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Articles
January 27, 2016
Open AccessLetter to the Editor

Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values

Abstract

Objective:

The aim of the study was to analyze John Cunningham virus (JCV) serology in natalizumab-treated patients over time and assess whether they are influenced by natalizumab treatment.

Methods:

German (n = 1,921; 525 longitudinally) and French (n = 1,259; 711 longitudinally) patients were assessed for JCV serology alongside their therapy with natalizumab.

Results:

JCV serostatus changed in 69 of 525 longitudinally followed German patients (13.1%) over 14.8 months. Seroconversion according to serostatus was seen in 43 of 339 initially JCV− German patients (12.7% in 14.8 months; 10.3% per year) and 41 of 243 initially JCV− French patients (16.9% in 24 months; 8.5% per year). JCV index values could be reproduced (R2 = 0.89) with the caveat of 8 of 50 samples (16%) being set into different risk categories between 2 assessments. Index values of JCV+ patients rose over time (p = 0.009) but not because of aging. Treatment with natalizumab was associated with a 15.9% increase of value in JCV+ patients in 14.8 months (12.9% per year).

Conclusions:

JCV seroconversion and index values may be influenced by treatment with natalizumab. It is therefore important to monitor patients' JCV serology but also to incorporate additional risk factors into the progressive multifocal leukoencephalopathy risk stratification.
Natalizumab was approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS) starting in 2006.1,2 The development of 566 cases of progressive multifocal leukoencephalopathy (PML) (June 20153) has been a significant problem of an otherwise successful treatment regimen. Patients are currently stratified using 3 measures: prior immunosuppressant use, duration of natalizumab treatment, and presence of antibodies against the PML-inducing John Cunningham virus (JCV).4 Recently, the JCV serology biomarker has been extended to include the level of anti-JCV antibody titers represented as a JCV index value.5 In April 2015, the European Medicines Agency initiated a re-review of the drug after data from an interim report of the STRATIFY-2 trial suggested that the JCV seroconversion during natalizumab therapy might be higher than previously assumed. We have been assessing JCV serostatus and index values in 2 large cohorts of German and French patients with multiple sclerosis (MS) treated with natalizumab. This study shows how JCV serology (status and index) is influenced by treatment with natalizumab in addition to the known JCV serostatus change by aging6 from a study in which patients were not treated with natalizumab but with many other disease-modifying treatments.

METHODS

Patients and biomaterials.

Serum samples of 1,921 patients (Germany) and 1,259 patients (France; BioNAT) with RRMS alongside natalizumab therapy were processed as published previously.7 The patient cohorts and their seroprevalence are shown in a flow diagram in figure e-1 at Neurology.org/nn.

Standard protocol approvals, registrations, and patient consents.

The study was approved by the local ethics committee (University of Muenster: Ethik-Kommission der Ärztekammer Westfalen-Lippe und der Medizinischen Fakultät der Westfälischen Wilhelms-Universität, registration number 2010-245-f-S; Comite ethique du sud ouest et outre mer II: 2-09-02), and informed written consent was obtained from all participants. This study was performed according to the Declaration of Helsinki.

Anti-JCV antibody status and index value.

Sera samples were processed and analyzed by Unilabs (Copenhagen, Denmark) with the second-generation ELISA kit STRATIFY JCV DxSelect8 (EL1950; Focus Diagnostics, Cypress, CA) according to the manufacturer's instructions.5

Statistics.

Continuous variables such as JCV index are characterized by means. Categorical variables such as JCV serostatus are described by absolute and relative frequencies. Univariate correlations are estimated by Spearman correlation coefficient. Data are visualized as scatterplots and supplemented by linear regression lines. Significance of longitudinal JCV index value changes was calculated using Wilcoxon matched-pairs signed rank test. The p values were considered significant at ≤0.05. No adjustment for multiplicity was performed. Statistical analyses were conducted using Prism (version 5; GraphPad, San Diego, CA).

RESULTS

JCV serostatus.

