Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: A 3-year follow-up multicentric study

Accepted Manuscript Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: A 3-year follow-up multicentric study

Vincent Planche, Xavier Moisset, Remy Morello, Emilie Dumont, Marion Gibelin, Julie Charré-Morin, Aurore Saubusse, Audrey Mondou, Françoise Reuter, Gilles Defer, Jean Pelletier, Bruno Brochet, Pierre Clavelou PII: DOI: Reference:

S0022-510X(17)34373-3 doi:10.1016/j.jns.2017.10.008 JNS 15603

To appear in:

Journal of the Neurological Sciences

Received date: Revised date: Accepted date:

31 July 2017 25 September 2017 5 October 2017

Please cite this article as: Vincent Planche, Xavier Moisset, Remy Morello, Emilie Dumont, Marion Gibelin, Julie Charré-Morin, Aurore Saubusse, Audrey Mondou, Françoise Reuter, Gilles Defer, Jean Pelletier, Bruno Brochet, Pierre Clavelou , Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: A 3-year follow-up multicentric study. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi:10.1016/j.jns.2017.10.008

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ACCEPTED MANUSCRIPT Improvement of quality of life and its relationship with neuropsychiatric outcomes in patients with multiple sclerosis starting treatment with natalizumab: A 3-year follow-up multicentric study

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Vincent Planche1 , Xavier Moisset1,2 , Remy Morello3 , Emilie Dumont1 , Marion Gibelin4 , Julie Charré-Morin5 , Aurore Saubusse5 , Audrey Mondou6 , Françoise Reuter7 , Gilles Defer6 , Jean Pelletier7 , Bruno Brochet5 and Pierre Clavelou1,2

1

Service de Neurologie, CHU de Clermont-Ferrand, Université Clermont Auvergne, F-63000, Clermont-Ferrand, France 2

Neuro-Dol, Inserm U1107, Université Clermont Auvergne, F-63000, Clermont-Ferrand, France 3

Réseau NeuroSEP Auvergne, F-63110, Beaumont, France

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Unité de Biostatistique et Recherche Clinique, CHU de Caen, Université de Normandie, F14033, Caen, France

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Service de Neurologie, CHU de Bordeaux, Université de Bordeaux, F-33007, Bordeaux, France Service de Neurologie, CHU de Caen, Université de Normandie, F-14033, Caen, France

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APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, F13000, Marseille, France

Corresponding author: Dr Vincent Planche, Service de Neurologie, CHU Clermont58

rue

Montalembert,

F-63000,

Clermont-Ferrand,

France;

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Ferrand,

[email protected]; tel.: 33 (0)4 73 75 22 05; fax: 33 (0)4 73 75 22 06

Word count: Abstract: 232, Article: 2535 Tables : 5. Figure: 1. References: 30

Keywords: health-related quality of life, multiple sclerosis, natalizumab, fatigue, depression, cognition

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ACCEPTED MANUSCRIPT Study funding: Biogen Idec. The sponsor did not participate in any aspect of the design or performance of the study, including data collection, management, analysis, and interpretation or the preparation, review, and approval of the manuscript.

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Disclosures: VP received travel expenses and/or consulting fees from the ARSEP

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Foundation, Biogen-Idec, Teva-Lundbeck and Merk-Serono. XM received travel expenses from Biogen, Sanofi-Pasteur-MSD and Genzyme and received honoraria from Merk-Serono, Teva, Astellas and Institut UPSA de la douleur. GD received personal compensation for

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serving on scientific advisory boards for Biogen Idec, Merck-Serono, Novartis, Sanofi Aventis, Genzyme and Teva; he has received funding for travel and/or speaker honoraria from

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Merck Serono, Biogen, Guerbet, Sanofi Aventis, Novartis, Genzyme and Teva; his institution received grants supporting research in his department from Merck Serono, Biogen, Sanofi

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Aventis and Novartis. JP has received compensation for serving as advisory board and research support from Biogen, Genzyme, MedDay, Novartis, Merck Serono, Sanofi and Teva.

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BB serves on scientific advisory boards for or has received honorar ia or research support for

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his institution from Biogen-Idec, Merck-Serono, Novartis, Genzyme, Teva, Roche, Medday and Bayer. PC received travel expenses and serves on scientific advisory boards for Teva-

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Pharma, Merck-Serono, Novartis, Biogen, Genzyme, Bayer, and Almirall. Other authors: nothing to declare.

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ACCEPTED MANUSCRIPT Abstract

Background: Health-related quality of life (HRQoL) is impaired in multiple sclerosis (MS) but can be improved by disease-modifying therapies such as natalizumab. However, the

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predictive factors and neuropsychiatric correlates of HRQoL improvement are unknown.

