike P Wattjes Department of Radiology, MS Centre Amsterdam, VU Medical Centre, The Netherlands
http://msj.sagepub.com 1
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Multiple Sclerosis Journal reaction (qPCR) in the cerebrospinal fluid (CSF). In the other patient, MRI lesions were characteristic for PML, but no JCV DNA was detected by qPCR in the CSF. PML diagnosis was further confirmed by clinical and MRI follow-up demonstrating a PML-IRIS five weeks after PLEX (for further details on PML diagnosis, see Wattjes et al.7). This study was approved by the local institutional board (reference 2014.256). Informed consent was obtained from all participants. Statistical analysis Since the anti-JCV antibody index was not normally distributed, log-transformation was performed. Subsequently, generalized estimating equations were used to investigate the association between anti-JCV antibody indexes and the presence of PML. Results are reported with their 95% confidence interval (CI). For continuous paired data, the Wilcoxon signed rank test was applied. The statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) version 20.0 (SPSS, Inc., Chicago, IL, USA), with a statistical significance level of 0.05. Results In this group of 193 consecutive patients with RRMS who were treated with natalizumab, four patients developed PML. The mean age at first sample collection was 34.8 years old in the PML patients and 36.3 years in the non-PML patients. Two patients with PML (50%) were women versus 131 (69%) in the non-PML patients. None of the PML patients used prior immunosuppressive medication. In the four patients with PML serum anti-JCV antibody indexes were already high at baseline and subsequently in all available samples until PML diagnosis. (Figure 1(a) to (d)). From three patients, pre-natalizumab anti-JCV antibody indexes were available and already showed high indexes before start of treatment. The median anti-JCV antibody index before and during natalizumab therapy in these four patients was 3.04 with a range of 2.04–3.59. In all four patients, the antiJCV antibody indexes had been relatively stable for years. Importantly, no meaningful increase was seen in the samples at the time of the diagnosis of PML compared with the baseline sample (median 3.05 vs. 3.16, p=0.72) or compared with the sample before diagnosis was made (median 3.05 vs. 2.78, p=0.07). From the 189 RRMS patients treated with natalizumab therapy who did not develop PML, we
obtained 669 serum samples, in which we measured the anti-JCV antibody index. These samples were obtained before and after the initiation of natalizumab treatment. Of the 176 patients in whom at least two samples were available, one of which after the start of natalizumab, 79 patients (44.9%) tested seronegative and 97 patients (55.1%) seropositive at the first moment of testing. The median index in the natalizumab treated MS patients who were positive at baseline and stayed positive or had no follow-up sample, but did not develop PML, was 2.105 with a range of 0.260-3.941. The patients who developed PML had a 1.82 times (95% CI 1.51–2.19, p 3.0), the explanation might be that high indexes technically cannot increase by reaching the saturation level of the assay.5 Until now, known risk factors for PML have been treatment duration with natalizumab for more than two years, prior immunosuppressive therapy, and positive JCV status in serum. The duration of treatment of the four PML patients varied between 14 and 78 (mean 53) infusions. None of them had used immunosuppressive medication prior to natalizumab. In this study we have shown that patients who developed natalizumab-associated PML had a consistently high anti-JCV antibody index which was even 1.82 times higher than in the JCV positive patients not developing PML. These findings confirm that the height of anti-JCV antibody indexes in serum may have additional prognostic value for the risk of developing PML, as was suggested in previous studies in which limited longitudinal samples were obtained.2-5
2 http://msj.sagepub.com
Downloaded from msj.sagepub.com at FUDAN UNIV LIB on May 14, 2015
A Vennegoor, JA van Rossum et al.
