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Keywords:

  • biomarker;
  • BIONAT ;
  • JCV ;
  • multiple sclerosis;
  • natalizumab;
  • progressive multifocal leukoencephalopathy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information

Background and purpose

BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing−remitting multiple sclerosis (MS) patients. The purpose of this study was to collect clinical, radiological and biological data on 1204 patients starting NTZ, and to evaluate the clinical/radiological response to NTZ after 2 years of treatment.

Methods

Patients starting NTZ at 18 French MS centres since June 2007 were included. Good response to NTZ was defined by the absence of clinical and radiological activity. Data analysed in this first report on the BIONAT study focus on patients who started NTZ at least 2 years ago (n = 793; BIONAT2Y).

Results

NTZ was discontinued in 17.78% of BIONAT2Y. The proportion of patients without combined disease activity was 45.59% during the first two successive years of treatment. Systematic dosage of anti-NTZantibodies (Abs) detected only two supplementary patients with anti-NTZ Abs compared with strict application of recommendations. A significant decrease of IgG,M concentrations at 2 years of treatment was found.

Conclusions

The efficacy of NTZ therapy on relapsing−remitting MS in a real life setting is confirmed in the BIONAT cohort. The next step will be the identification of biomarkers predicting response to NTZ therapy and adverse events.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information

BIONAT is a French multicentric phase IV study of natalizumab (NTZ)-treated relapsing−remitting multiple sclerosis (MS) patients. The main objective of the BIONAT study is to prospectively collect clinical, radiological and biological data on more than 1000 patients starting NTZ therapy, in the post-marketing setting, and to identify biological markers associated with the response to NTZ therapy and adverse events connected with it. NTZ is the first of a new class of selective adhesion molecule inhibitors used in relapsing−remitting MS. It was approved in France in April 2007. The results of the AFFIRM study demonstrated that this α4-integrin antagonist reduced the annualized relapse rate (ARR) by 68% over 2 years and the risk of sustained disability progression in relapsing−remitting MS by 42%–54% [1]. Up to now, the concept of freedom from disease activity in MS (no radiological and no clinical disease activity) has received little attention from the neurology community [2] but a post hoc analysis of the AFFIRM study showed that this goal could be attainable for 37% of patients in the NTZ arm versus 7% in the placebo group [3]. As new and increasingly effective treatments for MS are developed, it can be anticipated that ‘disease activity free’ status in MS will be an attainable goal for greater proportions of patients. Here, the results of 1204 NTZ-treated patients are presented with a focus on the proportion of patients free of disease activity at 2 years of NTZ treatment and biological parameters.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information

Patients with relapsing−remitting MS starting NTZ therapy at 18 MS centres in France since June 2007 were included and were followed prospectively. These 18 MS centres were located in various areas of France. Thus the BIONAT cohort could be considered as representative of MS French patients treated by NTZ. All patients gave their written informed consent to participate in the BIONAT study. The decision to treat with NTZ was based on the French guidelines for all the patients [at least one relapse during well conducted interferon-β therapy plus nine T2 lesions and/or gadolinium enhanced lesion(s) on brain MRI or two relapses plus T2 lesion load increasing and/or gadolinium enhanced lesion(s)]. NTZ was infused intravenously once every 4 weeks. All patients were followed up clinically [complete clinical and neurological evaluation for relapses; disability scored on the Expanded Disability Status Scale (EDSS) every 6 months]. All patients receiving NTZ underwent brain magnetic resonance imaging (MRI) just before initiation of the treatment and after completion of 1 and 2 years of treatment. Biological samples were collected at baseline before the first NTZ infusion, at 1, 2 years and planned at 5 years.

Good response to NTZ therapy was defined by the absence of disease activity. The same criteria as in the post hoc analysis of the AFFIRM study were used to determine ‘clinical disease activity’: occurrence of new relapses and/or sustained disability progression. Progression was defined as an increase in the EDSS of at least 1.5 from a baseline score of 0, at least 1.0 point from a baseline score between 1.0 and 5.0 and at least 0.5 from a baseline score higher than or equal to 5.5 [3, 4]. Regarding radiological disease activity, all brain MRI performed included axial T2 fluid attenuated inversion recovery and axial T1-weighted gadolinium-enhanced sequences. These examinations were not all performed in the same MRI centre and were not analysed with T2 lesion load measurement software. All brain MRI were analysed by two experienced neurologists in each MS centre. ‘Radiological disease activity’ was defined as the appearance of any new T2 hyperintense lesions and/or the presence of any gadolinium-enhancing lesions. It was not possible to measure enlarging T2 hyperintense lesions. Patients without clinical activity and without radiological activity were considered as free of combined activity and designated as disease activity free patients.