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Methods: In this study, 48 patients with relapsing-remitting MS were included in a 3-year open- label, single group, multicenter, clinical trial (NCT01392872). HRQoL was measured by the disease-specific MusiQoL questionnaire, together with physical disability, cognition,

months after starting natalizumab therapy.

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fatigue, anxiety and depression scores at baseline, 6 months, 12 months, 18 months and 36

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Results: Compared to baseline, global HRQoL, as measured with the index of the MusiQoL, was significantly increased 6 months after the beginning of natalizumab therapy, with

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medium effect-size (58.6±16.2 vs 69.8±18.9, p<0.001, Cohen’s d=0.63). This improvement

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was maintained over time for up to 3 years and mainly concerned activity of daily living, psychological well-being, symptoms and coping (p<0.001 for every dimensions). The

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variation of global HRQoL after 3 years was negatively correlated with the variation of fatigue score (r=-0.44, p=0.015). Furthermore, a higher fatigue score at baseline was

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correlated with improvement in global HRQoL 3 years afterwards (r=0.34, p=0.041), independently of age, educational level, disease duration and disability at baseline (β=2.45, p=0.020). Disability at baseline, cognitive impairment, anxiety and depression failed to predict or correlate with global HRQoL improvement in multivariate analyses. Conclusion: Natalizumab improved HRQoL quickly and sustainably in patients with relapsing-remitting MS. In terms of HRQoL, natalizumab seems to benefit mostly patients with more marked fatigue at baseline.

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ACCEPTED MANUSCRIPT Introduction

Health-related quality of life (HRQoL) has been widely studied in multiple sclerosis (MS) because this neurological disease affects young adults and strongly interferes with daily

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functioning [1]. Many patients with MS suffer from a decrease in HRQoL, which can be

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associated with a wide range of MS symptoms including physical disability, depression, anxiety, fatigue and cognitive impairment [1]. However, several discrepancies between studies have been reported, especially regarding the link between cognitive impairment and

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HRQoL, probably because of the considerable heterogeneity of the populations studied [2][3][4][5][6][7][8].

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Annualized relapse-rate (ARR) and physical disability progression are the traditional endpoints in MS clinical trials but they do not necessarily reflect the patient’s experience of

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the disease [9]. Furthermore, the impact of MS on vocational status, activity of daily living, social and family relationships, sexual dysfunction, pain, fatigue, coping, rejection, emotional

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well-being and cognition are important concerns and may influence the patient's adherence to

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long-term treatment. Thus, HRQoL scales have been progressively incorporated in drug trials in MS because HRQoL appears to be a meaningful measure for both clinicians and patients

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[10]. Observational studies failed to clearly demonstrate a positive effect of interferon-ß (IFNß) on HRQoL in patients with relapsing-remitting MS [11][12] but tertiary endpoints and post-hoc analyses of controlled clinical trials showed a beneficial effect over placebo in HRQoL scales for natalizumab [13], fingolimod [14] and dimethyl- fumarate [15]. However, these studies were usually short or mid-term follow-up studies (6 to 24 months) and they often used only a generic scale of HRQoL such as the S hort-Form (SF)-36. Only one recent study reported HRQoL improvement over 3 years of natalizumab treatment but it was

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ACCEPTED MANUSCRIPT restricted to the United-States population [16]. Furthermore, none of these studies attempted to properly analyse the correlates or the predictors of HRQoL improvement after the initiation of a new disease- modifying therapy (DMT). We hypothesized that the beneficial effect of DMT on HRQoL is not solely due to the reduction of relapse rate but could also be linked with neuropsychiatric outcomes such as fatigue, anxiety, depression and cognition.

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In this study, we specifically focused on starting treatment with natalizumab because it allowed us to study a relatively homogenous population of patients with high disease activity. Natalizumab is a very effective DMT [17][18] but its mode of administration, its potential adverse effects and its long-term management (particularly with regard to the risk of

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progressive multifocal leukoencephalopathy) are likely to negatively impact the HRQoL of patients. Consequently, our primary objective was to investigate the long-term (3 years) effect

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of natalizumab on HRQoL, evaluated with a disease-specific questionnaire. The secondary objectives of this study were to understand what could be the predictors and the correlates of

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HRQoL improvement regarding physical disability, psychiatric comorbidities and cognitive

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performances.

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ACCEPTED MANUSCRIPT Methods

Patients The CoQualSEP study was an open- label, single group, multicentric clinical trial

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(NCT01392872) that included 48 patients with MS between December 2009 and December

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2012 in four French MS centers, for a total follow-up of 3 years. The local institutional ethics review boards approved the study (CPP AU 797 and IDRDB 2009-A00402-55). All subjects gave their written informed consent prior to participation.