Overall JCV serostatus assessment set 1,052 of 1,921 German patients (54.7%) under treatment with natalizumab as JCV+ (figure 1A). Longitudinally, 525 of these patients were accompanied for a mean period of observation of 14.8 ± (SD) 8.2 months. Two hundred ninety-six of these 525 patients (56.4%) were JCV− during the complete period of observation and 171 were JCV+ (32.6%). Forty-three patients changed from being JCV− to JCV+ (8.2%) and 15 patients changed from being JCV+ to JCV− (2.9%). Overall, there were 11 patients (2.1%) who transiently changed serostatus during the period of observation but ended up with their initial serostatus (figure 1B). If JCV serostatus was used to determine seroconversion, the longitudinal assessment started out with 339 initially JCV− patients (initial seroprevalence of the longitudinal cohort 35.4%). The serostatus of 43 of these initially JCV− patients changed to JCV+, which is 12.7% in 14.8 months (10.30% per year or 0.86% per month; ultimate seroprevalence of the longitudinal cohort 40.8%) (figure 1C). In the French BioNAT cohort of 1,259 patients (seroprevalence of the whole cohort before start of treatment was 604 of 1,020 patients = 59% and of the longitudinally followed cohort 468 of 711 patients = 65.8%), of the initially 243 JCV− patients of 711 patients, where all 3 longitudinal time points were available, the serostatus of 20 changed to JCV+ in their first year of treatment (8.2%) and 21 in their second year of treatment (8.6% of 243 initially JCV− patients or 9.4% of the 223 patients, who were still JCV− after 1 year of treatment). Taken together, the serostatus of 41 of 243 patients (16.9%) changed to JCV+ in the first 2 years of natalizumab treatment (8.5% per year or 0.70% per month; ultimate seroprevalence of the French longitudinal cohort after 2 years 71.6%) (figure 1D).
Figure 1 JCV serostatus
(A) Serostatus of 1,921 natalizumab-treated patients with multiple sclerosis, with JCV− patients shown in black and JCV+ patients in red. A total of 1,052 of these 1,921 patients were set as JCV+ (54.76%). (B) Serostatus of a longitudinally assessed cohort of 525 patients during 14.8 months of natalizumab treatment. (C) Serostatus of the German cohort of 339 initially JCV− patients (of 525 patients) before and after the period of observation (14.8 months of natalizumab treatment). Forty-three of these 339 patients (12.7%) were set as JCV+ after the period of observation. (D) Serostatus of the French cohort (n = 1,259; 711 longitudinally; BioNAT) of the 243 initially JCV− patients of 711, where all 3 time points were available, during their first 2 years of treatment. Twenty of these patients (8.2%) were set as JCV+ after the first year and an additional 21 (8.6%) after the second year of treatment, resulting in 41 of 243 patients (16.9%) changing their serostatus to JCV+ in the first 2 years of treatment. JCV = John Cunningham virus.

JCV index value.

The JCV serostatus was recently extended to incorporate the level of anti-JCV antibodies in serum, normalized to a “JCV index” value. To assess the reproducibility of this value, 50 patient serum samples were measured twice by Unilabs. Overall reproducibility was very good with an R2 of 0.89. However, 8 of these 50 patients (16%) would have been set in different risk categories between the 2 measurements (thresholds from Plavina et al.,5 2014: JCV−/+, 0.9, 1.2, 1.5) with one sample actually being set as JCV+ in the first and JCV− in the second measurement and 2 samples being either measured at very high PML risk (JCV index >1.5) or very low risk (JCV index <0.9) (figure 2A) in the 2 measurements. The index values changed in 525 patients in the observation period. The proportion of patients with an index value <0.4 was reduced by 20 patients (from 65.1% to 61.3%), and the group of patients with low risk (between 0.4 and 0.9) was reduced by one patient to 7.8%. The patient groups with medium (0.9–1.5) and high risk (>1.5) grew by 7 patients from 4.6% to 5.9% and by 14 patients from 22.3% to 25%, respectively (figure 2B). Overall, this was a reflection of the change in serostatus (figure 1C) but also suggested that patients who changed serostatus directly presented with high anti-JCV antibody titers afterward, as the groups of low and medium risk did not grow substantially over time. This trend was also clearly visible in the complete cohort of patients (figure 2C), where up to 7 longitudinal samples were assessed from each patient and the seroconversion mostly led to JCV index values of >1.5 (figure 2D).
Figure 2 JCV index
(A) Fifty samples of natalizumab-treated patients with multiple sclerosis were assessed twice for their anti-JCV antibody index (JCV index) with an R2 of 0.89. Eight of these 50 samples (16%) showed 2 different risk associations with the thresholds JCV−/+, JCV index 0.4, 0.9, 1.2, and 1.5 in the 2 assessments. (B) JCV index value distributions of a longitudinal cohort of 525 patients at the start and end of the period of observation of 14.8 months. (C) Serial assessment of JCV index values of 525 patients alongside their natalizumab therapy (2–7 JCV serology assessments). Red lines indicate the thresholds 0.4, 0.9, and 1.5. (D) Serial assessment of JCV index values. Only patients whose index values changed by more than 30% over time and whose PML risk group changed are shown (0–0.4 [green], 0.4–0.9 [yellow], 0.9–1.5 [orange], >1.5 [red]). JCV = John Cunningham virus.

