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Figure.
Main Reasons for Stopping Natalizumab According to Progressive Multifocal Leukoencephalopathy (PML) Risk Stratification
Main Reasons for Stopping Natalizumab According to Progressive Multifocal Leukoencephalopathy (PML) Risk Stratification

The values represent percentages of the whole cohort (n = 333). Patients who had 2 or more PML risk factors primarily stopped natalizumab because of the risk of PML. Patients with a low PML risk profile according to stratification stopped natalizumab because of a lack of tolerance or efficacy. IS indicates immunosuppression; JCV, JC polyomavirus.

Table 1.  
Characteristics of the Cohort
Characteristics of the Cohort
Table 2.  
Statistical Analysis Assessing the Risk of Relapse During the Washout Period
Statistical Analysis Assessing the Risk of Relapse During the Washout Period
Table 3.  
Statistical Analysis Comparing the Patients With vs Without Relapse After Fingolimod Initiation
Statistical Analysis Comparing the Patients With vs Without Relapse After Fingolimod Initiation
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West  TW, Cree  BA.  Natalizumab dosage suspension: are we helping or hurting? Ann Neurol. 2010;68(3):395-399.
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Killestein  J, Vennegoor  A, Strijbis  EM,  et al.  Natalizumab drug holiday in multiple sclerosis: poorly tolerated. Ann Neurol. 2010;68(3):392-395.
PubMedArticle
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Miravalle  A, Jensen  R, Kinkel  RP.  Immune reconstitution inflammatory syndrome in patients with multiple sclerosis following cessation of natalizumab therapy. Arch Neurol. 2011;68(2):186-191.
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Borriello  G, Prosperini  L, Marinelli  F, Fubelli  F, Pozzilli  C.  Observations during an elective interruption of natalizumab treatment: a post-marketing study. Mult Scler. 2011;17(3):372-375.
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O’Connor  PW, Goodman  A, Kappos  L,  et al.  Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis. Neurology. 2011;76(22):1858-1865.
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Naismith  RT, Bourdette  D.  Interruption of natalizumab therapy for multiple sclerosis: what are the risks? Neurology. 2011;76(22):1854-1855.
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Borriello  G, Prosperini  L, Mancinelli  C, Giannì  C, Fubelli  F, Pozzilli  C.  Pulse monthly steroids during an elective interruption of natalizumab: a post-marketing study. Eur J Neurol. 2012;19(5):783-787.
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Magraner  MJ, Coret  F, Navarré  A,  et al.  Pulsed steroids followed by glatiramer acetate to prevent inflammatory activity after cessation of natalizumab therapy: a prospective, 6-month observational study. J Neurol. 2011;258(10):1805-1811.
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Sørensen  PS, Bertolotto  A, Edan  G,  et al.  Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler. 2012;18(2):143-152.
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Rinaldi  F, Seppi  D, Calabrese  M, Perini  P, Gallo  P.  Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler. 2012;18(11):1640-1643.
PubMedArticle
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Ghezzi A, Baroncini D, Annovazzi PO, Bianchi A, Minonzio G, Comi G. From natalizumab to fingolimod: an observational study of 32 patients. In: Final Programme: 28th Congress of the European Committee for Treatment and Research Into Multiple Sclerosis; October 10-13, 2012; Lyon, France. Lyon, France: European Committee for Treatment and Research Into Multiple Sclerosis; 2012. Poster 938. http://www.posters2view.com/ectrims2012/view.php?nu=857. Accessed January 19, 2013.
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Jander  S, Turowski  B, Kieseier  BC, Hartung  HP.  Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Mult Scler. 2012;18(11):1650-1652.
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Daelman  L, Maitrot  A, Maarouf  A, Chaunu  MP, Papeix  C, Tourbah  A.  Severe multiple sclerosis reactivation under fingolimod 3 months after natalizumab withdrawal. Mult Scler. 2012;18(11):1647-1649.
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Laroni  A, Brogi  D, Milesi  V, Abate  L, Uccelli  A, Mancardi  G.  Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab interruption. Mult Scler. 2013;19(9):1236-1237.
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Havla  J, Tackenberg  B, Hellwig  K,  et al.  Fingolimod reduces recurrence of disease activity after natalizumab withdrawal in multiple sclerosis. J Neurol. 2013;260(5):1382-1387.
PubMedArticle
Original Investigation
April 2014