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Patients over 18 years of age, with a relapsing-remitting (RR)-MS diagnosis according to the 2005-revised McDonald criteria [19] for more than 6 months and less than 10 years, with no

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relapse within one month before enrolment and an EDSS score lower than 7.0, were included in the study. Patients received natalizumab 300mg by intravenous infusion every 4 weeks

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according to the European Medical Agency recommendations because: (1) they failed to

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respond to an adequate course of IFN-ß or glatiramer-acetate with at least one relapse in the previous year while on therapy, or (2) they experienced a rapidly evolving and severe RR-

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MS, defined by at least 2 disabling relapses in one year. Treatments could be discontinued at any time by the patient’s referent neurologist. After baseline evaluation (M0) at the beginning

and M36).

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of natalizumab therapy, follow-up visits were set at 6, 12, 18 and 36 months (M6, M12, M18

Health-related quality of life evaluation HRQoL was assessed with the MS International Quality of Life questionnaire (MusiQoL, a 9dimension self- report measure of HRQoL) [20] which is a disease-specific instrument, validated in French, and known to be appropriate for severely disabled patients with putative 6

ACCEPTED MANUSCRIPT cognitive impairment [21]. The MusiQoL questionnaire comprises 31 items that describe the following nine dimensions: activity of daily living, psychological well-being, symptoms, relationships with friends, relationships with family, relationships with the healthcare system, sentimental and sexual life, coping, and rejection. It also yields a global index score,

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calculated as the mean of the individual dimension scores.

Neurological, neuropsychological and psychiatric outcomes

At each visit, patients underwent a neurological examination that included the determination

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of the current Expanded Disability Status Scale (EDSS) and the timed 25- foot walk (T25FW) scores. Upper- limb functions were assessed with the 9-hole peg test (9HPT) at M0, M18 and

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M36 (the two hands were averaged). Annualized-relapse rates (ARR) were calculated at M0, M18 and M36 regarding the number of relapses during the prior 18 months.

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Patients were assessed at M0, M18 and M36 with a comprehensive neuropsychological battery that focused on the cognitive domains usually affected in MS [22]. It included tests for

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attention, information processing speed and working memory with the Symbol-Digit

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Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT) and the forward and backward digit span subtest of the WAIS-III. Verbal episodic memory was assessed with

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the Selective Reminding Test (SRT with 15 items, French RLS-15) and executive functions were tested with the Stroop test (difference between denomination and inhibition scores) and with the Multiple Errands Test (“real-world environment”). Patients were assessed at each visit with questionnaires focused on depression (Beck depression Inventory, BDI-II [23]), anxiety (Covi 35) and fatigue (French version of the Fatigue Impact Scale, FIS [24]).

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ACCEPTED MANUSCRIPT Statistical analyses Statistical analyses were performed with SPSS software. The distribution of all continuous data was tested with the Shapiro-Wilk normality test and the variables were then displayed as mean ± standard deviation (SD) or median and range. We first compared available MusiQoL scores over time using paired t-tests with baseline scores (M0). To account for missing data, a

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multiple imputation model was used, followed by a mixed-effect model for the evolution of the MusiQoL scores. We also performed a last observation carry- forward (LOCF) analysis of variance. Cohen’s d was used to measure the effect size. Then, relationships between the absolute variations of MusiQoL scores (M18 and M36, compared to baseline: M18-M0 or

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M36-M0) and the variation of clinical, neuropsychological and psychiatric outcomes during the same period were assessed using Spearman correlation coefficients. Correlations between

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baseline characteristics and the variation of HRQoL at 36 months were also evaluated. When appropriate, the correlations were further tested in a multivariate context to take into account

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adjustment on covariables fixed according to univariate results and demographical variables

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at baseline. In order to explore multiple leads and to avoid rejecting a possibly important finding, we chose to report all the individual p-values without performing any mathematical

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correction for multiple comparisons, given the small sample size of the study [25]. All tests

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were two-tailed, with a type I error set at α=0.05.

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ACCEPTED MANUSCRIPT Results

Demographic and clinical characteristics at baseline Out of 48 included patients, 37 (77.1%) were female. The mean age was 41.1 years (±9.5), the

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average number of years of education was 12.5 (±2.9) and the mean disease duration was 8.0

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years (±5.5). The median EDSS at inclusion was 3.0 [0 – 6.5] and 23,8% (10/42) of patients had walking disability (EDSS>4). Annualized relapse-rate (ARR) at baseline was 1.3 (±0.5). Seven patients were naïve of any DMT prior to their first infusion of natalizumab, 26 were

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treated previously with IFN-ß, 11 were treated with glatiramer acetate and 5 with other immunosuppressants. Fatigue scores at baseline were not different between patients who

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received IFN-ß during the previous 3 months and others (p=0.27).

