# Intensive interdisciplinary specialized rehabilitation or regular physiotherapy for multiple sclerosis? A randomised controlled trial with economic evaluation

C Bonnyaud, S Hameau, Raphael Zory, M Sznajder, O Heinzlef, C Aymard, A Chenet, B Médée, M Jacota, P Gallien, et al.

<figure><img src="image_1.png" /></figure>

## ► To cite this version:

C Bonnyaud, S Hameau, Raphael Zory, M Sznajder, O Heinzlef, et al.. Intensive interdisciplinary specialized rehabilitation or regular physiotherapy for multiple sclerosis? A randomised controlled trial with economic evaluation. Annals of Physical and Rehabilitation Medicine, 2025, 68 (2), pp.101898. 10.1016/j.rehab.2024.101898. hal-04920817

HAL Id: hal-04920817

https://hal.science/hal-04920817v1

Submitted on 19 Feb 2025

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<figure><img src="image_2.png" /></figure>
Interdisciplinary specialized rehabilitation or physiotherapy in community for multiple sclerosis: a randomised controlled economic study

Bonnyaud C, PT, PhD<fnref n="1" />, <fnref n="2" />*, Hameau S PT, PhD<fnref n="3" />,<fnref n="4" />, Zory R PhD<fnref n="5" />,<fnref n="6" />, Sznajder M MD, PhD<fnref n="7" />, Heinzlef O MD, PhD<fnref n="8" />,<fnref n="9" />, Aymard C MD, PhD<fnref n="10" />, Chenet A MD, PhD¹¹, Médée B MD, PhD¹², Jacota M MD, PhD<fnref n="7" />, Gallien P MD, PhD¹³, Bensmail D MD, PhD¹⁴,¹⁵ and Rehabmuscle team

Rehabmuscle team: Derridj N PhD, Sanogo I MSc, Fournier Mehouas M MD, PhD, Blanchard-Dauphin A MD, PhD.

<footnote n="1">¹ Motion analysis laboratory, Functional Exploration Department, Raymond Poincaré Hospital, GHU Paris Saclay, APHP, Garches, France</footnote>

<footnote n="104">104 Bld Raymond Poincaré 92380 Garches</footnote>

<footnote n="2">² Paris-Saclay University, UVSQ, Research Unit ERPHAN, 78000, Versailles, France</footnote>

<footnote n="104">104 Bld Raymond Poincaré 92380 Garches</footnote>

<footnote n="3">³ Inserm, Clinical Investigation Center (CIC 1414), University Hospital Center, Rennes, France.</footnote>

<footnote n="104">104 Bld Raymond Poincaré 92380 Garches</footnote>

<footnote n="4">⁴ Physical and Rehabilitation medicine Department, University Hospital Center, 35000 Rennes, France.</footnote>

<footnote n="2">2 Rue Henri le Guilloux, 35000 Rennes</footnote>

<footnote n="5">⁵ Université Côte d'Azur, LAMHESS, Nice, France.</footnote>

<footnote>Bld du Mercantour B.P. 3259 06205 NICE Cedex 03</footnote>

<footnote n="6">⁶ Institut universitaire de France, France.</footnote>

<footnote n="1">1 rue Descartes 75231 Paris Cedex 05</footnote>

<footnote n="7">⁷ Clinical Research Unit, Ambroise Paré hospital, GHU Paris Saclay, APHP, Boulogne, France.</footnote>

<footnote n="9">9 Av. Charles de Gaulle, 92100 Boulogne-Billancourt</footnote>

<footnote n="8">⁸ Department of Neurology, Poissy-Saint-Germain-en-Laye Hospital, Poissy, France</footnote>

<footnote n="10">10 rue Champ Gaillard 78300 Poissy</footnote>
⁹ CRC SEP IDF Ouest, Poissy-Garches, France

104 Bld Raymond Poincaré 92380 Garches / 10 rue Champ Gaillard 78300 Poissy

¹⁰ Physical and Rehabilitation medicine Department, Fondation hospitalière Sainte-Marie, Paris, France.

167, rue Raymond Losserand 75014 Paris

¹¹ Physical and Rehabilitation medicine Department, University Hospital Nantes, France
85 Rue Saint-Jacques, 44093 Nantes

¹² Physical medicine and rehabilitation department, CHRU Brest, France
2 avenue Foch, 29609 Brest

¹³ Pole Saint Hélier, Rennes, France.

54 Rue Saint-Hélier, 35000 Rennes

¹⁴ Physical and Rehabilitation medicine Department, Raymond Poincaré Hospital, GHU Paris Saclay, APHP, Garches, France.

104 Bld Raymond Poincaré 92380 Garches

¹⁵ End: icap laboratory, Inserm Unit 1179, UVSQ, France

2 Av. de la Source de la Bièvre, 78180 Montigny-le-Bretonneux

Céline Bonnyaud : celine.bonnyaud@aphp.fr Tel: +33 1 71 14 49 21

Laboratoire d'analyse du mouvement, Service des Explorations fonctionnelles, Garches, GHU Paris Saclay, APHP.

Unité de Recherche ERPHAN, UVSQ, Paris Saclay

Hôpital Raymond Poincaré 104 Bld Raymond Poincaré 92380, Garches, France

**Keywords:** multiple sclerosis, interdisciplinary rehabilitation, specialised unit, community, follow-up, strength, quality of life

**Number of words in the abstract:** 299 words

**Number of references in the text:** 50

**Number of tables:** 3

**Number of figures:** 3

<footnote>*Corresponding author:</footnote>
Interdisciplinary specialized rehabilitation or physiotherapy in community for multiple sclerosis:

a randomised controlled economic study

**Abstract**

**Background:** The benefits of Interdisciplinary Rehabilitation in an Outpatient Specialised Unit (IROSU) have not been determined.

**Objectives:** To compare the effects of IROSU and physiotherapy in the community on impairment, function and Quality Of Life (QoL) of people with Multiple Sclerosis (pwMS) and to determine the medico-economic impact.

**Methods:** Pragmatic, multicentre, parallel, randomized (centralised computer-generated randomisation) controlled trial. 148 pwMS were analysed (73 in the IROSU group, 75 in the community group). IROSU included balance, stretching, walking, resistance and endurance training. The 6-Minute Walk Test (6MWT) was the primary outcome. Secondary outcomes were speed on 10m, Timed Up and Go and Stair test, balance (Berg Balance Scale, posturology), knee extensor and flexor strength (isokinetic dynamometer), peak power output (cycling test), fatigue (Fatigue Severity Scale, Modified Fatigue Impact Scale), QoL (EuroQol EQ5D3L, SEP59), anxiety and depression (Hospital Anxiety and Depression scale) and Multiple Sclerosis Impact Scale. Evaluations were performed before, after 4 weeks of training and 3 and 6 months after the start by therapists blinded to group allocation. Linear mixed effect models were used (intention-to-treat analysis). Cost-effectiveness and cost-utility ratios were analysed.

**Results:** 6MWT increased similarly in both groups from baseline to M1 (423.8 (126.7)m to 476.0 (119)m IROSU, 404.4 (99.3)m to 440.5 (112.1)m community, p<0.001), to M3 (p<0.001) and to M6 (p= 0.001). Knee extensor strength, power output and QoL-physical health improved significantly more in IROSU group (p<0.05, effect size 0.25-0.61). Many improvements were
maintained at 6-month follow-up. Gain in quality adjusted life years and cost-utility ratios were
in favour of IROSU.

**Conclusions:** Walking distance improved similarly in both groups but this was underpowered.
The larger improvements in secondary outcomes and quality-adjusted life years after IROSU,
maintained at the 6-month follow-up, suggest pwMS should have access to this program each
year. Regular physiotherapy in the community was also effective.