Switching From Natalizumab to Fingolimod in Multiple SclerosisA French Prospective Study

Author Affiliations
  • 1Department of Neurology, University Hospital of Nice, Nice, France
  • 2Department of Neurology, Salpêtrière Hospital, Paris, France
  • 3Department of Neurology, University Hospital of Reims, Reims, France
  • 4Department of Neurology, University Hospital of Strasbourg, Strasbourg, France
  • 5Department of Neurology, University Hospital of Lyon, Lyon, France
  • 6Department of Neurology, University Hospital of Toulouse, Toulouse, France
  • 7Department of Neurology, University Hospital of La Rochelle, La Rochelle, France
  • 8Department of Neurology, University Hospital of Nantes, Nantes, France
  • 9Department of Neurology, University Hospital of Montpellier, Montpellier, France
  • 10Department of Neurology, University Hospital of Mulhouse, Mulhouse, France
  • 11Department of Neurology, University Hospital of Bordeaux, Bordeaux, France
  • 12Department of Neurology, University Hospital of Nancy, Nancy, France
  • 13Department of Neurology, University Hospital of Rennes, Rennes, France
  • 14Department of Neurology, University Hospital of Grenoble, Grenoble, France
  • 15Department of Neurology, University Hospital of Poissy, Poissy, France
  • 16Department of Neurology, Tenon Hospital, Paris, France
  • 17Department of Neurology, University Hospital of Rouen, Rouen, France
  • 18Department of Neurology, University Hospital of Nimes, Nimes, France
  • 19Department of Neurology, University Hospital of Marseille, Marseille, France
  • 20Department of Neurology, University Hospital of Besançon, Besançon, France
  • 21Department of Neurology, University Hospital of Saint Etienne, Saint Etienne, France
  • 22Department of Neurology, University Hospital of Caen, Caen, France
  • 23Department of Neurology, University Hospital of Clermont Ferrand, Clermont Ferrand, France
  • 24Department of Neurology, University Hospital of Amiens, Amiens, France
  • 25Department of Neurology, University Hospital of Lille, Lille, France
  • 26Department of Neurology, University Hospital of Dijon, Dijon, France
JAMA Neurol. 2014;71(4):436-441. doi:10.1001/jamaneurol.2013.6240
Abstract

Importance  The safety and efficacy of switching from natalizumab to fingolimod have not yet been evaluated in a large cohort of patients with multiple sclerosis (MS) to our knowledge.

Objective  To collect data from patients with MS switching from natalizumab to fingolimod.

Design, Setting, and Participants  The Enquête Nationale sur l’Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a survey-based, observational multicenter cohort study among MS tertiary referral centers. Participants were patients for whom a switch from natalizumab to fingolimod was planned. Clinical data were collected on natalizumab treatment, duration and management of the washout period (WP), and relapse or adverse events during the WP and after the initiation of fingolimod.

Main Outcomes and Measures  Occurrence of MS relapse during the WP or during a 6-month follow-up period after the initiation of fingolimod.

Results  Thirty-six French MS tertiary referral centers participated. In total, 333 patients with MS switched from natalizumab to fingolimod after a mean of 31 natalizumab infusions (female to male ratio, 2.36; mean age, 41 years; and Expanded Disability Status Scale score at the initiation of natalizumab, 3.6). Seventy-one percent were seropositive for the JC polyomavirus. The Expanded Disability Status Scale score remained stable for patients receiving natalizumab. Twenty-seven percent of patients relapsed during the WP. A WP shorter than 3 months was associated with a lower risk of relapse (odds ratio, 0.23; P = .001) and with less disease activity before natalizumab initiation (P = .03). Patients who stopped natalizumab because of poor tolerance or lack of efficacy also had a higher risk of relapse (odds ratio, 3.20; P = .004). Twenty percent of patients relapsed during the first 6 months of fingolimod therapy. Three percent stopped fingolimod for efficacy, tolerance, or compliance issues. In the multivariate analysis, the occurrence of relapse during the WP was the only significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; P = .05).