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Figure 1. Longitudinal anti-JCV antibody indexes of four natalizumab-associated progressive multifocal leukoencephalopathy (PML) patients. In all PML patients a relatively stable anti-John Cunningham Virus (JCV) antibody index is seen. In patient (c), a minor increase in index is seen just before diagnosing the PML. After the diagnosis, plasmapheresis (PLEX) is started immediately. At the moment PLEX is started, there is a decrease of the anti-JCV antibody index, which increases again after the PLEX is stopped. In this patient (c), multiple samples before initiation of natalizumab show that already more than a year before start of treatment a high anti-JCV antibody index is seen, which does not show a further increase after start of the natalizumab. : Start natalizumab. : Diagnosis of PML. : Median anti-JCV antibody index in MS patients without PML. : Intravenous methylprednisolone 1000 mg for three days.
http://msj.sagepub.com 3
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Multiple Sclerosis Journal In particular, Plavina et al. recently published that higher anti-JCV antibody index, that is, > 1.5, is associated with a higher PML risk.5 In addition, we here confirm that anti-JCV antibody indexes decreased during PLEX, which was also described by Subramanyam et al.8 Furthermore, in line with data published by Ryschkewitsch and colleagues earlier,9 we also found that anti-JCV antibodies increased after the PLEX treatment was discontinued. In conclusion, we here show that natalizumab-associated PML can be associated with rather stable high anti-JCV antibody indexes in pre-PML samples obtained long before PML diagnosis was established. Possibly caused by reaching the saturation level of the assay, an increase of the anti-JCV antibody index in pre-PML samples, as previously suggested, has not been observed in our patients. Our findings are in line with the recently published findings of Plavina et al.5 suggesting that higher anti-JCV antibody indexes are associated with a higher risk of PML.
Visit SAGE journals online http://msj.sagepub.com
SAGE journals
Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. Funding This research received no specific grant from any funding agency in the public, commercial, or not-forprofit sectors.
References 1. Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880. 2. Warnke C, Ramanujam R, Plavina T, et al. Changes to anti-JCV antibody levels in a Swedish national MS cohort. J Neurol Neurosurg Psychiatry 2013; 84: 1199–1205. 3. Outteryck O, Zéphir H, Salleron J, et al. JC-virus seroconversion in multiple sclerosis patients receiving natalizumab. Mult Scler 2014; 20: 822–829.
Acknowledgement The STRATIFY JCV™DxSelect™ test and shipping of the samples are financially supported by Biogen Idec.
4. Trampe AK, Hemmelmann C, Stroet A, et al. Anti-JC virus antibodies in a large German natalizumabtreated multiple sclerosis cohort. Neurology 2012; 78: 1736–1742.
Conflict of interest AV has received speaking fees from TEVA. VU Medical Centre has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. JAR: VU Medical Centre has received financial support for research activities from Bayer Schering Pharma, Biogen-Idec, GlaxoSmithKline, Merck Serono, Novartis, and Teva. CHP has accepted consulting fees or speaking fees from Actelion, Biogen-Idec, Bayer Schering, Teva, Merck-Serono, Novartis, GlaxoSmithKline, UCB, Roche, and Antisense Therapeutics. He has received grant support from Biogen Idec, Bayer Schering, GlaxoSmithKline, Novartis, UCB, Merck-Serono, and Teva. MPW has received speaking fees from Janssen-Cilag, BayerSchering and Biogen-Idec; VU Medical Centre has received financial support for research activities from UCB, Merck-Serono, and Novartis. JK has received consulting fees from Merck-Serono, Biogen Idec, Teva, Genzyme and Novartis; VU Medical Centre has received financial support for research activities from
5. Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JCV antibody levels in serum of plasma further define risk of natalizumab-associated PML. Ann Neurol. Epub ahead of print 1 October 2014. 6. Lee P, Plavina T, Castro A, et al. A secondgeneration ELISA (STRATIFY JCV ™ DxSelect™) for detection of JCV virus antibodies in human serum and plasma to support progressive multifocal leukoencephalopathy risk stratification. J Clin Virol 2013; 57: 141–146. 7. Wattjes MP, Vennegoor A, Mostert J, et al. Diagnosis of asymptomatic natalizumab-associated PML: Are we between a rock and a hard place? J Neurol. Epub ahead of print 6 April 2014. 8. Subramanyam M, Plavina T, Khatri BO, et al. The effect of plasma exchange on serum anti-JC virus antibodies. Mult Scler 2013; 19: 912–919. 9. Ryschkewitsch CF, Jensen PN, Monaco MC, et al. JC virus persistence following progressive multifocal leukoencephalopathy in multiple sclerosis patients treated with natalizumab. Ann Neurol 2010; 68: 384–391.
4 http://msj.sagepub.com
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