**Keywords:** multiple sclerosis, interdisciplinary rehabilitation, specialised unit, community,
follow-up, strength, quality of life

**Trial registration Clinical Trials:** NCT01871818

**Funding:** PHRC 2012-A00563-40

**List of abbreviations**

6MWT: 6-minute walk test

10MWT: 10m walk test

BBS: Berg Balance Scale

EDSS: Expanded Disability Status Scale score

EQ-5D-3L: EuroQol scale, version 5D-3L

FSS: Fatigue Severity Scale

HAD: Hospital Anxiety and Depression scale

HRQOL: Health-related quality of life

IROSU: interdisciplinary rehabilitation in an outpatient specialised unit

M1: month 1, end of the intervention

M3 and M6: 3 and 6 months after the beginning of the intervention (follow-up)

MFIS: Modified Fatigue Impact Scale

MS: multiple sclerosis

MSIS-29: Multiple Sclerosis Impact Scale

MSQoL-54 Multiple Sclerosis Quality Of Life-54 scale

NMB monetary benefit

pwMS: people with multiple sclerosis

QALY: gain in quality-adjusted life years
QoL: quality of life

RPE: Rating of Perceived Exertion (Bord scale)

SEP59: quality of life scale specific for multiple sclerosis (SEP in French meaning multiple sclerosis)

TUG: Timed up and go

Wmax: peak power output

WTP willingness to pay

Introduction

People with multiple sclerosis (pwMS) have motor and cognitive impairments, functional disability and limited participation. The factor that has the greatest impact on the quality of life of pwMS is difficulty walking, and improving walking capacity is the priority goal of therapeutic interventions [1,2]. Long-distance walking is particularly an issue because of fatigue, and affects the participation of pwMS. Motor rehabilitation improves walking capacity whereas a lack of rehabilitation leads to deterioration of walking capacity [3]. A multidisciplinary approach to rehabilitation is recommended [3]. Evidence supports multidisciplinary rehabilitation programmes to reduce disability and improve the participation and quality of life of pwMS, with strong evidence for inpatient and weaker evidence for outpatient rehabilitation [4,5]. Multidisciplinary rehabilitation approaches induce longer-term improvements than non-multidisciplinary programs [5].

Interdisciplinary rehabilitation is a slightly different approach to multidisciplinary rehabilitation that has been little studied for pwMS. The multidisciplinary approach involves different rehabilitation professionals who have independent goals, whereas the interdisciplinary approach involves collaboration between healthcare professionals for the attainment of common goals that are determined together [6,7]. Interdisciplinary rehabilitation in specialised hospitals with intensive programs for pwMS (usually between 4 and 6 weeks, once a year), is provided in France and western Europe. However, despite preferences for interdisciplinary intensive rehabilitation, rather than care in the community, only a few pwMS
participate in interdisciplinary rehabilitation programs in specialised centres because of a lack of availability, and few studies have attempted to determine the effectiveness of this approach [8,9]. Therefore, in France, the majority of pwMS are treated by local physiotherapists in the community (outpatient, mainly non-specialised practice) [8,9]. The interdisciplinary approach has been shown to have greater benefits than the multidisciplinary approach for physical rehabilitation [7]. Some studies have demonstrated positive effects of interdisciplinary rehabilitation on psychological outcomes or self-reported daily activities in pwMS but the effects of short, intensive, specialised interdisciplinary programs have been little evaluated on gait capacity and other physical outcomes, or quality of life [10,11]. It is not known if the two conventional approaches for pwMS, physiotherapy in the community and interdisciplinary rehabilitation in specialist centres induce different effects. Such knowledge could optimise service organisation by determining the specific benefits of each type of rehabilitation, therefore ensuring that individuals receive the most appropriate type according to their needs.

The overall aim of this study was to compare the effects of a 4-week interdisciplinary rehabilitation in an outpatient specialised unit (IROSU) to 4 weeks of conventional community-based physiotherapy on all the dimensions of multiple sclerosis (MS) in pwMS with moderate disability. The primary aim was to compare change in walking distance, which reflects functional disabilities and is a priority for pwMS, between approaches. We hypothesised that the IROSU program would increase walking distance more than community physiotherapy and that these benefits would be maintained after several months [12]. The secondary aims were to compare the effects of the approaches on impairments, functional disabilities, fatigue, anxiety and depression and quality of life, since multidisciplinary rehabilitation improves these factors [5]. We also wished to evaluate the cost-effectiveness of both approaches to compare their medico-economic impact, and performed a cost-utility study including health-related quality of life [5].
# Methods

## Protocol and registration

This multicentre, parallel, randomized, controlled and single blind study (Rehabmuscle) was conducted in 7 participating hospitals (Raymond Poincaré APHP, Nantes, Brest, University Hospitals, Pole Saint Helier Rennes, Poissy-Saint-Germain-en-Laye Hospital and Fondation hospitalière Sainte-Marie). This study was pragmatic since it evaluates the effectiveness of interventions in real-life clinical practice, as they are routinely carried out. The study was registered on [ClinicalTrials.gov (NCT01871818)](https://ClinicalTrials.gov).

## Standard Protocol Approvals, Registrations, and Participant Consent

The study was approved by a randomly assigned ethics committee in France and was performed in accordance with the ethics codes of the World Medical Association (Declaration of Helsinki). All participants provided written consent for participation. The method is reported according to the CONSORT 2010 guidelines (supplementary file). No changes were made to the method after the beginning of the study.

## Participants

Recruitment was performed by the study investigators within each of the MS units of the 7 participating hospitals by asking eligible individuals if they wished to participate. The first inclusion was in May 2013 and the last was in April 2017.
**Eligibility Criteria**

**Inclusion criteria**

Inclusion criteria were aged ≥18 years, able to walk 200m without assistance or technical aids, Expanded Disability Status Scale score (EDSS) ≤5 (to limit heterogeneity and ensure the ability to walk without aids), no relapse within the previous 3 months, no current or recent (previous 6 months) participation in intensive rehabilitation, no change in MS medication for 6 months, and having provided signed, informed consent.

**Non-inclusion criteria**

Non-inclusion criteria were cognitive impairments that could interfere with the ability to engage in rehabilitation, involvement in another interventional study in the previous 3 months, a complicating medical condition or orthopaedic diagnosis that limited rehabilitation, cardiac or respiratory disease that could interfere with rehabilitation, under guardianship, pregnant or breastfeeding women, and not affiliated to the French social security system.

**Sample size**

The sample size calculation was based on the results of the 6-minute walk test (6MWT) in pwMS with 80% power and 0.05 risk [13]. The calculation showed that 119 participants per group would be necessary (including 10% of lost to follow-up).

**Study Schedule**

After enrolment by the medical doctor, participants were assigned to 1 of 2 groups by computer-generated block randomization, using blocks of variable sizes, generated and centralized by Cleanweb software, with secured and restricted computerized access (equal randomization 1:1):

- The experimental group (IROSU) participated in an interdisciplinary rehabilitation program in an outpatient specialized unit (see Interventions);
The community group underwent physiotherapy, provided by their usual outpatient physiotherapist in the community.

Before the study, all the participants underwent regular physiotherapy in the community.

Evaluations were carried out before the intervention (baseline), at M1 (end of the intervention), and at M3 and M6 (3 and 6 months after the beginning of the intervention). To avoid bias due to potential deception from being randomized to the community group, IROSU was proposed to this group at the end of the follow-up.

## Interventions

Both programs included 4 weeks of rehabilitation with 4 sessions per week. A minimum of 12 sessions was required.