A ‘patient with highly active disease’ was defined as a patient presenting at least two relapses in the year before NTZ initiation and at least one gadolinium-enhanced lesion on brain MRI within the 3 months preceding NTZ initiation. All other patients were considered as ‘non-highly active’ [5].

Disease activity during the first year, during the second year and after two successive years of treatment were analysed.

NTZ was interrupted for various reasons. Pregnancy or planned pregnancy and a patient's decision (not related to MS or because of fear of NTZ potential side effects) were not considered as treatment failure. For any other causes of treatment discontinuation in what was defined as ‘the worst-case scenario’ patients were considered as treatment failure with clinical and radiological disease activity in the 2 years of treatment if discontinuation occurred in the first year, and only in the second year if discontinuation occurred in the second year of treatment. In ‘the best-case scenario’, patients discontinuing NTZ were considered without clinical and radiological disease activity in the 2 years of treatment if discontinuation occurred in the first year, and only in the second year if discontinuation occurred in the second year of treatment. In ‘the intermediate-case scenario’, patients discontinuing NTZ were not considered for the calculation of clinical and radiological disease activity in the 2 years of treatment if discontinuation occurred in the first year, and only in the second year if discontinuation occurred in the second year of treatment.

The data analysed in this first report of the BIONAT study were extracted from our database in May 2012. The proportion of missing data is reported.

Anti-John Cunningham virus (JCV) antibody (Ab) prevalence was measured in the first group of patients included in BIONAT (n = 811 patients) with the first generation two-step validated ELISA test at baseline.

Tests for anti-NTZ Abs were performed systematically after 1 year of treatment and also after 6 months of treatment as recommended when a patient presented a clinical evolution [relapse(s) and/or disability progression] or repeated adverse events.

Lymphocyte count and immunoglobulin concentrations were recorded at baseline for the entire BIONAT cohort. In one MS centre of the BIONAT network (n = 133), prospective follow-up of lymphocyte count (CD3, CD4, CD8, CD19) and immunoglobulin (Ig; types G, A and M) concentrations was performed during 2 years of continuous treatment with NTZ. These analyses were performed on site with the same method throughout the follow-up.

Statistical analyses were performed with SPSS 15.0 software (Chicago, IL, USA). A Student's t test was used to compare mean values and the χ2 test to compare data distributions. When multiple comparisons were performed, a Bonferroni correction was applied. The level of statistical significance (P) was set at 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information

Description of the BIONAT cohort

The BIONAT study included 1204 patients. At the time of analysis, 65.9% of patients (n = 793) had started NTZ therapy at least 2 years previously. Amongst these patients, 41.4% (n = 328) were classified as having highly active disease.

Demographic characteristics of the BIONAT cohort, the cohort already at 2 years of treatment (BIONAT2Y) and the subgroup with highly active disease, itself already at 2 years of treatment (BIONATHA2Y), are shown in Table 1.

Table 1. Demographic, clinical and radiological characteristics of the BIONAT cohort
 AFFIRMBIONATBIONAT2Y patients at least 2 years from NTZ initiationBIONATHA2Y patients with highly active disease and at least 2 years from NTZ initiation
  1. ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; Gd+, gadolinium enhancement; IMD, immunomodulatory drugs; ISD, immunosuppressive drugs; NA, not applicable.