Change in JCV index values in JCV+ patients.

While most of the changes in JCV index values could be attributed to the seroconversion of initially JCV− patients, it was also important to see whether patients presented with stable index values once they converted to JCV seropositivity. Two hundred one JCV+ patients were therefore followed over time and it became clear that the biomarker showed changes over time with higher values after the period of observation (mean: 2.046 vs 2.158; p = 0.009) (figure 3A). That age had a role in these fluctuations was ruled out because the age of patients contributed to the overall rise in index values (Spearman r: −0.113; p < 0.0001) due to seroconversion, but the index values of JCV+ patients did not change with age (Spearman r: 0.0001; p = 0.996) (figure 3B); this was also true for patients who seroconverted during therapy with natalizumab. The index correlation with age in the whole population (JCV− and JCV+) is attributable to seroconversion, but if only JCV+ patients are considered, their index values do not differ with age; they only differ with prolonged treatment duration.
Figure 3 JCV index changes in JCV+ patients
(A) Increasing JCV index values of 201 JCV+ natalizumab-treated patients with multiple sclerosis at the beginning and end of a period of observation of 14.8 months (mean: 2.046 vs 2.158; p = 0.009). (B) Age (in years) and JCV index value of 1,921 natalizumab-treated patients with multiple sclerosis. Overall, there is a strong rise in index values by age (Spearman r: 0.113; p < 0.0001) but no rise in the index values of JCV+ patients (Spearman r: 0.0001; p = 0.996) or patients who converted to JCV seropositivity during treatment with natalizumab (Spearman r: 0.0257; p = 0.907). (C) Change of JCV index values of 201 JCV+ patients during natalizumab treatment in % (index value at the end of the period of observation/index value at the beginning of the period of observation × 100). Mean rise in index values was 15.9% in 14.8 months. One hundred sixty-one of 201 patients (80%) presented with stable index values (±30%), 34 patients (17%) presented with increasing index values, and 6 patients (3%) with decreasing index values. JCV = John Cunningham virus.
One hundred sixty-one of 201 JCV+ patients (80%) presented with stable JCV index values over time (±30% in the period of observation). However, the remaining 40 patients (20%) presented with fluctuations of more than 30% in 14.8 months. Only 6 of these patients (3%) presented with decreasing index values, but 34 (17%) presented with increasing index values (mean: 200.8%). Taken together, the index value of all JCV+ patients increased by 15.9% on average in 14.8 months (12.9% per year or 0.11% per month) (figure 3C).