### IROSU group

Before beginning training, the IROSU group underwent assessments with the physiotherapist, adapted physical activity coach and a consultation with the doctor in physical rehabilitation medicine. All these professionals were specialized in neurological rehabilitation and experienced in interdisciplinary rehabilitation. They collaborated to set common goals according to the participant's needs. Goals related to locomotor tasks, balance, strength, fatigue and quality of life. The team also determined together the functional exercises and muscles to target for stretching and strengthening. Sessions were standardized to include 1 hour of physiotherapy, 40 min of endurance training on a cycle ergometer and 40 min of resistance training on an isokinetic dynamometer with an adapted physical activity coach.

Physiotherapy mainly focused on gait training (25 min of indoor, outdoor or treadmill walking) and balance training (15 min of intrinsic and extrinsic destabilizations with or without foam and balls, in different standing positions and visual conditions). Lower limb muscle stretching and strength training with functional weight-bearing exercises, such as sit-to-stand and get-up-from-the-floor, were also included.
Resistance training involved 40 min of knee flexor and extensor muscle strengthening of both lower limbs using an isokinetic dynamometer (Contrex, CMV AG, Dubendorf, Switzerland). Six sets of 6 maximal voluntary concentric contractions of knee flexor and extensor muscles at 60°/s were performed, preceded by a warm-up of submaximal contractions and with 2 min rest periods between sets.

Endurance training involved a 5 min warm-up at 30% peak power output (Wmax), then 30 min of continuous cycling at 60% of Wmax (increased to 70% of Wmax) and a 5min cool-down at 30% of Wmax on a cycle ergometer, as recommended [14]. Peak power output was determined during the initial assessment using an incremental cycling test performed before the program.

The team met regularly to discuss the participant's progress and to progress the difficulty of the exercises.

## Community group

The community group underwent physiotherapy with their usual therapist in a non-specialised, state-reimbursed, outpatient practice. A standardised prescription specifying the duration and the frequency of exercises (4 weeks, 4 sessions per week, 30min per session) was provided to the physiotherapist. The prescription recommended including lower limb muscle stretching, lower limb muscle strengthening, endurance training, gait training, balance training, sit-to-stand training and getting-up-from-the-floor training. This corresponds to the usual approach to physiotherapy for pwMS in this setting. Sessions and exercises were recorded in a notebook by the participants and physiotherapists. The physiotherapists were not informed of the study aim.

Since this was a pragmatic study aiming to compare the effects of both conventional rehabilitation programs in routine practice, the therapy dose was not modified from the usual care dose in specialised hospitals, but it was standardised across centres, as was the content. Appendix A.1 presents both programs (IROSU and community).
## Outcomes

All assessments were performed by therapists blinded to group allocation. The outcomes were not changed after the start of the study and were collected in the rehabilitation units of the 7 hospitals involved. Like all pragmatic trials, this study explores a wide spectrum of assessments rather than few tests focused on a specific objective [15].

### Primary outcome

The primary outcome was the between-group difference in change in 6MWT distance from baseline to M1 for each intervention [16]. Participants were instructed to walk as many times as possible along a 50-metre corridor. Instructions, encouragements, and information about time remaining were standardised.

### Secondary outcomes

Locomotor performance was measured using the 10m walk test (10MWT) at spontaneous and maximal speed, the timed up and go (TUG) test at maximal speed (sit to stand, walk and 180° turn) and the Stairs Test at maximal speed using the handrail (total time to ascend and descend was recorded separately) [17].

Balance was assessed using the Berg Balance Scale (BBS) and a postural control assessment on force platforms (3 trials of 30 s eyes open and closed).

Maximal voluntary strength of the knee flexors and extensors of the weakest limb was assessed using an isokinetic dynamometer [18]. The position was standardised (and noted for the next sessions) with the joint centre aligned with the rotation axis of the dynamometer, the trunk and untested limb fixed, and the arms crossed on the chest. Submaximal contractions were performed for familiarization and warm up. Maximal voluntary strength was considered as the highest peak torque value of the 5 maximal voluntary concentric contractions at 30°/s [19]. Standardised verbal encouragements were given to ensure maximal effort.

Aerobic capacity and peak power output (Wmax) were evaluated using a maximal stress exercise test with incremental progressions of 10 W/min on a cycle ergometer with cardio-
respiratory monitoring. Rating of Perceived Exertion (RPE, Borg scale) was evaluated every minute and at the end of the test.

Health-related quality of life (HRQOL) was measured using the SEP59 (specific MS HRQOL adapted from the MSQoL-54) and EuroQol EQ-5D-3L. The SEP59 includes 15 dimensions with 2 composite scores (physical and mental), each subscale is scored from 0 to 100 [20].

Anxiety and depression were assessed using Hospital Anxiety and Depression scale (HAD).

The Fatigue Severity Scale (FSS) was used to assess fatigue and the Modified Fatigue Impact Scale (MFIS) was used to assess the impact of fatigue on daily life, with lower scores indicating low levels of fatigue for both scales.

The impact of multiple sclerosis on social participation was assessed using the Multiple Sclerosis Impact Scale (MSIS-29).

In addition, we assessed spasticity of the knee extensors and flexors, and ankle dorsiflexors (knee in extension and in flexion) (modified Ashworth scale) as well as passive toe clawing and hip and knee flexion and extension and ankle dorsiflexion with the knee in extension.

## Health economics evaluation

The EuroQol (EQ-5D-3L) was used for HRQOL; it is a validated generic questionnaire relevant for health status recording and designed for medico-economic evaluations [21-23].

The gain in quality-adjusted life years (QALY), corresponding to the life expectancy associated with the notion of quality of life, was used to compare both therapeutic approaches. The approach was collective, including all direct costs involved in people care, (except travel since this was not considered by the National Health Insurance) and excluding loss of productivity [24]. Because of their chronic disabling pathology, pwMS are fully covered by the National Health Insurance:

- Community group: unit costs and duration of the acts performed by the physiotherapist (in French "cotation AMK"=2.15€ per act x9.5 for this disease; AMK being an act performed by physiotherapists in private practice in the community).
- IROSU group: cost of day hospital rehabilitation sessions (in French "cotation HDJ SSR"=244.9€ per day; HDJ being outpatient in hospital and SSR being post-acute and rehabilitation care).

The analysis included the incremental cost-effectiveness ratios, representing the additional cost per unit of additional effectiveness, namely the possible greater improvement in 6MWT distance by the IROSU compared to the community group. The incremental cost-utility ratio (the cost per QALY gained in one group compared to the other group) was also analysed. Sensitivity deterministic analyses were conducted on the incremental and cost-utility ratios [25]. The net monetary benefit (NMB) constitutes a complementary to the ratio. It represents the value of an intervention in monetary terms when the threshold of willingness to pay (WTP) per unit (cost per QALY) is known. NMB is calculated as follows: (additional benefit x threshold) - additional cost = (Δ Efficacy*WTP) - Δ Costs. This incremental NMB measures the difference in NMB between the interventions. A positive incremental NMB indicates that the intervention is cost-effective relative to the alternative, at the defined willingness-to-pay threshold. The cost-effectiveness acceptability curve is a method for summarizing the uncertainty in estimates of cost-effectiveness, with results expressed as the probability of being cost-effective.

## Statistical Analysis

R software was used for the outcome variables (R version 3.4.4; 2018-03-15) and TREEAGE for the medico-economic analysis. Significance for all analyses was set at 0.05. Statistical analysis was performed at the end of the follow-up period for all participants after freezing of the database. Clinical efficacy criteria were analysed on a modified intention-to-treat basis, without imputation of missing data (on all randomised participants with available data on the variables of interest). Safety criteria were analysed on a per-protocol basis for all participants who participated in at least one rehabilitation session. Continuous variables are presented as means (SD) and categorical variables as frequencies and proportions. Linear mixed effect models were used to model change for all endpoints at all time-points and for each group. Randomization group (IROSU versus community), time, and group x time
interaction were the independent variables. If interactions were significant, between-group
analysis was performed at each time-point (M1, M3, M6). The Cohen test was used to
determine the effect size.