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Evolution of HRQoL over time

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Out of 48 patients, 46 (95.8%) were assessed at 18 months and 36 (75.0%) completed the

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follow-up visit at 3 years. All these patients received natalizumab for the entire duration of their follow- up period, without discontinuation. Compared to baseline, global HRQoL, as

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measured with the index of the MusiQoL, was significantly increased 6 months after the beginning of natalizumab therapy with a medium effect-size (58.8 vs 68.7, p<0.001, Cohen’s d=0.55) and this improvement was maintained over time fo r up to 3 years (p<0.001, d=0.56 at M12; p=0.024, d=0.25 at M18 and p=0.011, d=0.62 at M36). The multiple imputations model and the last observation carry- forward (LOCF) analysis of variance led to the same results (respectively index=69.8 and index=67.7 at M36, p=0.002 and p=0.014 compared to baseline) (Fig. 1). The detailed evolution of the 9 dimensions of the MusiQoL over time is reported in table 1, according to the multiple imputations model: improvement in HRQoL was significant

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ACCEPTED MANUSCRIPT regarding activity of daily living, psychological well-being, symptoms and coping (p<0.001 for every dimensions).

Evolution of neurological, neuropsychological and psychiatric scores over time

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The annualized relapse-rate dramatically decreased after the initiation of natalizumab (1.3

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(±0.5) before treatment, 0.6 (±0.7) during the first 18 months and 0.2 (±0.4) during the M18M36 period, p<0.001, respectively). Disability was broadly stable over 3 years except for a slight increase in 9HPT scores.

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At baseline, considering the whole population of patients, mean depressive symptoms were considered “minimal” (BDI-II<13) [23] and mean fatigue score was very close to what had

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previously been reported in the French MS population [24]. Cognitive scores and psychiatric scales remained globally unchanged during the follow-up period, except for an improvement

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in learning performances at 18 months, confirmed at 36 months, and a transient worsening in

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executive functions at 18 months (table 2).

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Correlates of HRQoL variations at 18 months

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Correlations between the variation of HRQoL during the first 18 months of treatment and the variation of neurological, neuropsychological and psychiatric scores during the same period are summarized in table 3. The improvement of global HRQoL, as measured with the MusiQoL index, was correlated with an improvement of information processing speed performances (r=0.43, p=0.003 for SDMT) and with a decrease in depression and fatigue scores (r=-0.37, p=0.013 for BDI and r=-0.52, p<0.001 for FIS, respectively). In a multivariate regression analysis including FIS, BDI and SDMT, the improvement of global

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ACCEPTED MANUSCRIPT HRQoL correlated only with the decrease in fatigue (β=-0.37, p=0.001) and with a trend towards improved information processing speed (β =0.37, p=0.095).

Correlates of HRQoL variations at 3 years

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During the 3- year follow- up period, the variation of the global HRQoL was negatively

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correlated with the variation of fatigue score (r=-0.44, p=0.015). The correlates of the variations of the 9 dimensions of the MusiQoL are reported in table 4.

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Predictors of HRQoL variations at 3 years

The only demographical variable at baseline that correlated with improvement of global

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HRQoL at year 3 was a lower educational level (r=-0.34, p=0.041). We then investigated whether neurological, neuropsychological or psychiatric scores at baseline, before the first

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infusion of natalizumab, correlated with the variation of HRQoL during the 3-year follow- up

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(table 5). A higher fatigue score at baseline was correlated with improvement in global HRQoL, as measured with the MusiQoL index (r=0.34, p=0.041). This correlation was still

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significant after adjustment on age, disease duration, educational level and disability at

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baseline (β=2.45, p=0.020). A higher depression score and higher physical disability at baseline were correlated with improvement in certain dimensions of the MusiQoL, especially in activities of daily living (respectively r=0.39, p=0.018 for EDSS and r=0.39, p=0.020 for BDI). However, in a multivariate regression analysis including EDSS and BDI , the improvement in activities of daily living only correlated with a trend towards higher EDSS at baseline (β =1.78, p=0.082).