Conclusions and Relevance  In this study, switching from natalizumab to fingolimod was associated with a risk of MS reactivation during the WP or shortly after fingolimod initiation. The WP should be shorter than 3 months.

Fingolimod was licensed in France in early 2012 for patients with active relapsing-remitting multiple sclerosis (MS), with identical conditions of prescription compared with natalizumab. Therefore, fingolimod and natalizumab are supposed to be comparable in terms of prescription intent, efficacy, and safety.

Depending on the patient or neurologist, switching from natalizumab to fingolimod can be considered an option in various situations, including patients treated with natalizumab who have tolerance or efficacy issues and patients who have a high risk of developing progressive multifocal leukoencephalopathy (PML). However, the safety and efficacy of switching from natalizumab to fingolimod have not been evaluated in a large cohort of patients with MS to date.

Several variables need to be clarified. The requirement of a washout period (WP) between natalizumab withdrawal and fingolimod initiation is mandatory because of the immunosuppressive mechanisms of each molecule, but its exact duration has yet to be determined. Medical authorities have not reached a consensus concerning the WP. It should be as short as possible because of the known risk of a return of MS disease activity after natalizumab discontinuation.16 The use of intravenous corticosteroids and immunomodulatory drugs during the WP could be helpful, but their efficacy in this situation is limited.7,8 Furthermore, the use of an immunomodulatory drug between natalizumab withdrawal and fingolimod initiation for less than 3 to 6 months raises an efficacy issue.

We present a national prospective study of patients with MS for whom a switching strategy from natalizumab to fingolimod was chosen. The safety and outcome were assessed.

Methods

The Enquête Nationale sur l’Introduction du Fingolimod en Relais au Natalizumab (ENIGM) study, a national survey on switching from natalizumab to fingolimod, is a French prospective multicenter study. The aim of the ENIGM study was to assess the safety of the treatment and its efficacy on the outcome of patients switching from natalizumab to fingolimod.

Every MS tertiary care center in France was contacted to prospectively collect real-life data from patients for whom a switching strategy from natalizumab to fingolimod was intentionally planned at the time of natalizumab withdrawal. Patients who stopped natalizumab and who were then unexpectedly treated with fingolimod were not included. Data were anonymously collected using a Google Docs form (http://www.google.com/google-d-s/createforms.html). All study patients gave oral informed consent to be included in the European Database for Multiple Sclerosis (http://www.edmus.org). Therefore, no additional consent or institutional review board approval was obtained for patients’ participation in this study.

To determine the PML risk according to the current risk stratification,9 we collected the following demographic and clinical data during the natalizumab treatment period: the annualized relapse rate during the year before natalizumab initiation, the number of administered infusions, the Expanded Disability Status Scale (EDSS) score at the initiation and at the final infusion, and the JC polyomavirus status and the history of immunosuppressive treatments. The main reason for natalizumab discontinuation was chosen from the following list of possible answers: fear of PML, a natalizumab tolerance issue, the development of anti-natalizumab antibodies, a perceived lack of natalizumab efficacy by the physician, and a decision by the patient or physician.

Data concerning the WP included the duration, the use of a rescue or planned treatment (methylprednisolone or an immunomodulatory drug) during the WP, and the occurrence of relapse during this period. Data concerning fingolimod treatment initiation included the EDSS score at the initiation and the occurrence of a relapse or adverse event during the first 6 months of treatment.

All anonymous data were gathered in the MS tertiary care center in Nice, France, on behalf of the Club Francophone de la Sclérose en Plaques, a French-speaking MS club. The ENIGM study included patients who were managed in real-life settings; therefore, the assessment of treatment efficacy and relapse was left to the discretion of each physician.

A univariate statistical analysis was performed using the t test for comparison of continuous variables and the χ2 test for comparison of the distribution of categorical data between groups. Relevant data were then included in a binary logistic regression model for multivariate analysis. Statistical analysis was performed using available software (SPSS Statistics version 20; SPSS Inc) on a personal computer (Mac OS X; Apple Inc). Results were considered statistically significant at P < .05.