Results

Among the 153 eligible individuals, 73 were allocated to the IROSU group and 75 to the physiotherapy in the community group (flow chart, Figure 1). The planned inclusion period did not allow for the inclusion of the entire planned sample. Sixty pwMS were included in Centre 1, 36 in Centre 2, 21 in Centre 3, 14 in Centre 4, 12 in Centre 5, 4 in Centre 6 and 1 in Centre 7. Statistical analysis showed that there was no centre effect (p=0.999). Baseline participant characteristics are shown in Table 1. Mean age was 49.9 (10.5) years, mean time since MS diagnosis was 11.1 (8.3) years and the EDSS ranged from 3.5 to 5 points. Baseline characteristics did not differ between groups.

Four participants experienced a serious adverse event that was not related to the programme,
3 of which required hospitalization (2 for cardiac symptoms and 1 for cognitive degradation),
and 1 was a severe depressive episode.

Table 2 and Table 3 present the outcomes for both groups at each time point. Baseline outcomes did not differ between groups, except for 3 items of the SEP59 scale and the RPE at the end of the incremental cycling test.

At M1, both groups had exceeded the minimum number of 12 training sessions, with no
between group difference in the mean number of sessions (IROSU group 14.3 [2.9] and
community group 14.2 [3.1] sessions, p=0.95).

Primary Outcome

6MWT distance increased in both groups from baseline to M1 (p<0.001), to M3 (p<0.001) and to M6 (p= 0.001), without significant between group difference. Figure 2 present the results.
The increase after training in the IROSU (+52.2m) was non-significantly higher than that in the community group (+36.1m).

## Secondary Outcomes

Comfortable gait speed increased significantly (p<0.001) and Stair test performance time decreased significantly (p<0.001 for ascent, p=0.008 for descent) with time for all participants with no between-group difference. Most improvements were maintained at M6 (Table 2).

BBS score decreased significantly with time, for all participants (p<0.001) with no between-group difference. Mean postural sway velocity (centre of pressure displacements) did not change at any time point (p>0.05).

Knee extensor strength increased significantly from baseline to M1 in the IROSU group only (+15.4 N/m, p=0.001, effect size 0.61, figure 3). This increase was not maintained at M3 and M6. Knee flexor strength increased significantly from baseline for all participants (p<0.001) with no between-group difference.

Peak power output increased from baseline to M1 in the IROSU group only (p=0.023, effect size 0.46). Maximal oxygen consummation (VO2max) increased from baseline to M1 (p=0.03) but RPE did not change.

SEP59 physical sub-scores increased significantly from baseline in the IROSU group only (Table 3). Some SEP59 sub-scores increased significantly from baseline to M6 and similarly for both groups. EQ5D3L score increased from baseline for all participants (p=0.03).

HAD, MSIS-29 scores and MFIS scores decreased significantly (improved) from baseline for all participants (p<0.001) with no between-group difference. The decrease was maintained at M6 for HAD score and MFIS and, at M3 for MSIS-29 score (p<0.001). FSS decreased significantly from baseline for all participants (p<0.001) with no between-group difference.

Results for spasticity and orthopaedic assessments are provided in Appendix A.2. There were no-between group differences for these variables.
## Missing data

For the primary outcome 6MWT distance, data were missing for 14 of 148 participants at baseline, 18 after the training, 27 at the 3-month follow-up and 30 at the 6-month follow-up. For the other variables, data were missing for 0 to 28 participants at baseline, depending on the variable. After the training, data were missing for 18 to 38 participants, for 28 to 44 at the 3-month follow-up and for 32 to 49 at the 6-month follow-up.

## Results of the medico-economic evaluation

The IROSU group performed a median (Q1;Q3) 15 sessions (14;16) group and the community group a median 16 (14;16) sessions. The costs of day hospital attendance in a specialized unit and of a physiotherapy session in the community take into account the time spent with the therapist(s) and are known. Considering these data, the total cost was respectively 3674 (3600-6060) euros for the IROSU programme, and 488 (408-706) euros for the community programme. The HRQOL (EQ5D) did not differ statistically between groups at M1 (0.58 for the IROSU group, 0.52 for the community group, p=0.2), but the median gain in QALY was 0.157 at M1, 0.163 at M3 and 0.179 at M6 in favour of the IROSU programme.

The IROSU programme had an incremental cost-effectiveness ratio of 1274€ per metre gained on the 6MWT at M1. At M3 and M6, the incremental cost-effectiveness ratio showed that IROSU was less effective and more expensive than community physiotherapy. In contrast, the incremental cost-utility ratio was 20293€ per QALY gained at M1, 19546€ at M3 and 17799€ at M6, in favour of the IROSU programme. The net monetary benefit (NMB) was in favour of the IROSU program at the WTP threshold of 18 k€/QALY. The cost-effectiveness acceptability curve showed that the IROSU strategy had a 100% probability of being cost-effective from the WTP threshold of 20 k€/QALY.
Discussion

In contrast with our hypothesis, this study found no statistically significant difference in
walking capacity (6MWT distance) between IROSU and physiotherapy in the community.
Similar results were found for the other locomotor tests (10MWT, TUG and Stair test). A
posteriori power calculation based on the 6MWT showed a power of only 47%. A larger sample
size was thus required to ensure statistical power for the locomotor tests. However, the
increase in 6MWT distance exceeded the minimum clinically important difference for pwMS
(+22m) in both groups although it was greater in the IROSU group (+52.2m) than in the
community group (+36.1m), considering that the standard error of measurement of the 6MWT
for pwMS is 32m [16,26,27]. Furthermore, the mean increase in 6MWT distance after exercise
programs is generally around 36.5m (95% CI, 15.1-57.8), a magnitude that was exceeded in
the IROSU group [28].

Significantly greater improvements were found for the IROSU group than the community
group for knee extensor strength, peak power output, SEP59 physical composite score, SEP59
physical health, SEP59 emotional well-being and social functions. Knee extensor strength
improved in the IROSU group (moderate effect size: 0.61), with no improvement in the
community group. This is consistent with improvements after focused resistance training
programmes in pwMS [13,29,30]. Knee flexor strength improved to a similar extent in both
groups. Other studies also found a greater improvement in knee extensor compared to flexor
strength following resistance training in people with MS [31,32].

Peak power on the maximal aerobic exercise test also increased significantly in the
IROSU (+19%) but not the community group. VO2 max increased similarly and RPE did not
change in either group, suggesting that the power increase in the IROSU group was not
associated with more dyspnoea. The improvement in peak power was greater than the 9%
improvement in maximum tolerated power on a cycle ergometer previously found in pwMS
after a 12-week program of high-intensity interval training combined with resistance training
[33]. Furthermore, the increase was clinically relevant [34]. This increase in peak power
appears consistent with the increase in knee extensor strength in the IROSU group. This
difference in effectiveness between the 2 approaches is likely due to the use of specific tools
(isokinetic dynamometer, leg press and cycle ergometer with power incrementation) in the
IROSU program that was not possible in the community.

Studies that assessed multidisciplinary outpatient rehabilitation in pwMS found
improvements in locomotion and motor function (items of the Functional Independence
Measure) compared to community or home exercises [35,36]. However, strength has been
little explored in this context, and is more often evaluated in rehabilitation studies focused on
resistance training or gait training [13,37].