DISCUSSION

There has been strong debate about whether the underlying JCV seroconversion rate by aging is influenced by treatment with natalizumab.911 The high seroconversion, which has already been suggested (Plavina et al.,5 2014; n = 553; 0.45%–0.72% per month depending on the definition of seroconversion), and the data of seroconversion rates in longitudinally monitored JCV− patients in our study (10.3% and 8.5% per year) clearly support the facilitation by treatment with natalizumab. It is important to distinguish between seroconversion (a JCV− patient converting to JCV+) and an increase in seroprevalence (the percentage of JCV+ patients within a cohort). The published rise in seroprevalence by age is 0.5% per year,6,12 which translates into a JCV seroconversion of approximately 1% per year in the 40% to 45% of JCV− patients within these cohorts. However, in both calculations, our observed seroconversion of 8% to 10% per year and the rise in seroprevalence of 5% to 6% in 15 to 24 months is at least 8 to 10 times as much as would be expected by age. This dataset suggests that not every patient with MS is susceptible to JCV seroconversion by treatment, but natalizumab might facilitate it in patients who are susceptible. There has recently been an extensive study of 7,724 patients and their JCV serostatus in a group of control patients.6 The authors clearly show that when adjusted for age, sex, and country of origin, the duration of MS treatment has no influence on JCV seroprevalence, leaving treatment with natalizumab as the only factor in our study, as sex and country of origin do not change in longitudinal cohorts. Because as yet there are no studies on the influence of other treatments on JCV index values, and despite a very recent study also supporting this hypothesis,13 we cannot be certain that it was the treatment with natalizumab that led to the rising index values in our study. However, because there was no correlation with age in JCV+ patients and these patients have certainly been treated longer with disease-modifying drugs the older they are, it can be speculated that it is specifically the treatment with natalizumab that induces rising JCV index values (and, therefore, anti-JCV titers). The high seroconversion (putatively induced by higher JCV activity) is also in agreement with the published lower CD62L values induced by natalizumab treatment,7 as both are associated with higher PML risk. Because previous hypotheses concerning JCV titers suggested that higher titers are the result of a higher replication rate of the virus,1416 it is conceivable that a higher replication rate is attributable to the fact that the compromised immune cells of natalizumab-treated patients are less capable of suppressing the viral activity of JCV. As long as these biological backgrounds are not fully elucidated, it seems prudent to include the theory of (re)infection with JCV as a source for seroconversion. However, since there are patients who shed the virus in their urine without being antibody seropositive,17 it seems unlikely that the process leading to seropositivity is solely linked to (re)exposure to JCV.
One drawback of our study is the fact that JCV− patients naturally tend to reassess their JCV serology more often than JCV+ patients for a potential seroconversion. Therefore, our prospective longitudinal German cohort, in which patients could decide for themselves how often to assess their serostatus, has a much lower seroprevalence than the overall patient population. This might overexaggerate the percentage of seroconverters in the entire natalizumab-treated MS collective, which is why it is important to calculate the seroprevalence in addition to the seroconversion. Apart from this, it was recently shown that IV immunoglobulin treatment may cause transiently high anti-JCV antibody titers and thereby transient false-positive JCV serostatus results. However, we can rule this out for our seroconverting patients, as well as for the complete cohort, because IV immunoglobulins are usually not applied during natalizumab treatment in Europe.18
Both observations of this study—the high seroconversion and the rising index values in JCV+ patients—have implications for PML risk stratification using JCV serology. It is important to regularly check patients' JCV serology (status and index) for an accurate assessment of their PML risk according to this biomarker. Unfortunately, with a JCV index value mean of more than 2, most JCV+ patients are set into the highest PML risk category, with very few of these patients ultimately developing PML. JCV serology should not be the only PML risk biomarker used in the stratification of patients treated with natalizumab. The exploration and potential application of additional biomarkers such as CD62L in peripheral blood7,19 or IgM bands in CSF20 is needed to accurately inform patients of their PML risk and ultimately help in reducing PML incidences.
If the hypothesis that treatment with natalizumab is associated with enhanced JCV seroconversion and higher index values is proven, it would also be important to determine whether cessation of natalizumab therapy (or perhaps prolonged infusion intervals) could lead to lower JCV index values as well. This remains to be seen in the studies currently under way regarding switching to other therapies or prolonged infusion intervals. However, from a risk stratification point of view, this would not influence patients because they should always assume the highest measured risk to be on the safe side, and even lowered JCV index values should not suggest that a patient's risk has diminished. These further and larger clinical studies with a strict study protocol should be performed to assess in which capacity natalizumab influences JCV seroconversion and whether this is influenced by treatment dosage/intervals.
Taken together, JCV serology is a sensitive biomarker for PML risk, but it is very dynamic and should be regarded as such. JCV− patients should reassess their status regularly and JCV+ patients should check their JCV index values until they have reached the highest risk category, after which JCV serology loses some of its usefulness. The fact that treatment with natalizumab is associated with a very high rate of seroconversion and rising index values does not diminish its clinical efficacy, but calls for more elaborate strategies for PML risk stratification according to current scientific developments, also regarding patients with prior use of immunosuppressants, where the JCV index is not helpful.5