Number6271204793328
Age (NTZ initiation; years)
Mean ± SD35.6 ± 8.536.67 ± 9.7936.61 ± 9.7134.45 ± 9.29
Median [min;max][18;50]36 [15;72]36 [17;72]33 [17;60]
Gender (sex ratio F/M)2.523.213.033.37
Disease duration (years)
Mean ± SD 11.57 ± 6.9212.15 ± 6.8711.06 ± 6.53
Median [min;max]5 [0;34]10 [1;45]11 [2;45]9 [2;33]
ARR
Mean ± SD1.53 ± 0.912.05 1.12.1 ± 1.092.7 ± 0.95
Median [min;max][0;12]2 [1;8]2 [1;8]2 [2;8]
EDSS
Mean ± SD2.3 ± 1.23.35 ± 1.663.36 ± 1.673.26 ± 1.68
Median [min;max][0;6]3.25 [0;8]3.5 [0;8]3 [0;8]
Brain MRI
Number of Gd+ lesions2.2 ± 4.71.18 ± 3.031.07 ± 2.523.07 ± 3.78
Proportion of patients with Gd+ lesions51%63.8%64.4%100%
Proportion of patients with IMD > 6 months0%88.9%90.5%84.2%
Number of IMD
Mean ± SDNA1.3 ± 0.731.33 ± 0.721.23 ± 0.75
Median [min;max]NA1 [0;4]1 [0;4]1 [0;3]
Proportion of patients with ISDNA20.09%21.4%22.7%
Number of ISD
Mean ± SDNA0.26 ± 0.570.28 ± 0.60.3 ± 0.61
Median [min;max]NA0 [0;3]0 [0;3]0 [0;3]

BIONAT and BIONAT2Y compared with the AFFIRM pivotal trial

BIONAT and BIONAT2Y cohorts were very similar to the NTZ arm of the AFFIRM pivotal trial and had similar mean age and gender distributions. However, they had significantly higher pre-NTZ ARR and EDSS (P < 0.01) with less radiological activity, measured by the number of gadolinium-enhanced lesion(s) (P < 0.01).

BIONATHA2Y versus BIONAT/BIONAT2Y

The BIONATHA2Y cohort was younger (P < 0.01) with higher ARR and higher radiological activity (P < 0.01) than the BIONAT/BIONAT2Y cohorts.

NTZ discontinuations

Table 2 summarizes the numerous causes and various times of discontinuation in BIONAT2Y. Discontinuation occurred in 17.78% (n = 141) of BIONAT2Y, mostly in the first year (60.28%) and with mean treatment duration at NTZ discontinuation of 10.89 ± 6.56 months. The most frequent causes, together representing more than half the discontinuations, were pregnancy planning (24.82%), cutaneous allergy (17.02%), always occurring in the first year, conversion to a secondary progressive form of MS (12.06%) and serious adverse event (8.51%).

Table 2. Causes, time and distribution of NTZ discontinuation in BIONAT2Y and BIONATHA2Y
Causes of NTZ discontinuation and number of patient(s) Year 0–1Year 1–2Year 0–2
  1. SPMS, secondary progressive multiple sclerosis; PML, progressive multifocal leukoencephalopathy; Ab, antibody; values for BIONATHA2Y are indicated in parentheses.

Pregnancy planning16 (9)19 (9)35 (18)
Pregnancy1 (0)4 (4)5 (4)
Moving away1 (0)1 (0)2 (0)
Patient wish without validated medical reason5 (1)3 (2)8 (3)
Cutaneous allergy24 (10)0 (0)24 (10)
SPMS9 (2)8 (4)17 (6)
Serious adverse event7 (6)5 (1)12 (7)
Lack of efficacy without anti-NTZ Ab5 (4)1 (0)6 (4)
Unknown3 (1)6 (5)9 (6)
Psychiatric disorder3 (0)2 (2)5 (2)
Fear of PML1 (0)3 (2)4 (2)
Relapse(s) + anti-NTZ Ab5 (3)2 (1)7 (4)
Adverse event + anti-NTZ Ab2 (1)0 (0)2 (1)
Intolerance without anti-NTZ Ab2 (1)0 (0)2 (1)
Absence of compliance1 (0)1 (1)2 (1)
Total85 (38)56 (31)141 (69)

NTZ tolerance and antibodies against NTZ

Serious adverse events in BIONAT2Y were one progressive multifocal leukoencephalopathy (PML) (19th infusion), five neoplasms (two breast, one rectal, one uterine, one basocellular carcinoma), one lethal Hurst acute encephalopathy (reported on autopsy analysis), one autoimmune haemolytic anaemia, one pulmonary embolism, one myelodysplasic syndrome, one case of repeated bronchopneumonia and one case of elevated hepatic cytolysis. Five cases of PML were also observed in the BIONAT cohort but after the first 2 years of treatment (39th, 44th, 44th, 45th and 50th infusion; see Table 3).