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ACCEPTED MANUSCRIPT Discussion

We demonstrated in a post-marketing non-controlled trial that natalizumab improved HRQoL by month 6, with a medium effect-size. We also demonstrated on a European population that

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this positive effect of natalizumab on HRQoL is maintained for up to 3 years after the

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beginning of therapy [16]. In addition, we used the MusiQoL questionnaire, a disease-specific instrument that focuses on the concerns of patients with MS, rather than using a generic scale such as the SF-36, previously used in the AFFIRM study [13][17]. The improvement in

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HRQoL was mainly driven by improvement in activities of daily living, psychological wellbeing, symptom perception and coping. Augmenting the “objective” measure of decreased

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ARR, these results for HRQoL take into account both the benefit and the adverse effects associated with natalizumab (including anxiety linked to the risk of PML) and confirm that

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natalizumab is a meaningful treatment for patients with active relapsing-remitting MS. Counter intuitively, despite the strong decrease in ARR after starting natalizumab, the

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variation of HRQoL during the 3- year follow-up of patients was unrelated to ARR and

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physical disability. This finding is consistent with previous studies because the link between disability and quality of life is rather weak in MS or only related to physical HRQoL [3][6].

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The variation of HRQoL was mostly correlated with a decrease in depression and fatigue scores at month 18 and with decreased fatigue at year 3. These results are consistent with the literature as natalizumab was efficient in reducing fatigue in patients with MS in a dedicated open- label trial [26] and because fatigue and depression are known to correlate with HRQoL in transversal studies [3][27][28][29]. However, these correlations between fatigue and HRQoL should be interpreted with caution since, as previously highlighted by Benedict et al.,

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ACCEPTED MANUSCRIPT “self-report predicts [and correlates with] self-report” [3] because fatigue, depression and HRQoL are inherently “subjective” measures. We reported few correlations between the variation in cognitive performances and the variation in MusiQoL dimensions and they did not appear to be independent of fatigue in multivariate analyses. These findings are corroborated by a previous transversal study in

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which cognitively- impaired and cognitively-preserved patients with MS reported the same HRQoL measures [5]. This was confirmed by longitudinal studies that underlined that cognitive impairment can predict long-term vocational status but not HRQoL [3][6]. In this study, we also sought to identify patients for whom treatment with natalizumab would

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be the most beneficial in terms of HRQoL. We mainly found that a higher fatigue score at

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baseline was correlated with an improvement in global HRQoL 3 years after, independently of age, disease duration, educational level and disability. Then, our results appear slightly discordant with a previous work showing that lower baseline EDSS was related to larger

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HRQoL improvement [16]. In contrast to this study, the relative moderate disability of our

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population (76,2% of patients with EDSS<4) probably explained this discrepancy.

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Furthermore, this previous work did not assess cognition, depression and fatigue. The first limitation of this study is its non-controlled design although the positive effect of

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natalizumab on HRQoL has already been described against placebo [13]. Furthermore, placebo-controlled studies in RRMS are currently considered non-ethical. We must also acknowledge that a large number of comparisons were made to fully evaluate our data and that the marginal p-values should be interpreted with caution. Finally, another limitation of the study is that only 75% of the patients completed the study after 3 years (95.8% at month 18). This reflects current clinical practices where many JC-virus antibody-positive patients who are stable on natalizumab switch to other therapies after 2 years to avoid PML [30]. However, the multiple imputations model and the last observation carry-forward analyses of

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ACCEPTED MANUSCRIPT our data led to the same results regarding the improvement of HRQoL, suggesting that our findings were not biased by missing data at year 3. To conclude, natalizumab therapy quickly and sustainably improved HRQoL in patients with relapsing-remitting MS. We showed that improvement in fatigue was the most important correlate of improvement in HRQoL at year 3. In terms of HRQoL improvement, natalizumab

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mainly seems to benefit patients with higher fatigue symptoms at baseline, independently of disabilitity, disease duration, age, and educational level. However, considering the explorative nature of this study, our results should be considered as preliminary and require further

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investigations to be confirmed.

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ACCEPTED MANUSCRIPT

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Figure

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Figure 1: Evolution of global health-related quality of life (HRQoL) over time after starting natalizumab therapy (as measured with the index of the MS International Quality of Life

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(MusiQoL) questionnaire). To take into account missing data, a multiple imputations model (Multiple Imput.) and a last observation carried forward (LOCF) analysis was performed and

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the results are presented together with the raw data. The detailed evolution of the 9

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dimensions of the MusiQoL over time is reported in table 1. The results are shown as

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mean±SEM. *p<0.05; **p<0.01; ***p<0.001, compared to baseline.