GLOSSARY

JCV
John Cunningham virus
MS
multiple sclerosis
PML
progressive multifocal leukoencephalopathy
RRMS
relapsing-remitting multiple sclerosis

ACKNOWLEDGMENT

The authors thank Barbara Wrobel, Petra Babucke, and Verena Schütte for excellent technical assistance and the patients for their participation in the study.

Data Supplement

Files in this Data Supplement:
Data Supplement - Microsoft Word file
e-Figure - Microsoft Word file

Footnote

Supplementary Material

File (bionat_study_group_data.docx)
File (e-figure_1.docx)

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Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:1870–1880.
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Plavina T, Subramanyam M, Bloomgren G, et al. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol 2014;76:802–812.
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Bozic C, Subramanyam M, Richman S, Plavina T, Zhang A, Ticho B. Anti-JC virus (JCV) antibody prevalence in the JCV Epidemiology in MS (JEMS) trial. Eur J Neurol 2014;21:299–304.
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Schwab N, Schneider-Hohendorf T, Posevitz V, et al. L-selectin is a possible biomarker for individual PML risk in natalizumab-treated MS patients. Neurology 2013;81:865–871.
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Lee P, Plavina T, Castro A, et al. 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 2013;57:141–146.
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Outteryck O, Ongagna JC, Duhamel A, et al. Anti-JCV antibody prevalence in a French cohort of MS patients under natalizumab therapy. J Neurol 2012;259:2293–2298.
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Olsson T, Achiron A, Alfredsson L, et al. Anti-JC virus antibody prevalence in a multinational multiple sclerosis cohort. Mult Scler 2013;19:1533–1538.
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Trampe AK, Hemmelmann C, Stroet A, et al. Anti-JC virus antibodies in a large German natalizumab-treated multiple sclerosis cohort. Neurology 2012;78:1736–1742.
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Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol 2010;68:295–303.
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Raffel J, Gafson AR, Malik O, Nicholas R. Anti-JC virus antibody titres increase over time with natalizumab treatment. Mult Scler 2015;21:1833–1838.
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Bohl DL, Brennan DC, Ryschkewitsch C, Gaudreault-Keener M, Major EO, Storch GA. BK virus antibody titers and intensity of infections after renal transplantation. J Clin Virol 2008;43:184–189.
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Pastrana DV, Brennan DC, Cuburu N, et al. Neutralization serotyping of BK polyomavirus infection in kidney transplant recipients. PLoS Pathog 2012;8:e1002650.
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Pastrana DV, Wieland U, Silling S, Buck CB, Pfister H. Positive correlation between Merkel cell polyomavirus viral load and capsid-specific antibody titer. Med Microbiol Immunol 2012;201:17–23.
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Berger JR, Houff SA, Gurwell J, Vega N, Miller CS, Danaher RJ. JC virus antibody status underestimates infection rates. Ann Neurol 2013;74:84–90.
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Kister I, Kuesters G, Chamot E, et al. IV immunoglobulin confounds JC virus antibody serostatus determination. Neurol Neuroimmunol Neuroinflamm 2014;1:e29.
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Villar LM, Costa-Frossard L, Masterman T, et al. Lipid-specific immunoglobulin M bands in cerebrospinal fluid are associated with a reduced risk of developing progressive multifocal leukoencephalopathy during treatment with natalizumab. Ann Neurol 2015;77:447–457.
Letters to the Editor
22 February 2016
Re:Time to audit all reported PML cases
Nicholas Schwab, Assistant Professor
T. Schneider-Hohendorf; H. Wiendl;