Table 3. Demographic data of PML patients
  1. PML, progressive multifocal leukoencephalopathy; JCV, John Cunningham virus; IM, intramuscular; SC, subcutaneous.

SexFFFFMF
Number of NTZ infusions at PML diagnosis193944444550
Pre-NTZ treatment historyInterferon β1a IM

Interferon β1a IM

Copolymer acetate

Mitoxantrone

Cyclophosphamide

Interferon β1a IMInterferon β1a IM

Interferon β1a SC

Interferon β1a IM

Interferon β1a IM

Interferon β1a SC

JCV status++++++

Tests for anti-NTZ Abs were performed in clinical practice after 6 months of treatment as recommended when a patient presented clinical evolution (mainly relapses) or repeated adverse events. Detection of neutralizing Abs against NTZ involved 1.1% (9/793) of BIONAT2Y and represented 6.4% (9/141) of discontinuations in BIONAT2Y. The Abs were mainly detected in the first year (77.8% of BIONAT2Y) and most often detected after a relapse rather than for repeated adverse event occurrence.

A systematic assay of anti-NTZ Abs at 1 year of treatment was also performed, which was positive in 2.6% (21/793) of cases in BIONAT2Y versus 1.1% by following recommendations. The other 1.5% were represented by nine patients with cutaneous allergy during the first injections which stopped NTZ therapy, two patients without any clinical or radiological activity during the first and also the second year of treatment and one patient with pregnancy planned during the first year of treatment. Finally, systematic testing for anti-NTZ Abs detected only two supplementary patients with anti-NTZ Abs compared with strict application of the recommendations. In the BIONATHA2Y cohort the causes, time and distribution of NTZ discontinuation were fully comparable with BIONAT2Y.

Analysis of disease activity under NTZ

The proportions of patients free of disease activity in BIONAT2Y and BIONATHA2Y are reported and compared with the post hoc AFFIRM study in Fig. 1, which considered only the worst-case scenario. At the time of analysis, to evaluate clinical, radiological and combined disease activity, missing data were noted. Missing data were observed in 8%, 22% and 22.5% for clinical disease activity at year 0–1, year 1–2 and year 0–2 respectively; in 13%, 25% and 26% for radiological disease activity at year 0–1, year 1–2 and year 0–2 respectively; in 15%, 27% and 28% for combined disease activity at year 0–1, year 1–2 and year 0–2 respectively. Proportions of patients without clinical, radiological and combined disease activity at year 0–2 in BIONAT2Y according to the worst-, intermediate- and best-case scenarios are reported in Table 4. Only six patients presented radiological activity without clinical activity during their first 2 years of treatment. These patients represented only 1.4% of patients from the BIONAT2Y cohort with two complete years of treatment and full data available (6/432).

Table 4. Proportion of patients without clinical, radiological and combined disease activity in the worst versus the best scenario
 Worst scenarioIntermediate scenarioBest scenario
Clinical (%)
Year 0–162.4167.3269.71
Year 1–257.6468.4873.46
Year 0–247.4356.4263.36
Radiological (%)   
Year 0–188.8896.3196.59
Year 1–282.2598.6798.89
Year 0–280.8596.8897.40
Combined (%)
Year 0–161.2866.5669.20
Year 1–256.4167.9573.40
Year 0–245.5955.0962.84
image

Figure 1. Proportion of patients without radiological, clinical and combined disease activity in BIONAT2Y and BIONATHA2Y according to the worst-case scenario.

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None of the demographical, clinical or radiological baseline data of the BIONAT2Y cohort were predictive of a better response to NTZ, whatever the scenario considered (Table 5).