The perception of health status (EQ5D3L) was increased in both groups, while physical
health-related quality of life (SEP59) and several perceived limitations during physical daily
activities improved significantly in the IROSU group only. We believe these differences relate
to the services provided (multiple staff members, specialized training, individual raining and
group sessions). Strong evidence shows that coordinated interdisciplinary rehabilitation
improves quality of life in people with MS more than rehabilitation performed by one general
community physiotherapist [3]. Multidisciplinary rehabilitation (6-12 weeks) has previously
been demonstrated to improve quality of life and social functioning in outpatients with MS [5].
The similar improvement in fatigue, anxiety, depression, and the impact of MS on social
participation between groups suggests that community physiotherapy is sufficient to improve
these outcomes.

To summarise, this study found that an interdisciplinary rehabilitation program in a
specialised outpatient unit significantly improved lower limb strength and power and health-
related quality of life of pwMS, but not walking distance (lack of power) compared to
physiotherapy in the community.

Effects of a short 4-week rehabilitation programme and retention
We designed our 4-week intensive programme to correspond to that proposed annually in most specialised outpatient units in France and West Europe in addition to community physiotherapy provided throughout the year [8].

Only 2 other controlled studies reported the effects of short programs (≤ 4 weeks) on gait [28,38,39]. They showed that endurance training increased walking distance and speed compared to a control group (stretching, balance and coordination training) or no training [38,39]. Together with our results, these findings suggest that short programs can effectively improve gait performance.

Short-term resistance training has been little studied in pwMS but results appear positive [29,30]. The +19% strength increase in the IROSU group is similar to the +20% increase found after 4 weeks of maximal resistance training [29]. These results suggest 4-week strength training programs (specific protocols with appropriate tools) may be effective in pwMS. Such programs likely induce short-term improvements via neural factors rather than actual muscular changes [40]. Furthermore, power output improved to a similar extent after 4 weeks (19%), as after a 6-month multimodal intervention (20%) [41,42].

As recommended [3,10], we performed a long-term follow-up. The significant improvements in the locomotor tests, limitations related to physical and mental health, emotional well-being, energy and cognitive items of the SEP59 quality of life scale, anxiety and depression and fatigue persisted 5 months after the end of the programs in both groups. Few studies have analysed such long-term effects. One found that improvements in strength and walking were maintained 6 months after a 6-month resistance training program whereas the other found no maintenance of the positive effects 3 months after 10 weeks of community-based exercise interventions [43,44]. Only one study assessed long-term outcomes after a short (3-week) rehabilitation program (stretching and active interventions) in pwMS; functional improvements persisted for 9 weeks for transfers, self-care and locomotion, and for 15 weeks for self-care and locomotion [45]. Our study is thus the first to highlight the benefits of a short, 4-week rehabilitation program 5 months after the end of the training on locomotion, strength,
quality of life and fatigue in pwMS. These results suggest that regular physiotherapy in the community (as well as interdisciplinary rehabilitation in specialised hospitals) is beneficial for pwMS. Furthermore, it should be noted that balance capacity (BBS scores) were maintained during the programs and at 3 months follow-up (similarly in both groups) but decreased at 6months follow-up. It could be supposed that balance function was less trained after the standardised protocol.

## Health economics component

As recommended, we examined the cost-utility and cost-effectiveness of the rehabilitation programmes [5,46]. Although the cost-effectiveness analysis (based on 6MWT distance) was not in favour of the IROSU, the cost-utility analysis, which better reflects the individual's point of view, showed that this strategy, in spite of higher costs, is acceptable at the society level. This result completes that of a recent study showing that regular physiotherapy in addition to usual care leads to benefits with a few additional quality-adjusted life-years [25].

The IROSU program cost almost 20k€ per quality-adjusted life years gained at M1 and M3. This is higher than the incremental costs per QALY found in 2 studies of home or self-exercise performed in United Kingdom (10-15 k£) but lower than therapy focused on foot drop in pwMS (30k€/QALY) [25,47,48]. Note that the National Institute for Health in United Kingdom and Care Excellence established conventional thresholds of 20k£ (23k€) to 30k£ (34k€) per quality-adjusted life year. The World Health Organisation guidelines report that the threshold of willingness to pay of cost/QALY is at least the Gross National Product per capita (30k$-50k$ per capita in the developed countries) [49,50].

Finally, although the costs of the IROSU were higher than those of the physiotherapy in the community, it may be considered as useful for pwMS. This more specialized form of care could be proposed at regular intervals in addition to the usual community physiotherapy provided continuously for chronic diseases in France. This economical study of these major
rehabilitation care strategies in France provides essential data for evidence-based practice.

Further studies should identify the optimal number of interdisciplinary programmes in specialized units recommended within 1 or 2 years.

## Limitations

The first limitation of this study is the sample size, which did not provide sufficient power for the primary outcome, the 6MWT (but was sufficient for strength, power output and the SEP59 physical health items). This ambitious project aimed to include 238 pwMS (119 per group) across several partner hospitals in France, but the inclusion criteria and also the local conditions of some hospital units (eg lack of staff) limited the number of participants. The a posteriori statistical power for the 6MWT was 47%; therefore, we cannot conclude as to a real lack of difference in this criterion between programmes. Calculation of the sample required using data from this study results in 164 participants per group; this was not feasible despite the multicentre design. Nevertheless, our sample of 148 pwMS allowed us to conclude on effects of both programmes on other reliable measures. Furthermore, there was no effect of centre, therefore this cannot be considered as a limitation. It is also to be noted that 83% of pwMS included had an EDSS between 3.5 and 5 points, which could affect generalization of the results. Another limitation could be the lack of information regarding the content of what was actually done during the community physiotherapy sessions. A detailed prescription of sessions, as is conventional, was transmitted to each physiotherapist to avoid heterogeneity. Also, the number of sessions was not different between the groups, and program contents (exercises type and duration) were standardized across centres. The longer sessions for IROSU than community physiotherapy related to the study design (pragmatic study testing real-life conditions), however, this could be a confounding factor and could explain the superiority of the IROSU program for strength, power output and physical health-related quality of life. The same tools used for the assessments and for the training of the IROSU group could also be a confounding factor since participants in the IROSU group might be more familiar with
these tools than the community group. Similarly, the greater improvement in health-related quality of life measured with SEP59 scale in the IROSU group compared to the community group could be explained by the different services provided in the specialised centre, which was an integral part of the IROSU package.

## Conclusion

This first pragmatic study comparing two conventional rehabilitation programmes for people with MS, an interdisciplinary rehabilitation outpatient programme in specialized units and physiotherapy in the community, in real conditions found no significant between-group differences in walking capacity after the training (likely because of lack of power). In contrast, knee extensor strength, peak power output and quality of life related to physical health improved significantly more after the IROSU than the usual community program. The improvements of most outcomes in both groups shows the necessity of regular participation in physiotherapy, and in specialised interdisciplinary programmes to particularly improve strength, power output and quality of life. The improvements induced by this 4-week programme were maintained 5 months after the end of the training. These results, and those of the medio-economic evaluation (gain in quality-adjusted life years), suggest that a short, specialised, interdisciplinary outpatient rehabilitation program results in worthwhile improvements in strength and quality of life for people with MS and could thus be recommended at least once a year in addition to regular community physiotherapy.

## Acknowledgements

We thank collaborators of Assistance Publique - Hôpitaux de Paris, Philippe Aegerter and Lamiae Grimaldi, methodologists, for their advices for this study, Issa Sanogo for the data management and Nawal Derridj, for the coordination with the Direction of Clinical Research and Innovation (DRCI). We would like to thank all the subjects included for their voluntary
participation in this study and the physiotherapists involved in the training. We also thank
Johanna Robertson, PT, PhD, translator and medical writer for constructive criticism and
editing.