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ACCEPTED MANUSCRIPT Tables

Psychological well-being Symptoms Relationships with friends Relationships with family Sentimental and sexual life Coping Rejection

M12

M18

M36

(n=45)

(n=46)

(n=36)

58.6±16.2

68.7±18.7***

68.1±17.4***

40.6±23.4

54.5±26.9***

52.7±25.7***

43.6±23.2

50.8±23.0*

43.1±22.1

59.2±26.7***

60.4±27.3***

49.1±28.3

59.2±25.1**

49.1±25.4

66.2±24.2***

62.7±25.5***

52.0±25.9

64.2±22.2**

64.5±30.2

66.8±31.6

67.1±29.0

68.5±27.7

72.9±22.1

70.1±27.1

70.5±21.7

73.8±22.3

71.4±22.3

78.0±22.3

61.3±30.5

67.6±27.7

61.0±28.4

63.5±30.2

64.3±27.4

45.3±32.0

65.8±30.9***

65.0±30.0***

59.0±35.7**

64.4±27.9**

73.1±30.2

83.3±24.1

82.5±25.4

77.5±28.0

79.8±22.2

79.5±17.4

77.5±18.1

81.2±16.8

74.7±18.2

78.6±17.4

62.5±17.9*

69.8±16.2**

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syst.

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Relationships w. health care

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Activity of daily living

M6 (n=47)

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Index

M0 (n=48)

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MUSIQOL

Table 1: Evolution of health-related quality of life (HRQoL) over time after starting

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natalizumab therapy. The index of the MS International Quality of Life (MusiQoL)

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questionnaire assesses the global HRQoL whereas its subscores evaluate 9 domains more specifically. Scores at baseline (M0) and at month 6 (M6), month 12 (M12), month 18 (M18)

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and year 3 (M36). The results are shown as mean ± standard deviation. *p<0.05, **p<0.01 and ***p<0.001 compared to baseline (multiple imputation model, with a mixed-effect model).

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ACCEPTED MANUSCRIPT

M36

1.3 (0.5) 3 [0 – 6.5] 21.8 [17.1 – 35.9]

3 [0 – 7]

3 [0 – 7]

-

-

0.6 (0.7)*** 3 [0 – 7] 23.4 [16.6 – 42.6]*

0.2 (0.4)*** 3.5 [0 – 7] 23.1 [17.9 – 52.5]**

5.1 [3.6 - 10.3]

5.5 [3.7 – 24.0]

5.2 [3.4 – 23.5]

5.2 [3.7 – 12.7]

5.4 [3.1 – 88.0]

49.6 (11.7) 40.7 (10.5)

-

-

49.0 (10.4) 39.4 (11.1)

49.0 (12.5) 40.6 (11.5)

6 [4 – 8]

-

-

6 [3 – 8]

6 [4 – 8]

4 [2 – 7]

-

-

4 [2 – 8]

5 [3 – 8]

60.4 (22.9)

-

-

69.9 (22.2)**

70.0 (23.2)*

13 [5 – 15]

-

-

14 [4 – 15]

14 [5 – 15]

53.1 (31.2) 73.1 (18.4)

-

-

49.3 (23.3) 64.3 (22.0)*

51.5 (26.7) 70.1 21.7)

11 [0 – 44] 0 [0 – 8] 58.6 (17.6)

11 [0 – 47] 0 [0 – 8] 57.4 (19.5)

12 [0 – 47] 0 [0 – 6] 58.8 (19.7)

11 [0 – 42] 0 [0 – 4] 61.4 (16.8)

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10 [0 – 44] 0 [0 – 4] 57.9 (20.0)

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M18

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Attention/IPS/WM SDMT, mean (SD) PASAT, mean (SD) Forward digit span, median [range] Backward digit span, median [range] Episodic memory RLS-learning, mean (SD) RLS-DR, median [range] Executive functions Stroop, mean (SD) Errand, mean (SD) Psychiatric symptoms BDI, median [range] CoVi,, median [range] FIS, mean (SD)

M12

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FW25, median [range]

M6

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Disability ARR, mean (SD) EDSS, median [range] 9HPT, median [range]

M0

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Table 2: Evolution of neurological, neuropsychological and psychiatric symptoms over time

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after starting natalizumab therapy. ARR: Annualized Relapse Rate ; BDI: Beck Depression Inventory; Covi35: Covi anxiety scale; EDSS: Expanded Disability Status Scale; FIS: Fatigue Impact Scale; PASAT: Paced Auditory Serial Addition Test; RLS-15: French Selective Reminding Test (with 15 items, DR: Delayed-Recall); SD: Standard Deviation; SDMT: Symbol- Digit Modalities Test; T25FW: Timed 25-Foot Walk; 9HPT: 9-Hole Peg Test . *p<0.05, **p<0.01 and ***p<0.001 compared to baseline.

17

0.05

-0.03

0.10

-0.14

0.14

-0.15

-0.28

-0.22

0.07

0.01

-0.01

0.03

9HPT

-0.11

0.09

0.01

0.08

-0.23

0.31*

-0.20

FW25

-0.15

0.07

-0.28

-0.13

0.05

0.43**

0.24

0.20

0.17

0.28

PASAT Forward digit span Backward digit span Episodic memory RLS-learning

0.07

0.14

0.09

-0.07

-0.03

0.29

0.22

0.03

0.01

0.20

0.28

0.09

-0.10

-0.17

0.29

0.19

-0.04

0.17

0.07

RLS-delayed recall

0.22

-0.08

0.03

0.04

Executive functions Stroop

-0.01

0.19

0.05

Errand

0.12

0.15

-0.16

MA

BDI

-0.37**

-0.38**

CoVi

-0.17

-0.11

0.52***

0.56***

Index

Relationships w. health care syst.