Table 5. Demographic, clinical and radiological baseline characteristics in subgroups of BIONAT2Y according to the best-/intermediate-/worst-case scenario and their disease activity status
 Best-case scenarioIntermediate-case scenarioWorst-case scenario
FreeNot freeFreeNot freeFreeNot free
  1. ARR, annualized relapse rate; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; Gd+, Gadolinium enhancement. Patients discontinuing NTZ for pregnancy or planned pregnancy and personal decision (not related to MS or because of fear of NTZ potential side effects) and patients without complete available data at 2 years of treatment are not included in this analysis. No significant difference was noted.

Number328194238194238284
Age (years)
Mean ± SD37.22 ± 9.9937.39 ± 9.5237.13 ± 10.3137.39 ± 9.5237.13 ± 10.3137.40 ± 9.39
Median [min;max]37 [18;65]37 [17;64]37 [18;65]37 [17;64]37 [18;65]37 [17;64]
Gender (sex ratio)2.952.882.552.882.553.30
Disease duration (years)
Mean ± SD12.53 ± 7.2612.79 ± 6.7812.54 ± 7.3212.79 ± 6.7812.54 ± 7.3212.70 ± 6.89
Median [min;max]11 [2;45]11 [3;37]11 [3;45]11 [3;37]11 [3;45]11 [2;40]
ARR
Mean ± SD2.05 ± 1.042.21 ± 1.201.99 ± 0.992.21 ± 1.201.99 ± 0.992.22 ± 1.18
Median [min;max]2 [0;6]2 [0;8]2 [0;5]2 [0;8]2 [0;5]2 [0;8]
EDSS
Mean ± SD3.51 ± 1.783.42 ± 1.643.40 ± 1.763.42 ± 1.643.40 ± 1.763.53 ± 1.71
Median [min;max]3.5 [0;8]3.5 [0;8]3.5 [0;8]3.5 [0;8]3.5 [0;8]3.5 [0;8]
Brain MRI
Number of Gd+ lesion(s)1.09 ± 2.420.85 ± 2.881.06 ± 2.460.85 ± 2.881.06 ± 2.460.96 ± 2.72
Proportion of patients with Gd+ lesion(s) (%)55.9046.953.3946.953.3951.79

Annualized relapse rates of BIONAT2Y at year 0–1 and year 1–2 were 0.45 ± 0.78 and 0.32 ± 0.61 respectively. Thus reduction of ARR in BIONAT2Y was evaluated as 78.6% in the first year, with an additional reduction of 28.9% in the second year. ARRs of BIONATHA2Y at year 0–1 and year 1–2 were 0.45 ± 0.81 and 0.29 ± 0.58 respectively. Thus reduction of ARR in BIONATHA2Y was higher than in BIONAT2Y and evaluated as 83.3% in the first year, with an additional reduction of 35.6% in the second year.

Biological analysis

The anti-JCV Ab prevalence of our first 811 patients included in the BIONAT study (BIONATJCV) was evaluated: 57.7% of these patients had anti-JCV antibodies. The mean ages in years (± SD) of anti-JCV seronegative and seropositive patients were 34.56 ± 9.67 and 37.53 ± 9.72 respectively and were shown to be statistically different by the Student t test (P < 0.01). Statistical significance was also observed when the distribution of JCV serological status on either side of the mean age of our cohort (≤ 36 years and > 36 years) was compared by the χ2 test (P < 0.01). Positive anti-JCV serostatus was not associated with the use of immunosuppressive or immunomodulatory pretreatment(s). No difference in terms of anti-JCV serological status between women (57.02% of anti-JCV seropositive) and men (57.67% anti-JCV seropositive) was observed. The mean ages (± SD) of women (36.77 ± 9.83 years) and men (35.61 ± 10.33 years) in BIONATJCV were not statistically different (P = 0.15). Because serological analysis was performed on patients' serum at baseline, it was not possible to evaluate whether NTZ exposure duration was a risk factor for being anti-JCV seropositive. Nevertheless, an evaluation of the annual rate of JCV seroconversion in the BIONAT cohort is planned.

At baseline, mean IgA,G,M values could be considered as normal according to laboratory normative values (IgA, 0.88–4.10 g/l; IgG, 6.90–14.00 g/l; IgM, 0.40–2.40 g/l). After 1 year of continuous NTZ therapy, significant increases in all lymphocyte subtypes, a significant decrease in IgM concentrations and a trend towards decreasing IgG concentrations were observed. These biological modifications persisted and remained or became significant at 2 years of treatment (Table 6).