Results

All 36 French MS tertiary referral centers participated in the survey. Between April 10 and August 31, 2013, a total of 333 patients having MS treated with natalizumab were facing a switching strategy. The demographic and clinical features of the cohort are summarized in Table 1. Patients had received a mean of 31 natalizumab infusions, and the EDSS score had remained stable during this period. Seventy-one percent of patients were seropositive for the JC polyomavirus, and 65.2% of patients in the cohort had at least 2 risk factors for developing PML.9 The JC polyomavirus status was unknown for 22.1% of patients. The main reasons for stopping natalizumab were putative risk of PML, the patient’s decision, and a lack of natalizumab efficacy. Overall, 31.2% of patients stopped natalizumab because of tolerance or efficacy issues, and 69.1% were considered good responders. No compliance issue related to natalizumab use was reported. The distribution of reasons for stopping natalizumab with respect to PML risk stratification is shown in the Figure.

The mean WP was 17 weeks (range, 2-156 weeks). The WP was shorter than 3 months for 31.3% of patients, between 3 and 6 months for 47.0% of patients, and longer than 6 months for 21.7% of patients. Fifty-five percent of patients received no treatment during the WP, and other patients were treated with sequential methylprednisolone infusions (38.9%) or temporarily with an immunomodulatory drug (6.2%). Twenty-seven percent of patients relapsed during the WP. In the univariate analysis, no difference was found between patients with vs without relapse in terms of age, EDSS score, or the use of a rescue or planned treatment (methylprednisolone or an immunomodulatory drug) during the WP. There were significantly more women in the group of patients that relapsed during the WP (32.4% vs 16.7%, P = .04). The risk of relapse was significantly higher for patients who had the longest MS duration and for patients who stopped natalizumab because of tolerance or efficacy issues compared with other patients (Table 2). A longer WP was the strongest risk factor for MS reactivation (P < .001). The percentages of patients who relapsed depending on the WP were 19.9% for less than 3 months, 31.3% for 3 to 6 months, and 59.1% for greater than 6 months. In the multivariate analysis, a WP shorter than 3 months was associated with a significantly lower risk of relapse (odds ratio, 0.23; 95% CI, 0.10-0.65; P = .001). Stopping natalizumab because of a lack of tolerance or efficacy was associated with a significantly higher risk of relapse (odds ratio, 3.20; 95% CI, 1.44-5.10; P = .004).

At the initiation of fingolimod, the mean EDSS score was 3.7 (Table 3). To date, 6-month follow-up data have been collected for 69.1% of 333 patients (n = 230). Twenty percent of 333 patients (n = 66) relapsed during the first 6 months of fingolimod therapy. Early fingolimod withdrawal was recorded for 3.0% of patients because of tolerance, efficacy, or compliance issues. In the univariate analysis, both the WP and the occurrence of relapse during the WP correlated with the risk of relapse during fingolimod therapy. In the multivariate analysis, the occurrence of relapse during the WP was the only statistically significant prognostic factor for relapse during fingolimod therapy (odds ratio, 3.80; 95% CI, 1.26-7.58; P = .05). The MS disease activity before natalizumab initiation and the reason for stopping natalizumab did not correlate with disease reactivation during the first months of fingolimod treatment.

Discussion

We collected data from one of the largest available samples to date of patients with MS switching from natalizumab to fingolimod. At the time of data collection, this cohort represented close to 100% participation of French MS tertiary care centers. Statistical analysis revealed 2 important findings that must be taken into consideration in clinical practice.

First, this study underlines the substantial risk of relapse during the WP. As expected, the risk correlated with MS disease activity before natalizumab initiation and with the duration of the WP. The risk increased significantly for patients with a WP of 3 months or longer. The use of a short-term rescue or planned treatment (methylprednisolone or an immunomodulatory drug) did not mitigate the risk of relapse. Those findings have already been reported in multiple natalizumab withdrawal studies.1,2,48 Conversely, patients who had a short WP (<3 months) had a lower risk of relapse.