Relationships with family Sentimental and sexual life

-0.07

Rejection

Relationships with friends

0.05

M18 – M0

Coping

Symptoms

ARR EDSS

Activity of daily living

Psychological well-being

ACCEPTED MANUSCRIPT

-0.13

0.06

0.02

0.14

0.09

0.13 0.06

Disability

T

SC RI P -0.04

0.01

0.20

0.27

0.16

0.23

0.09

0.39**

0.17

0.41**

0.09

-0.20

0.04 0.03

0.22

0.20

0.15

0.28

0.01 0.15

0.17

0.15

0.26

0.29

0.20

0.14

0.10

NU

0.24

-0.06

-0.04

0.11

0.01

-0.05

0.21

0.01

-0.16

-0.18

-0.22

-0.31*

0.12

-0.24

-0.21

-0.06

-0.30*

-0.10

0.03

0.07

-0.08

-0.37*

-0.33*

-0.37*

-0.02

-0.17

0.24

-0.27

-0.22

0.03 0.18

-0.10 -0.11

0.19 0.10 0.29 0.07

0.09 0.01 0.03

CE

FIS

-0.03

0.11

0.03

PT

Psychiatric symptoms

0.07

0.02

-0.10

ED

Attention/IPS/WM SDMT

0.17 0.05 0.13 0.12

Table 3: The correlates of improvement in health-related quality of life (HRQoL) at month

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18 (M18). Spearman correlation coefficients between the variations of HRQoL scores at month 18 (M18-M0) and the variations of neurological, neuropsychological and psychiatric scores at month 18 (M18-M0). ARR: Annualized Relapse Rate; BDI: Beck Depression Inventory; Covi35: Covi anxiety scale; EDSS: Expanded Disability Status Scale; FIS: Fatigue Impact Scale; PASAT: Paced Auditory Serial Addition Test; RLS-15: French Selective Reminding Test (with 15 items); SD: Standard Deviation; SDMT: Symbol-Digit Modalities

18

ACCEPTED MANUSCRIPT Test; T25FW: Timed 25-Foot Walk ; 9HPT : 9-Hole Peg Test . *p<0.05, **p<0.01 and

AC

CE

PT

ED

MA

NU

SC RI P

T

***p<0.001.

19

Relationships w. health care syst.

0.31

0.13

-0.01

-0.01

0.15

0.09

-0.14

0.02

-0.16

0.06

0.09

0.01

-0.09

-0.08

0.00

-0.13

0.10

-0.13

0.11

-0.10

0.15

-0.08

Index

M36 – M0

Coping

-0.19

Sentimental and sexual life

0.10

Relationships with friends Relationships with family

-0.19

Symptoms

-0.10

Psychological well-being

0.13 0.10

Activity of daily living

Rejection

ACCEPTED MANUSCRIPT

SC RI P

ARR EDSS 9HPT

0.18

0.17

0.23

0.21

0.05

FW25

-0.05

-0.09

-0.17

-0.21

0.04

-0.26

0.18

Attention/IPS/WM SDMT

0.04

0.21

0.06

0.10

0.04

0.01

-0.16

PASAT

-0.26

0.09

-0.06

-0.03

-0.09

-0.31

0.12

0.08

0.16

0.00

0.20 0.28

-0.24

0.06

0.03

0.03

-0.21

0.07

0.06

-0.01

0.16

0.27

-0.11

0.06

0.06

0.17

0.21

0.14

0.24

0.05

0.14

0.16

-0.44*

-0.41*

0.04

-0.13

-0.17

0.06

0.03

0.28

-0.07

MA

NU

-0.21

0.08

0.06

-0.13

0.06

0.28

0.03

0.19

0.22

0.08

-0.10

0.22

0.49**

0.07

0.10

0.12

0.14

-0.31

0.19

0.51**

0.31

0.20

-0.23

0.38*

0.13 0.02

0.18

0.13

0.18

0.07

0.00

0.14

.0.21

0.27

0.29

-0.37*

0.11

0.24 0.56**

0.10 0.53**

0.00 0.19

0.21

0.22

-0.14

0.22

-0.10

-0.08

0.24 0.29

-0.20

-0.28

AC

BDI CoVi FIS

-0.11

0.10

CE

Psychiatric symptoms

-0.03

-0.03

ED

Errand

0.23

-0.08

0.12 0.24 0.10

PT

Forward digit span Backward digit span Episodic memory RLS-learning RLS-delayed recall Executive functions Stroop