We thank Dr. Avasarala for the thoughtful comment on our recent article. [1] He is correct that JC virus (JCV) serology is currently the most sensitive biomarker to assess a patient's risk of developing PML during treatment with natalizumab and that patients and physicians should check for JCV serology. As noted in our article, [1] regular monitoring is recommended, as anti-JCV negative patients might convert at any time and even the index values of anti-JCV positive patients are subject to changes during treatment with natalizumab. However, many patients are anti-JCV positive even before start of therapy and, of the JCV-positive patients, most present with JCV index values of >0.9. Therefore, while the biomarker is extremely sensitive, its specificity prevents it from being an exclusion criterion. Furthermore, if the biomarker cannot be used as an exclusion criterion, it would be difficult to force patients or physicians to use it in daily clinical practice. It should, of course, be available to every patient and every physician should counsel their patients accordingly, but it seems unwise to force a biomarker with such little specificity on patients.

As suggested by Dr. Avasarala, a database with the JCV serostatus of all known PML cases would be a valuable resource for researchers.

We do not yet understand the biological background of the changes reported in our article and, after talking with colleagues around the world, we found that while many see similar trends, there are a few patient cohorts without these developments. It is a task for future studies to elucidate the influence of virus-host connections and environmental factors on the development of anti-JCV antibodies and, subsequently, of PML. We hope to contribute more to this important topic in the coming years.

1. Schwab N, Schneider-Hohendorf T, Pignolet B, et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm 2016;3:e195.

For disclosures, please contact the editorial office at [email protected].

16 February 2016
Time to audit all reported PML cases
Jagannadha Avasarala, Associate Professor of Neurology

The findings by Schwab et al. that a high JC virus (JCV) seroconversion and rising JCV index values were associated with natalizumab (Tysabri) use in patients with multiple sclerosis (MS) are worrisome. [1]

The TOUCH (Tysabri Outreach: Unified Commitment to Health program) program, created in 2006, is a risk minimization plan for progressive multifocal leukoencephalopathy (PML); it was developed by Biogen Idec, intended to ensure physicians and patients understand the benefits and potential risks associated with the use of Tysabri, particularly the risk of PML. Under the TOUCH program, every patient who receives Tysabri is closely monitored for PML and other serious opportunistic infections. However, as noted in my recent article, [2] the TOUCH program has failed in protecting patients as testing for JCV antibody is not mandatory, allowing physicians to continue Tysabri use despite not checking the JCV antibody status. JCV antibody positive status is a risk factor for developing PML, but a negative JCV antibody status does not confer protection against PML development either. Since JCV antibody positive status implies higher risk of PML development, checking JCV antibody status must be made mandatory in the TOUCH program. In Biogen's defense, when the TOUCH program was originally instituted, there was no JCV antibody testing and the test (Stratify JCV Antibody ELISA test) developed to check for JCV antibody status was not approved by the FDA until January 2012. With this approval, testing should have been made mandatory, but instead it remains optional. Physicians who continue prescribing the drug without testing for JCV antibody status are jeopardizing patient safety. At a minimum, withholding the drug when JCV antibody testing status is not reported to Biogen would alert the physician to test for JCV antibody status. Of course, physicians must be aware of prior immunosuppressant drug use as well as how long the patient had been on Tysabri, since both factors also figure in PML risk assessment.

The latest PML count is 614, as of December 2015, per the quarterly report by Biogen. [3] What if one of these cases was due to failure of checking for JCV antibody status? Also, why are raw data not publicly available on these 614 PML cases along with their JCV antibody status?

1. Schwab N, Schneider-Hohendorf T, Pignolet B, et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm Epub 2016 Jan 27.

2. Avasarala J. The TOUCH program and natalizumab: Fundamental flaw in patient protection [version 1; referees: 1 approved with reservations]. F1000Research 2015;4:1450.