Table 6. Biological follow-up of lymphocytic immunophenotyping and Ig G, A, M concentrations in BIONAT (n = 1204) and in a subgroup of BIONAT2Y (n = 133) at baseline, first and second years of NTZ therapy
 T0 (n = 1204)T0* (n = 133)T1*T2*T0* vs. T1T1* vs. T2T0* vs. T2*
  1. No statistical differences were observed between T0 and T0*. Significant differences are indicated in bold. NS, non-significant.

IgG (g/l)9.89 ± 2.5510.07 ± 2.539.58 ± 2.409.10 ± 2.24NSNSP = 0.024
9.77 [0.47–19.7]10.19 [5.6–16.5]9.6 [4.6–16]8.9 [3.6–15.6]
IgA (g/l)2.01 ± 0.862.05 ± 0.761.89 ± 0.741.92 ± 0.81NSNSNS
1.9 [0.09–9.38]1.975 [0.78–4.15]1.73 [0.58–4.55]1.67 [0.6–4.76]
IgM (g/l)1.34 ± 0.911.27 ± 0.700.79 ± 0.510.75 ± 0.48P < 0.001NSP < 0.001
1.2 [0.05–18]1.17 [0.24–5.03]0.69 [0.15–3.45]0.61 [0.14–3.00]
Total lymphocytes (cells/mm3)2230 ± 24301913 ± 7223365 ± 10333489 ± 991P < 0.001NSP < 0.001
1.81 [0.19–33.8]1798 [792–4200]3281 [1279–7992]3406 [1699–7440]
CD3 (/mm3)NA1389 ± 5352182 ± 7382263 ± 727P < 0.001NSP < 0.001
1283 [385–2919]2042 [767–4955]2103 [927–4587]
CD4 (/mm3)NA921 ± 3731419 ± 4861468 ± 471P < 0.001NSP < 0.001
856.5 [276–1933]1376 [558–3157]1365 [638–2842]
CD8 (/mm3)NA457 ± 213852 ± 335886 ± 334P < 0.001NSP < 0.001
408 [129–1124]810 [270–1972]818 [293–1928]
CD19 (/mm3)NA271 ± 131779 ± 348776 ± 327P < 0.001NSP < 0.001
261 [51–813]741 [96–2107]740 [88–1953]

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information

Analysis of disease activity is of prime importance in the BIONAT study because the identification of biomarkers of good response to NTZ therapy will depend on it. In this first report of the BIONAT study, missing data were reported at reasonable levels and did not interfere with data interpretation. The BIONAT cohort was comparable with the AFFIRM study in terms of age and sex ratio [1] but, as in many post-marketing studies already published, patients of the BIONAT cohort also presented more severe disease with higher pre-NTZ EDSS score and ARR [6-10]. Real life NTZ practice in France and other European countries shows that NTZ is, in fact, mainly proposed as a second-line therapy.

NTZ discontinuation causes are most often associated with a bad response to NTZ. All three scenarios excluded from the disease activity analysis were patients discontinuing NTZ for pregnancy or pregnancy planning and also patients' decision not related to MS or to fear of NTZ potential side effects. Thus it could be considered that the worst-case scenario is closer to the real life NTZ efficiency than the other scenarios. The proportion of patients without clinical or radiological disease activity in BIONAT2Y seemed to be similar to that reported in the post hoc analysis of the AFFIRM study. However, substantial differences could be noted. Reduction of clinical disease activity was less marked in BIONAT2Y and reduction of radiological activity was greater in BIONAT2Y than in the post hoc study of AFFIRM. It was also noted that NTZ-treated patients with radiological activity but without clinical activity are fewer than in AFFIRM/SENTINEL pivotal studies [11] and another post-marketing study (17%) [12]. It could be speculated that this difference is due to the high clinical disease activity of our cohort and to a potential underestimation of radiological activity because it was not possible to determine enlarging T2 lesions. The greatest reduction of ARR was observed in BIONATHA2Y, which concerns younger patients with higher ARR pre-NTZ and more gadolinium-enhanced lesions on brain MRI. These previous demographic and clinical characteristics are known to be in favour of a better response to NTZ [5]. However, younger age and higher ARR pre-NTZ were not found to be predictive of a better response to NTZ whichever scenario was considered.