T

Disability

Table 4: The correlates of improvement in health-related quality of life (HRQoL) at month 36 (M36). Spearman correlation coefficients between the variations of HRQoL scores at month 36 (M36-M0) and the variations of neurological, neuropsychological and psychiatric scores at month 18 (M36-M0). ARR: Annualized Relapse Rate; BDI: Beck Depression Inventory; Covi35: Covi anxiety scale; EDSS: Expanded Disability Status Scale; FIS: Fatigue Impact Scale; PASAT: Paced Auditory Serial Addition Test; RLS-15: French Selective

20

ACCEPTED MANUSCRIPT Reminding Test (with 15 items); SD: Standard Deviation; SDMT: Symbol-Digit Modalities

AC

CE

PT

ED

MA

NU

SC RI P

T

Test; T25FW: Timed 25-Foot Walk; 9HPT : 9-Hole Peg Test . *p<0.05, **p<0.01.

21

Symptoms

Relationships with friends Relationships with family

Sentimental and sexual life

Coping

Rejection

-0.09

0.11

-0.06

-0.19

-0.5

0.08

0.07

-0.23

-0.03

0.25

0.39*

0.11

0.10

0.09

-0.11

0.00

0.13

9HPT

-0.10

-0.18

-0.09

-0.20

0.08

-0.11

-0.24

-0.04

0.15

FW25

0.30

0.24

0.10

0.19

0.02

0.01

-0.18

0.23

0.06

Attention/IPS/WM SDMT

0.01

-0.02

-0.03

-0.02

0.29

0.16

0.12

-0.23

0.20

PASAT

0.07

-0.08

0.14

0.12

0.48**

0.04

0.09

-0.13

0.25

Forward digit span

0.05

0.06

0.10

0.27

0.28

0.04

0.03

-0.36*

0.20

Backward digit span

-0.03

0.13

-0.02

0.21

0.31

-0.06

-0.08

0.01

0.07

Episodic memory RLS-learning

-0.12

-0.07

-0.07

-0.04

-0.06

-0.24

RLS-delayed recall

-0.9

-0.13

-0.11

MA

0.10 0.03

0.07

-0.12

-0.24

Stroop

-0.02

-0.08

Errand

-0.08

0.01

BDI

0.27

CoVi FIS

Index

Baseline scores vs HRQoL variation

Activity of daily living

Psychological well-being

Relationships w. health care syst.

ACCEPTED MANUSCRIPT

0.01

SC RI P

NU

0.08 0.07 0.24 0.25 0.20 0.14

0.49**

0.02 0.07 0.18 0.10

0.07 0.01

-0.06

-0.29

0.19

-0.29

0.01

-0.10

0.37*

PT

Executive functions

0.14

ED

ARR EDSS

T

Disability

-0.14

-0.09

0.12

-0.20

-0.18

-0.12

0.28

0.01 0.05

0.39*

0.28

0.26

0.14

-0.15

0.10

0.38*

0.44

0.09

-0.04

0.07

-0.03

0.01

0.00

-0.26

-0.08

-0.05

0.14

0.34*

0.30

0.37*

0.39*

0.08

0.06

0.06

0.37*

0.33*

0.28 0.09

AC

CE

Psychiatric symptoms

Table 5: Predictors at baseline of health-related quality of life (HRQoL) improvement after 3 years of natalizumab therapy. Spearman correlation coefficients between the variations of HRQoL scores at month 36 (M36-M0) and the neurological, neuropsychological and psychiatric scores at baseline (M0). ARR: Annualized Relapse Rate ; BDI: Beck Depression Inventory; Covi35: Covi anxiety scale; EDSS : Expanded Disability Status Scale ; FIS: Fatigue Impact Scale; PASAT: Paced Auditory Serial Addition Test; RLS-15: French

22

ACCEPTED MANUSCRIPT Selective Reminding Test (with 15 items); SD: Standard Deviation; SDMT: Symbol-Digit Modalities Test; T25FW : Timed 25-Foot Walk ; 9HPT : 9-Hole Peg Test . *p<0.05,

AC

CE

PT

ED

MA

NU

SC RI P

T

**p<0.01.

23

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Highlights

T SC RI P NU MA ED PT CE

  

Natalizumab significantly increased HRQoL 6 months after the beginning of treatment This improvement is maintained over time for up to 3 years The variation of HRQoL is negatively correlated with the variation of fatigue Higher fatigue score at baseline is independently correlated with improvement in HRQoL 3 years afterwards

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

28