Funding

The Rehabmuscle study was supported by the PHRC 2012-A00563-40

Disclosure of interest

The authors declare that they have no competing interests.

Data Availability

Data will be made available on request to the corresponding author.

Contributors

Rehabmuscle team:

<table>
   <tr>
    <td>
     Fisrt name
    </td>
    <td>
     Last name
    </td>
   </tr>
   <tr>
    <td>
     Nawal
    </td>
    <td>
     Derridj
    </td>
   </tr>
   <tr>
    <td>
     Issa
    </td>
    <td>
     Sanogo
    </td>
   </tr>
   <tr>
    <td>
     Manuella
    </td>
    <td>
     Fournier Mehouas
    </td>
   </tr>
   <tr>
    <td>
     Anne
    </td>
    <td>
     Blanchard-Dauphin
    </td>
   </tr>
  </table>

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Tables

<caption>Table 1. Participant characteristics at baseline</caption>

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
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Table 2. Walking, balance, strength and incremental cycling test outcomes at baseline, after the training and follow-up for the IROSU and community groups.

Table 3. Quality of life, fatigue and anxiety outcomes at baseline, after the training and follow-up for the IROSU and community groups

## Figures

Figure 1: Flow Diagram (CONSORT 2010)

Figure 2: 6MWT main comparison between groups after training

Figure 3: Strength and power output in both groups

## Appendix

Appendix A.1: Presentation of the programs in both groups

Appendix A.2: Results of the spasticity and passive range of motion (ROM) assessments for the IROSU and community groups

Additional material: CONSORT checklist
<figure><img src="image_3.png" /><figcaption>Table 1. Participant characteristics at baseline</figcaption></figure>

<table><thead><tr><th></th><th>IROSU group (n=73)</th><th>Community group (n=75)</th><th>Total (N=148)</th></tr></thead><tbody><tr><td>Age (years)</td><td>49.1 (10.8)</td><td>50.7 (10.2)</td><td>49.9 (10.5)</td></tr><tr><td>Sex (% female / % male)</td><td>63 / 37</td><td>64 / 36</td><td>63.5 / 36.5</td></tr><tr><td>Body mass index</td><td>23.7 (4.4)</td><td>23.8 (4.6)</td><td>23.7 (4.5)</td></tr><tr><td>EDSS, n (%)</td><td></td><td></td><td></td></tr><tr><td>0-3</td><td>17</td><td>17</td><td>17</td></tr><tr><td>3.5-5</td><td>83</td><td>83</td><td>83</td></tr><tr><td>Disease, n (%)</td><td></td><td></td><td></td></tr><tr><td>Relapsing–remitting</td><td>58</td><td>56</td><td>57</td></tr><tr><td>Secondary progressive</td><td>27</td><td>30</td><td>29</td></tr><tr><td>Primary progressive</td><td>15</td><td>14</td><td>14</td></tr><tr><td>Time since diagnosis (years), mean (SD)</td><td>10.6 (7.7)</td><td>11.6 (8.8)</td><td>11.1 (8.3)</td></tr><tr><td>Relapses in past 2 years, %</td><td>22</td><td>22</td><td>22</td></tr><tr><td>Professional activity (yes/ no), %</td><td>47 / 53</td><td>51 / 49</td><td>49 / 51</td></tr></tbody></table>

Community group = physiotherapy in a non-specialised, state-reimbursed, outpatient practice
EDSS Expanded Disability Status Scale

IROSU group = interdisciplinary rehabilitation program in outpatients specialized unit.
<figure><img src="image_4.png" /></figure>

Table 2. Walking, balance, strength and incremental cycling test outcomes at baseline, after the training and follow-up for the IROSU and community groups
<table><thead><tr><th rowspan="2"></th><th colspan="3">IROSU group (n= 73)</th><th colspan="3">Community group (n= 75)</th><th rowspan="2">Time effect p</th><th rowspan="2">Group x Time effect P</th></tr><tr><th>Baseline</th><th>After training (1 month)</th><th>Follow up (3 months after beginning)</th><th>Baseline</th><th>After training (1 month)</th><th>Follow up (3 months after beginning)</th><th>Follow up (6 months after beginning)</th></tr></thead><tbody><tr><td>Walking distance on the 6MWT (m)</td><td>423.8 (126.7)</td><td>476.0 (119)</td><td>469.5 (152.2)</td><td>404.4 (99.3)</td><td>440.5 (112.1)</td><td>442.4 (107.8)</td><td>446.1 (100.6)</td><td>p&lt; 10<sup>-3</sup><br>M1 es=-0.31<br>M3 es=-0.21<br>M6 es=-0.21</td><td>p=0.71</td></tr><tr><td>Comfortable walking speed 10MWT (m/s)</td><td>1.1 (0.3)</td><td>1.2 (0.3)</td><td>1.2 (0.3)</td><td>1.0 (0.2)</td><td>1.1 (0.2)</td><td>1.1 (0.2)</td><td>1.1 (0.2)</td><td>p&lt; 10<sup>-3</sup><br>M1 es=-0.25<br>M3 es=-0.32<br>M6 es=-0.33</td><td>p=0.96</td></tr><tr><td>Maximal walking speed 10MWT (m/s)</td><td>1.5 (0.4)</td><td>1.6 (0.5)</td><td>1.6 (0.5)</td><td>1.5 (0.3)</td><td>1.5 (0.4)</td><td>1.5 (0.3)</td><td>1.5 (0.3)</td><td>p=0.002<br>M1 es=-0.28<br>M3 es=-0.30<br>M6 es=-0.24</td><td>p=0.72</td></tr><tr><td>Timed up and go (s)</td><td>8.7 (3.1)</td><td>7.4 (2.2)</td><td>7.7 (3.1)</td><td>8.0 (3.8)</td><td>8.0 (2.5)</td><td>7.9 (2.7)</td><td>7.5 (2.0)</td><td>p&lt; 10<sup>-3</sup><br>M1 es=0.35<br>M3 es=0.09<br>M6 es=0.002</td><td>p=0.22</td></tr><tr><td>Time to ascend a flight (s)</td><td>7.0 (3.4)</td><td>6.1 (2.7)</td><td>6.2 (2.7)</td><td>6.6 (3.6)</td><td>7.3 (3.3)</td><td>6.6 (2.1)</td><td>6.5 (2.7)</td><td>p&lt; 10<sup>-3</sup><br>M1 es=0.06<br>M3 es=0.02<br>M6 es=0.14</td><td>p=0.32</td></tr><tr><td>Time to descend a flight (s)</td><td>7.0 (4.1)</td><td>6.1 (3.3)</td><td>5.9 (3.1)</td><td>6.5 (3.7)</td><td>7.1 (3.4)</td><td>6.5 (3.1)</td><td>6.5 (2.8)</td><td>p=0.008<br>M1 es=0.14<br>M3 es=0.19<br>M6 es=0.01</td><td>p=0.7</td></tr><tr><td>BBS (score /56)</td><td>46 (16)</td><td>45 (20)</td><td>41 (22)</td><td>41 (22)</td><td>47 (15)</td><td>46 (17)</td><td>44 (19)</td><td>p&lt; 10<sup>-3</sup><br>M1 es=0.06<br>M3 es=0.15<br>M6 es=0.06</td><td>p=0.67</td></tr></tbody></table>
<table><tr><td>Postural sway, mean speed EO (mm/s)</td><td>17.7 (9.5)<br>19<br>.3 (7.3)</td><td>18.6 (9.1)<br>18.3 (8.2)</td><td>18.5<br>(11.4)</td><td>15.7 (6.9)<br>27.4<br>(15.4)</td><td>16.9 (7.3)<br>27.9 (14.6)</td><td>15.6 (5.9)<br>24.4 (11.4)</td><td>p=0.72<br>M1 es=-0.003<br>M3 es=0.19<br>M6 es=0.06</td><td>p=0.76</td></tr><tr><td>Postural sway, mean speed EC (mm/s)</td><td>30.8 (19.4)<br>31.2 (16.9)</td><td>33.1 (19.1)<br>34.1 (18.1)</td><td>30.7<br>(23.1)</td><td>27.4<br>(15.4)</td><td>27.9 (14.6)<br>27.9 (14.6)</td><td>24.4 (11.4)<br>24.4 (11.4)</td><td>p=0.81<br>M1 es=-0.04<br>M3 es=0.37<br>M6 es=0.08</td><td>p=0.09</td></tr><tr><td>Extensor strength at 30°/s (N/m)</td><td>82.8 (28)<br>98.2 (35.5)†</td><td>92.2 (26.0)<br>92.5 (33.5)</td><td>73.7<br>(28.1)</td><td>73.6<br>(26.3)</td><td>71.7 (26.3)<br>71.7 (26.3)</td><td>74.7 (29.2)<br>74.7 (29.2)</td><td>p=0.002<br>M1 es=-0.84<br>M3 es=-0.83<br>M6 es=-0.63</td><td>p=0.01<br>(M1 es=0.61)</td></tr><tr><td>Flexor strength at 30°/s (N/m)</td><td>51.5 (17.9)<br>60.7 (26.1)</td><td>59.3 (21.7)<br>59.3 (22.9)</td><td>45.1<br>(21.3)</td><td>50.4<br>(23.5)</td><td>47.9 (21.3)<br>47.9 (21.3)</td><td>49.5 (20.5)<br>49.5 (20.5)</td><td>p&lt; 10<sup>-3</sup><br>M1 es=-0.40<br>M3 es=-0.55<br>M6 es=-0.44</td><td>p=0.79</td></tr><tr><td>Max oxygen consumption VO2max at the end of incremental cycling test (mL/kg/min)</td><td>21.9 (7.2)<br>24.0 (7.9)</td><td>-</td><td>-</td><td>21.5 (6.6)<br>23.9 (6.7)</td><td>-</td><td>-</td><td>p=0.03<br>es=-0.02</td><td>p=0.63</td></tr><tr><td>Rating of Perceived Exertion at the end of incremental cycling test (score range 6 to 20)</td><td>16.1 (2.3)<br>16.1 (2.4)</td><td>-</td><td>-</td><td>17.1 (2.4)<br>16.7 (2.8)</td><td>-</td><td>-</td><td>p=0.3<br>es=0.24</td><td>p=0.43</td></tr><tr><td>Peak power output at the end of incremental cycling test (W)</td><td>92.1 (28.6)<br>109.9<br>(32.6)†</td><td>-</td><td>-</td><td>93.7<br>(36.8)</td><td>99.8<br>(41.1)</td><td>-</td><td>p=0.01<br>es=-0.27</td><td>p=0.023<br>es=0.46</td></tr></table>
EO Eyes open / EC Eyes closed