3. Biogen medical information. Available at: https://medinfo.biogenidec.com. Accessed December 10, 2015.

For disclosures, please contact the editorial office at [email protected].

Information & Authors

Information

Published In

Neurology® Neuroimmunology & Neuroinflammation
Volume 3Number 1February 2016
PubMed: 26848486

Publication History

Received: July 29, 2015
Accepted: November 10, 2015
Published online: January 27, 2016
Published in print: February 2016

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Disclosure

N. Schwab received travel funding from Biogen, speaker honoraria from Novartis, holds a patent for usage of L-selectin as a predictive marker for PML, and received research support from DFG, University Munster. T. Schneider-Hohendorf received travel funding from Biogen, holds a patent for usage of L-selectin as a predictive marker for the risk to develop PML. B. Pignolet and J. Breuer report no disclosures. C.C. Gross received speaker honoraria and/or travel funding from Genzyme, Novartis Pharma GmbH, and Bayer Health Care, is a review editor for Frontiers in Immunology, and received research support from the German Research Foundation, University of Munster. K. Göbel reports no disclosures. D. Brassat receives travel funding and/or speaker honoraria from Biogen, Sanofi-Genzyme, Teva, Merck Serono, Bayer, and Almirall, received research support from the French Ministry of Health, French Multiple Sclerosis Society, and the European Union. H. Wiendl is on the scientific advisory board for Bayer Healthcare, Biogen Idec, Sanofi-Genzyme, Merck Serono, Novartis, Roche, and Teva, received travel funding and/or speaker honoraria from Bayer Vital GmbH, Bayer Schering AG, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Sanofi-Genzyme, Merck Serono, OmniaMed, Novartis, and Teva, is on the editorial board for Journal of Clinical Practice, Journal of Neuroinflammation, and PLoS One, has consulted for Biogen Idec, Merck Serono, Novartis, OmniaMed, Roche, and Sanofi-Genzyme, received research support from Bayer Healthcare, Bayer Vital, Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme, Sanofi US, Teva Pharma, German Ministry for Education and Research, Deutsche Forschungsgesellschaft, European Union, Else Kroner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies Muenster, RE Children's Foundation, and Else Kroner Fresenius Foundation. Go to Neurology.org/nn for full disclosure forms.

Study Funding

This study was funded by Deutsche Forschungsgesellschaft (DFG) grant CRC128 Project B1 to N.S. and H.W., Project Z2 to H.W., the PML consortium to N.S. and H.W., the Kompetenznetz Multiple Sklerose (Competence Network for Multiple Sclerosis) funded by the Federal Ministry of Education and Research (FKZ 01GI1308B 01GI0907) to H.W., French Ministry of Health (PHRC 2008-005906-38), ARSEP (French MS Society grant 2009 and 2011) to D.B., and the EU (BEST-MS, FP7, 305477) to D.B. and H.W.