Second, our results demonstrate an early relapse during fingolimod therapy and a 3.0% rate of treatment withdrawal. This prevents our drawing any conclusions in terms of comparison of efficacy between natalizumab and fingolimod but is important to take into consideration, particularly for patients who were good responders to natalizumab. In a 22-patient cohort switching from natalizumab to fingolimod with a 9-month follow-up period, Rinaldi et al10 reported MS disease reactivation in 27% of patients, which is similar to our data. When including magnetic resonance imaging data, disease reactivation was present in 50% of patients in the cohort. We did not systematically collect radiologic data in our study. At the 28th Congress of the European Committee for Treatment and Research Into Multiple Sclerosis, Ghezzi et al11 presented similar results for a 32-patient cohort. In addition, some authors have reported isolated cases of patients treated with fingolimod after natalizumab discontinuation who manifested severe relapse and tumefactive magnetic resonance images.12,13

A more recent study14 reports data from 19 patients who stopped natalizumab after a mean period of 30 months. Patients were nonrandomly treated with fingolimod (n = 11), received an immunomodulatory drug (n = 4), or remained untreated (n = 4). The WP was 4 months for patients who switched to fingolimod. After a 34-week follow-up period, only 1 patient in the group that switched to fingolimod relapsed compared with 5 patients in the other groups. Comparable results were reported in a recent article from a group of 26 patients who switched to fingolimod compared with 10 patients who remained untreated after natalizumab discontinuation.15 In this cohort, the risk of disease reactivation during fingolimod therapy correlated with the duration of WP, which could not be confirmed in our sample. To date, no other published cohort study or registry is available among patients switching from natalizumab to fingolimod.

The results of the ENIGM study suggest that switching from natalizumab to fingolimod can be an option for patients with tolerance or efficacy issues during natalizumab therapy. In this subgroup of patients, our results suggest that the MS disease activity was greater during the WP but not after fingolimod initiation.

If the switch was motivated by the risk of developing PML (slightly >1% for patients in the highest risk category according to the latest stratification data9), the benefit-risk ratio between maintaining natalizumab therapy vs a switching strategy has to be carefully balanced. In all cases, our results suggest that the WP should be shorter than 3 months if a switch is chosen.

The main limitation of this study is the survey-based approach. Participants were asked to include all patients who switched from natalizumab to fingolimod, but there was no oversight to ensure that all possible individuals were enrolled in the survey and that all data time points were captured. Therefore, it would be relevant to confirm those results in a true prospective cohort study. It would also be germane to gather longer follow-up data about patients with a shorter WP to assess the safety and efficacy of this schedule.

Conclusions

The ENIGM study gathered data from 333 patients with MS who switched from natalizumab to fingolimod in France. According to our data, switching can be an option for patients who develop tolerance or efficacy issues with natalizumab therapy. For patients who are good responders to natalizumab, the risk of MS reactivation should be taken into consideration. The WP should be shorter than 3 months.

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Article Information

Accepted for Publication: January 2, 2014.

Corresponding Author: Mikael Cohen, MD, Department of Neurology, University Hospital of Nice, 30 Voie Romaine, 06000 Nice, France (cohen.m@chu-nice.fr).

Published Online: February 24, 2014. doi:10.1001/jamaneurol.2013.6240.

Author Contributions: Dr Cohen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Cohen, Lebrun.

Acquisition of data: All authors.

Analysis and interpretation of data: Cohen, Lebrun.

Drafting of the manuscript: Cohen, Lebrun.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cohen, Lebrun.

Administrative, technical or material support: Cohen, Lebrun.

Study supervision: Cohen, Lebrun.