IROSU group = interdisciplinary rehabilitation program in outpatients specialized unit.

† significant difference for interaction group x time, p<0.05

es = effect size (Cohen test)
<table><caption>Table 3. Quality of life, fatigue and anxiety outcomes at baseline, after the training and follow-up for the IROSU and community groups</caption><thead><tr><th rowspan="2"></th><th colspan="3">IROSU group (n= 73)</th><th colspan="3">Community group (n= 75)</th><th rowspan="2">Time effect p</th><th rowspan="2">Group x Time effect p</th></tr><tr><th>Baseline</th><th>After training (1 month)</th><th>Follow up (3 months after beginning)</th><th>Follow up (6 months after beginning)</th><th>Baseline</th><th>After training (1 month)</th><th>Follow up (3 months after beginning)</th><th>Follow up (6 months after beginning)</th></tr></thead><tbody><tr><td>SEP59 Physical health (score / 100)</td><td>50.2 (22.4)</td><td>63.4 (22.4)†</td><td>63.4 (24.6)†</td><td>58.5 (26.0)†</td><td>48.2 (21.7)</td><td>53.5 (23.7)</td><td>53.6 (25.0)</td><td>49.6 (22.8)</td><td>p&lt;10<sup>-3</sup><br>M1 es=-0.43<br>M3 es=-0.39<br>M6 es=-0.37</td><td>p=0.02<br>es=-0.31</td></tr><tr><td>SEP59 Limitations related to physical health (score / 100)</td><td>45.5 (39.6)†</td><td>39.1 (40.5)</td><td>33.6 (37.6)</td><td>40.9 (40.0)</td><td>58.8 (38.9)</td><td>40.7 (39.3)</td><td>46.4 (40.5)</td><td>55.7 (41.5)</td><td>p=0.002<br>M1 es=0.04<br>M3 es=0.33<br>M6 es=0.36</td><td>p=0.31</td></tr><tr><td>SEP59 Limitations related to mental health (score / 100)</td><td>43.3 (41.0)</td><td>28.8 (40.8)</td><td>28.9 (37.9)</td><td>35.1 (41.9)</td><td>46.3 (44.6)</td><td>30.6 (39.7)</td><td>33.3 (40.9)</td><td>41.7 (45.9)</td><td>p&lt;10<sup>-3</sup><br>M1 es=0.05<br>M3 es=0.11<br>M6 es=0.15</td><td>p=0.92</td></tr><tr><td>SEP59 Pain (score / 100)</td><td>71.4 (23.1)†</td><td>75.4 (18.5)</td><td>74.6 (23.6)</td><td>70.5 (25.3)</td><td>60.0 (24.8)</td><td>65.5 (25.4)</td><td>63.8 (23.3)</td><td>63.0 (24.6)</td><td>p=0.002<br>M1 es=-0.44<br>M3 es=-0.46<br>M6 es=0.30</td><td>p=0.75</td></tr><tr><td>SEP59 Emotional well-being (score / 100)</td><td>60.3 (19.5)</td><td>72.7 (18.7)†</td><td>67.4 (23.1)†</td><td>65.1 (22.6)</td><td>57.5 (21.6)</td><td>66.3 (20.4)</td><td>64.1 (18.6)</td><td>58.8 (21.8)</td><td>p&lt;10<sup>-3</sup><br>M1 es=-0.33<br>M3 es=-0.16<br>M6 es=-0.28</td><td>p=0.21</td></tr><tr><td>SEP59 Energy (score / 100)</td><td>40.8 (16.9)</td><td>51.6 (18.8)</td><td>49.3 (20.7)</td><td>44.2 (22.5)</td><td>36.8 (18.4)</td><td>46.0 (21.0)</td><td>44.7 (20.8)</td><td>41.3 (21.6)</td><td>p&lt;10<sup>-3</sup><br>M1 es=-0.24<br>M3 es=-0.12</td><td>p=0.55</td></tr></tbody></table>
<table><tbody><tr><td>SEP59 Health perception (score / 100)</td><td>41.6 (17.5)</td><td>47.3 (18.0)</td><td>49.5 (18.3)†</td><td>44.1 (18.7)</td><td>44.0 (16.6)</td><td>48.0 (17.0)</td><td>46.2 (16.3)</td><td>45.4 (15.3)</td><td>M6 es=-0.07<br>p&lt;10<sup>-3</sup><br>M1 es=0.04<br>M3 es=-0.19<br>M6 es=0.08</td><td>p=0.006<br>es=0.02</td></tr><tr><td>SEP59 Social functions (score / 100)</td><td>62.6 (21.0)</td><td>73.3 (22.1)†</td><td>71.6 (20.3)†</td><td>67.6 (23.1)</td><td>61.6 (21.5)</td><td>64.3 (21.6)</td><td>64.1 (18.5)</td><td>62.8 (20.7)</td><td>p&lt;10<sup>-3</sup><br>M1 es=-0.41<br>M3 es=-0.38<br>M6 es=-0.22</td><td>p=0.008<br>es=-0.25</td></tr><tr><td>SEP59 Cognitive functions (score / 100)</td><td>64.5 (23.3)</td><td>74.7 (22.6)</td><td>69.7 (22.4)</td><td>67.1 (24.1)</td><td>56.5 (25.3)</td><td>62.5 (23.9)</td><td>64.8 (22.3)</td><td>60.9 (23.0)</td><td>p&lt;10<sup>-3</sup><br>M1 es=-0.53<br>M3 es=-0.22<br>M6 es=-0.26</td><td>p=0.19</td></tr><tr><td>SEP59 Distress (score / 100)</td><td>55.4 (24.0)</td><td>69.2 (22.3)</td><td>64.2 (24.9)</td><td>59.5 (23.8)</td><td>50.2 (23.4)</td><td>60.5 (20.8)</td><td>58.6 (22.0)</td><td>57.7 (24.2)</td><td>p&lt;10<sup>-3</sup><br>M1 es=-0.40<br>M3 es=-0.24<br>M6 es=-0.08</td><td>p=0.2</td></tr><tr><td>SEP59 Sleep (score / 100)</td><td>42.9 (13.8)</td><td>41.4 (15.1)</td><td>44.0 (12.4)</td><td>44.5 (15.5)</td><td>46.9 (14.1)</td><td>47.3 (12.7)</td><td>45.9 (12.6)</td><td>43.2 (11.8)</td><td>p=0.8<br>M1 es=0.43<br>M3 es=0.15<br>M6 es=-0.09</td><td>p=0.06</td></tr><tr><td>SEP59 Sexual functions (score / 100)</td><td>24.2 (26.9)†</td><td>23.3 (25.0)</td><td>23.3 (26.7)</td><td>24.6 (29.5)</td><td>37.3 (33.3)</td><td>29.9 (28.9)</td><td>32.6 (31.3)</td><td>34.4 (31.9)</td><td>p=0.5<br>M1 es=0.24<br>M3 es=0.32<br>M6 es=-0.32</td><td>p=0.39</td></tr><tr><td>SEP59 Sexual satisfaction (score / 100)</td><td>34.8 (38.0)</td><td>37.0 (41.0)</td><td>34.0 (39.4)</td><td>37.6 (39.5)</td><td>26.3 (34.1)</td><td>28.3 (36.4)</td><td>27.0 (37.3)</td><td>21.5 (31.4)</td><td>p=0.81<br>M1 es=-0.23<br>M3 es=-0.18<br>M6 es=-0.45</td><td>p=0.77</td></tr><tr><td>SEP59 Social support (score / 100)</td><td>58.8 (32.6)</td><td>57.7 (36.8)</td><td>61.3 (33.6)</td><td>62.1 (35.5)</td><td>51.3 (34.0)</td><td>54.1 (36.2)</td><td>55.9 (34.7)</td><td>50.6 (34.2)</td><td>p=0.96<br>M1 es=-0.10<br>M3 es=-0.16<br>M6 es=-0.33</td><td>p=0.55</td></tr></tbody></table>
<table><tr><td>SEP59 General quality of life (score / 100)</td><td>69.0 (18.7)</td><td>72.5 (17.5)</td><td>71.3 (20.0)</td><td>69.8 (20.6)</td><td>63.5 (21.3)</td><td>66.5 (17.2)</td><td>65.7 (17.2)</td><td>61.6 (16.6)</td><td>p=0.025<br>M1 es=-0.35<br>M3 es=-0.30<br>M6 es=-0.44</td><td>p=0.64</td></tr><tr><td>SEP59 Physical composite score (score / 100)</td><td>49.8 (12.3)</td><td>57.3 (12.0)†</td><td>55.2 (13.4)†</td><td>52.7 (14.2)</td><td>48.4 (11.1)</td><td>52.3 (11.4)</td><td>52.0 (10.1)</td><td>50.6 (11.4)</td><td>p&lt;10<sup>-3</sup><br>M1 es=-0.43<br>M3 es=-0.29<br>M6 es=-0.17</td><td>p=0.009<br>es=-0.25</td></tr><tr><td>SEP59 Mental composite score (score / 100)</td><td>57.8 (10.9)</td><td>61.6 (9.2)</td><td>59.1 (10.6)</td><td>58.3 (10.4)</td><td>54.8 (10.5)</td><td>56.1 (10.5)</td><td>56.5 (9.9)</td><td>55.3 (10.4)</td><td>p=0.09<br>M1 es=-0.56<br>M3 es=-0.25<br>M6 es=-0.29</td><td>p=0.26</td></tr><tr><td>EQ5D3L Perception of health status (score /100)</td><td>61.4 (18.9)</td><td>68.3 (18.4)</td><td>66.4 (18.3)</td><td>61.8 (21.8)</td><td>57.8 (20.5)</td><td>61.1 (19.7)</td><td>58.9 (21.0)</td><td>59.4 (19.9)</td><td>p=0.03<br>M1 es=-0.38<br>M3 es=-0.37<br>M6 es=-0.11</td><td>p=0.35</td></tr><tr><td>Hospital Anxiety and Depression scale (score / 42)</td><td>12.2 (7.6)</td><td>9.3 (7.0)</td><td>9.0 (7.9)</td><td>9.4 (8.4)</td><td>13.6 (7.5)</td><td>10.9 (8.3)</td><td>11.3 (9.0)</td><td>10.0 (8.8)</td><td>p&lt;10<sup>-3</sup><br>M1 es=0.21<br>M3 es=0.27<br>M6 es=0.07</td><td>p=0.46</td></tr><tr><td>Fatigue severity scale (mean score / 7)</td><td>5.1 (1.4)</td><td>4.8 (1.3)</td><td>4.8 (1.3)</td><td>5.1 (1.2)</td><td>5.4 (1.2)</td><td>5.0 (1.5)</td><td>5.1 (1.5)</td><td>5.2 (1.5)</td><td>p=0.01<br>M1 es=0.15<br>M3 es=0.26<br>M6 es=0.05</td><td>p=0.57</td></tr><tr><td>Modified fatigue impact scale MFIS (total score / 84)</td><td>40.9 (18.7)</td><td>27.6 (21.1)</td><td>29.6 (22.2)</td><td>31.9 (23.0)</td><td>45.5 (18.8)</td><td>33.4 (25.0)</td><td>35.4 (24.1)</td><td>32.0 (26.8)</td><td>p&lt;10<sup>-3</sup><br>M1 es=0.25<br>M3 es=0.25<br>M6 es=0.002</td><td>p=0.28</td></tr><tr><td>Multiple sclerosis impact scale MSIS29 (total score / 100)</td><td>67.3 (21.4)</td><td>56.8 (20.4)</td><td>59.4 (21.9)</td><td>65.2 (24.4)</td><td>73.4 (22.3)</td><td>64.7 (20.6)</td><td>67.8 (21.2)</td><td>69.8 (20.2)</td><td>p&lt;10<sup>-3</sup><br>M1 es=0.38<br>M3 es=0.39<br>M6 es=0.21</td><td>p=0.18</td></tr></table>

Community group = physiotherapy in a non-specialised, state-reimbursed, outpatient practice
EQ-5D-3L: EuroQol scale, version 5D-3L

IROSU group = interdisciplinary rehabilitation program in outpatients specialized unit.

SEP59: specific quality of life scale

† significant difference for interaction group x time, p<0.05

es = effect size (Cohen test)
<figure><img src="image_5.png" /></figure>
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