As in all previous studies [13-17], seroprevalence for anti-JCV antibodies increased with age. In contrast to some previous studies [14, 16, 17] but in agreement with others [13, 15, 18], males were not found to be over-represented in the anti-JCV seropositive population. In the STRATIFY-1 cohort male gender was a risk factor for being JCV seropositive but there was only a trend towards significance in the TYGRIS-US cohort [14] as in a large German NTZ-treated MS cohort [16]. The mean ages of women and men cohorts are not known and a confounding effect of age could not be excluded. In the BIONAT cohort, past history of immunosuppressive or immunomodulatory drugs was not associated with risk of being anti-JCV seropositive like most post-marketing cohorts [14-16, 18] but unlike one study [19].

The frequency of anti-NTZ Abs in BIONAT2Y was lower than reported for the NTZ pivotal studies [20]. Our data confirm the interest of anti-NTZ Ab screening in the case of relapse or repeated adverse events but do not argue for a systematic screening of anti-NTZ Abs.

It is well known that duration of NTZ exposure is a PML risk factor for MS patients [21]. A decrease of serum Ig concentrations in MS patients under NTZ therapy is reported for the first time. The decrease of IgM and IgG concentrations at 2 years observed in a subsequent analysis of the BIONAT cohort could be considered to be in agreement with maximum PML risk after 2 years of treatment. Nevertheless, these data were not compared with those of healthy controls and a slight hypergammaglobulinemia in our MS patients before NTZ initiation that could be corrected with efficient therapy cannot be excluded. Nevertheless, MS is not a known cause of hypergammaglobulinemia and baseline Ig values of our cohort are in normal range. In MS patients, NTZ significantly increases the numbers of B cells and particularly immature pre-B cells [22] that highly express VLA4 antigen but that are also decreased in the blood and increased in cerebrospinal fluid in the earliest clinical stage of the disease [23]. The modification of B cell distribution under NTZ is concomitant with others' findings: disappearance of oligoclonal bands in MS patients [24], decreasing IgG [25, 26] and IgM intrathecal secretion [25]. To the best of our knowledge, there is no previous report about a significant decrease of IgG and IgM rates under NTZ. Although NTZ is associated with the occurrence of PML [21], it has never been clearly demonstrated that it could induce other opportunistic infections or facilitate other infections in general. Humoral immune response in NTZ-treated patients seems comparable with that achieved in healthy individuals [27]. At this time, humoral changes under NTZ are not well understood.

This is the first report of the BIONAT study. It is planned to complete all missing values at 2 years but also project clinical, radiological and biological follow-up at 5 years. The next step of the BIONAT study (planned for 2014) is a genome and transcriptome screening of the 1204 patients and, of course, potential identification of biomarkers predicting response to NTZ therapy as planned in the Best-MS network (Best therapeutic choice for MS, a 2012 FP7 Health Innovation 1 supported network). Pre-PML samples from six patients up to 50 months before PML diagnosis were also collected. The aim is to determine whether any biomarkers are associated with PML prediction.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information

The authors would like to thank CFSEP (Club Francophone de la SEP, Dr Heinzleff), the REFGENSEP (Réseau français de Recherche sur la Génétique de la SEP, Professor Fontaine), TYSEDMUS and the Eugène Devic Foundation (Professors Confavreux and Vukusic) for their help and constant support. BIONAT is funded by the French Ministry of Health (Projet Hospitalier de Recherche Clinique, PHRC 2008) the French MS Society (ARSEP 2007, 2008, 2010) and an FP7 Health Innovation 1 grant (2012). JC virus serology and 1-year neutralizing antibody determination were funded by Biogen Idec at FOCUS Diagnostics (CA, USA) and Pasteur France.

Disclosure of conflicts of interest

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information

Please refer to Data S1 for the full list of disclosures.

References

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  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Disclosure of conflicts of interest
  9. References
  10. Supporting Information
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ene12204-sup-0001-Disclosures_Outteryck.docWord document25KData S1. Author disclosures.

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