Conflict of Interest Disclosures: Dr Cohen served as a consultant for Biogen Idec, Novartis, Teva Pharmaceuticals, sanofi-aventis, Merck Serono, and Bayer Schering Pharma. Dr Tourbah received consulting and lecture fees from Novartis, sanofi-aventis, Genzyme, and Teva Pharmaceuticals; research support from Biogen Idec, Novartis, Merck Serono, sanofi-aventis, and Agence Nationale Recherche; and participated in clinical trials for Biogen Idec, Novartis, Merck Serono, Bayer Schering Pharma, and Roche. Dr De Sèze participated in clinical trials for Biogen Idec, Merck Serono, Bayer Schering Pharma, LFB, UCB, AB Sciences, sanofi-aventis, Teva Pharmaceuticals, and Genzyme and received consulting fees from Biogen Idec, Merck Serono, Bayer Schering Pharma, LFB, sanofi-aventis, Teva Pharmaceuticals, Genzyme, Allergan, and Almirall. Dr Vukusic received consulting and lecture fees, travel grants, and research support from Bayer Schering Pharma, Biogen Idec, Genzyme, Novartis, Merck Serono, sanofi-aventis, and Teva Pharmaceuticals. Dr Brassat received consulting and lecture fees from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, Teva Pharmaceuticals, and Genzyme. Dr Wiertlewski received fees from Biogen Idec, Novartis, sanofi-aventis, Teva Pharmaceuticals, and Bayer Schering Pharma. Dr Camu received research grants from Biogen Idec, Bayer Schering Pharma, Merck Serono, and sanofi-aventis. Dr Courtois served as a consultant for Biogen Idec. Dr Ruet participated as a speaker at symposia organized by Biogen Idec and Teva Pharmaceuticals. She is or was an investigator for studies supported by Novartis, Bayer Schering Pharma, Roche, Lilly, Peptimmune, and Merck Serono and has received funding for this activity. She received research support from Novartis. She is also a recipient of a fellowship grant from the Fondation pour la Recherche Médicale. Dr Debouverie has participated in consulting research or workshops for Biogen Idec, Bayer Schering Pharma, Genzyme, Merck Serono, Novartis, sanofi-aventis, and Teva Pharmaceuticals. Dr Le Page served on a scientific advisory board for Genzyme and received honoraria for lectures to nurses and for manuscript preparation for Neurologies. Dr Casez received consulting fees from Teva Pharmaceuticals, Novartis, Biogen Idec, and AstraZeneca. Dr Heinzlef served on a scientific advisory board for Bayer Schering Pharma, Novartis, Almirall, Teva Pharmaceuticals, and Genzyme; received travel grants from Teva Pharmaceuticals, Novartis, Biogen Idec, Bayer Schering Pharma, and Merck Serono; received royalties for publications by John Libbey Eurotext; and received honoraria for speaking at engagements supported by Merck Serono, Teva Pharmaceuticals, Novartis, Biogen Idec, and Bayer Schering Pharma. Dr Stankoff received consulting and lecture fees from Biogen Idec, Novartis, Merck Serono, sanofi-aventis, Teva Pharmaceuticals, and Bayer Schering Pharma and received research support from Biogen Idec, sanofi-aventis, Programme Hospitalier de Recherche Clinique (Assistance Publique–Hôpitaux de Paris), and Agence Nationale Recherche. Dr Bourre received consulting fees from Biogen Idec and travel grants from Bayer Schering Pharma, Merck Serono, Biogen Idec, Teva Pharmaceuticals, and sanofi-aventis. Dr Rico received consulting fees and travel grants from Bayer Schering Pharma, Biogen Idec, Novartis, Merck Serono, sanofi-aventis, Genzyme, and Teva Pharmaceuticals. Dr Berger served as a consultant for Biogen Idec and Novartis. Dr Camdessanche received fees for lectures, consulting, writing of articles, or training courses from Biogen Idec, CSL-Behring, Laboratoire Français des Biotechnologies, Merck Serono, Novartis, Teva Pharmaceuticals, Edimark, Editions Scientifiques L&C, Expression Santé, Natus, Science, and SNF-Floerger. Dr Defer received personal compensation for participation in a scientific advisory board from Biogen Idec, Novartis, sanofi-aventis, Genzyme, and Teva Pharmaceuticals and received funding for travel or speaker honoraria from Merck Serono, Biogen Idec, Guerbet, sanofi-aventis, Novartis, Genzyme, and Teva Pharmaceuticals. Dr Clavelou received travel grants and speaker honoraria from Teva Pharmaceuticals, Novartis, Biogen Idec, Bayer Schering Pharma, sanofi-aventis, and Genzyme. Dr Al Khedr received consulting fees and travel grants from Biogen Idec, Novartis, Bayer Schering Pharma, Teva Pharmaceuticals, and sanofi-aventis. Dr Zephir served on a scientific advisory board for Biogen Idec, Genzyme, and Teva Pharmaceuticals; served as a consultant for Biogen Idec, Bayer Schering Pharma, Merck Serono, Novartis, sanofi-aventis, and Teva Pharmaceuticals; received research support from Teva Pharmaceuticals; and received payments for lectures for Biogen Idec, Bayer Schering Pharma, and Novartis. Dr Papeix served on a scientific advisory board for Biogen Idec, Teva Pharmaceuticals, Bayer Schering Pharma, sanofi-aventis, Genzyme, and Roche and received payments for lectures from Biogen Idec, Bayer Schering Pharma, Teva Pharmaceuticals, sanofi-aventis, Genzyme, and Roche. Dr Brochet or his institution received honoraria for speaking at scientific meetings and for serving as a member of scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Genzyme, Novartis, and Teva Pharmaceuticals, and his institution received research grants from Bayer Schering Pharma, Teva Pharmaceuticals, Merck Serono, Novartis, Biogen Idec, sanofi-aventis, Fondation pour l’Aide à la Recherche sur la Sclérose En Plaques, and Roche. Dr Pelletier served as a consultant for Allergan, Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, sanofi-aventis, and Teva Pharmaceuticals; served on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Genzyme, Merck Serono, Novartis, sanofi-aventis, and Teva Pharmaceuticals; served on steering committees for Biogen Idec and Novartis; and received unconditional research grants from Bayer Schering Pharma, Biogen Idec, Bristol-Myers Squibb, GlaxoSmithKline, Merck Serono, Novartis, Peptimmune, Roche, sanofi-aventis, Teva Pharmaceuticals, and Wyeth. Dr Lebrun served as a consultant for Allergan, Almirall, Biogen Idec, Genzyme, Bayer Schering Pharma, Merck Serono, Novartis, sanofi-aventis, and Teva Pharmaceuticals. No other disclosures were reported.