Authors

Affiliations & Disclosures

Nicholas Schwab, PhD*
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
NONE
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1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Biogen, travel expenses, (2) Novartis, speaking honoraria
Editorial Boards:
1.
NONE
Patents:
1.
(1) Usage of L-selectin as predictive marker for PML.
Publishing Royalties:
1.
NONE
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1.
NONE
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NONE
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1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
(1) DFG CRC128 B1, starting 2012 (2) University M?nster, IMF, starting 2011
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Tilman Schneider-Hohendorf, PhD*
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Biogen, travel support for scientific conference attendance.
Editorial Boards:
1.
NONE
Patents:
1.
(1) usage of L-selectin as predictive marker for the risk to develop PML (pantent nr.: EP 11 185 439 & EP 12 158 369)
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Béatrice Pignolet, PhD
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Johanna Breuer, PhD
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Catharina C. Gross, PhD
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
I received speaker honoraria and travel expenses for attending meetings from Genzyme, Novartis Pharma GmbH, and Bayer Health Care.
Editorial Boards:
1.
Frontiers in Immunology, Review Editor, Since 2015
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
German Research Foundation (DFG), GR3946/2-1, 01/2013-12/2015
Research Support, Academic Entities:
1.
Innovative Medical Science Grant (IMF-grant) of the medical faculty of the University of M?nster, KL111421, 07/2014-06/2016
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Kerstin Göbel, MD
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
David Brassat, MD, PhD
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
Chugai pharma
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Biogen idec, sanofi genzyme, teva, merck serono, bayer, almirall
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
French Ministry of Health 2007 PI, French multiple sclerosis Society 2005, 2006, 2007, 2008, European Union FP7 marie curie Action, 2008
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Heinz Wiendl, MD
From the Department of Neurology (N.S., T.S.-H., J.B., C.C.G., K.G., H.W.), University of Münster, Germany; and Pole des Neurosciences Centre Hospitalier Universitaire Toulouse (B.P., D.B.), CPTP INSERM UMR 1043 et Université de Toulouse, UPS, Toulouse, France. D.B. also represents the BioNAT Study Group.
Disclosure
Scientific Advisory Boards:
1.
(1) Bayer Healthcare (2) Biogen Idec (3) Sanofi- Genzyme (4) Merck Serono (5) Novartis (6) Roche (7) Teva
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
(1) Bayer Vital GmbH (2) Bayer Schering AG (3) Biogen (4) CSL Behring (5) EMD Serono (6) Fresenius Medical Care (7) Sanofi - Genzyme (8) Merck Serono (9) Omniamed (10) Novartis (11) Teva
Editorial Boards:
1.
(1) Journal of Clinical Practice, Editorial Board member, since 2006 (2) Journal of Neuroinflammation, Editorial Board member, since 2007 (3) PLOS ONE, Editorial board member, since 2013
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
(1) Biogen Idec (2) Merck Serono (3) Novartis (4) Omniamed (5) Roche (6) Sanofi-Genzyme.
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
(1) Bayer Healthcare (2) Bayer Vital (3) Biogen Idec (4) Merck Serono (5) Novartis (6) Sanofi ? Genzyme (7) Sanofi US (8) TEVA Pharma
Research Support, Government Entities:
1.
(1) German Ministry for Education and Research (BMBF), BD120300, Principal Investigator, 2012-2015 (2) German Ministry for Education and Research (BMBF), BD604262, Principal Investigator, 2013-2016 (3) Deutsche Forschungsgesellschaft (DFG), WI 1722/12-1, Principal Investigator, 2012-2015 (4) Deutsche Forschungsgesellschaft (DFG), WI 1722/13-1, Principal Investigator, 2012-2015 (5) European Union, BD604219, 2013-2015 (6) Deutsche Forschungsgesellschaft (DFG), SFB 1009 TP A3, Principal Investigator, 2012-2015 (6) Deutsche Forschungsgesellschaft (DFG), SFB 128 TP A9, Principal Investigator, 2012-2015 (7) Deutsche Forschungsgesellschaft (DFG), SFB 128 TP B1, Principal Investigator, 2012-2015 (8) Deutsche Forschungsgesellschaft (DFG), SFB 128 TP Z2, Principal Investigator, 2012-2015 Else Kr?ner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, Merck Serono, Novartis, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, RE Children?s Foundation. (5) Novartis (6) Sanofi Aventis NovoNordisk)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
(1) Else Kr?ner Fresenius Foundation (2) Fresenius Foundation (3) Hertie Foundation (4) RE Children?s Foundation.
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence to Prof. Wiendl: [email protected] or Dr. Schwab: [email protected]
*
These authors contributed equally to this work.
Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the University of Münster.
BioNAT Study Group coinvestigators are listed at Neurology.org/nn.

Author Contributions

N.S. designed and performed research, collected data, analyzed data, and generated funding. T.S.-H. designed and performed research, collected and analyzed data. B.P. performed research, collected and analyzed data. J.B., K.G., and C.C.G. performed research, collected and analyzed data. D.B. performed research, collected and analyzed data, and generated funding. H.W. designed research, analyzed data, and generated funding. All authors wrote the manuscript. H.W. and N.S. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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