Role of the Sponsors: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: The Club Francophone de la Sclérose en Plaques Investigators were Pascal Barth, MD, Saverne, France; Frederic Blanc, MD, PhD, Strasbourg, France; Clotilde Boulay, MD, Mulhouse, France; William Camu, MD, PhD, Montpellier, France; Loic Chambaud, MD, Mulhouse, France; Pierre Clavelou, MD, PhD, Clermont-Ferrand, France; Nicolas Collongues, MD, PhD, Strasbourg, France; Marc Coustans, MD, Quimper, France; Alain Creange, MD, PhD, Créteil, France; Faycal Derouiche, MD, Mulhouse, France; Gilles Edan, MD, PhD, Rennes, France; Marie Fleury, MD, Strasbourg, France; Olivier Gout, MD, Paris, France; Anne Marie Guennoc, MD, Tours, France; Audrey Kopf, MD, Haguenau, France; Pierre Labauge, MD, PhD, Montpellier, France; Francois Lallement, MD, Saint Brieuc, France; David Laplaud, MD, PhD, Nantes, France; Pierre Louiset, MD, PhD, Bordeaux, France; Irina Malikova, MD, Marseille, France; Thibault Moreau, MD, PhD, Dijon, France; Jean Christophe Ouallet, MD, PhD, Bordeaux, France; Sophie Pittion, MD, Nancy, France; Francois Rouhart, MD, Brest, France; Lucien Rumbach, MD, PhD, Besançon, France; Pierrette Seeldrayers, MD, Charleroi, Belgium; Frederic Taithe, MD, Clermont-Ferrand, France; Gregory Taurin, MD, Saint Malo, France; Eric Thouvenot, MD, PhD, Nimes, France; Patrick Vermersch, MD, PhD, Lille, France; and Christian Zaenker, MD, Colmar, France.

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PubMedArticle
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PubMedArticle
3.
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