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High-intensity resistance training in people with multiple sclerosis experiencing fatigue: A randomised controlled trial

  • S. Englund
    Correspondence
    Corresponding author at: Department of Clinical Neuroscience, Karolinska Institutet, SE-17177, Stockholm, Sweden.
    Affiliations
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Academic Specialist Center, Center of Neurology, Stockholm Health Services, SE-113 65 Stockholm, Sweden
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  • F. Piehl
    Affiliations
    Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    Academic Specialist Center, Center of Neurology, Stockholm Health Services, SE-113 65 Stockholm, Sweden
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  • M. Kierkegaard
    Affiliations
    Academic Specialist Center, Center of Neurology, Stockholm Health Services, SE-113 65 Stockholm, Sweden

    Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
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Open AccessPublished:August 13, 2022DOI:https://doi.org/10.1016/j.msard.2022.104106

      Abstract

      Background

      Exercise studies including only fatigued persons with multiple sclerosis (PwMS) with fatigue as primary endpoint are lacking.

      Objective

      To evaluate the effects of high-intensity resistance training (HIRT) on self-reported fatigue in fatigued PwMS in a single center randomised controlled trial.

      Methods

      We recruited 71 PwMS scoring ≥ 53 on the Fatigue Scale for Motor and Cognitive Functions (FSMC), who were randomised 1:1 to either twice (group A) or once (group B) weekly supervised HIRT for twelve weeks. A non-randomised FSMC score-matched group (n=69) served as non-intervention control.

      Results

      Between HIRT-group differences were non-significant for primary and most secondary endpoints. Mean difference in FSMC score (95% confidence intervals) was -10.9 (-14.8; -6.9) in group A and -9.8 (-13.2; -6.3) in group B. Corresponding values for combined HIRT groups vs non-intervention control were -10.3 (-12.9; -7.7) and 1.5 (-0.6;3.6), respectively, p<0.001. Secondary endpoints also improved in both HIRT groups, though only Hospital Anxiety and Depression Scale anxiety and MS Impact Scale-29 psychological subscales significantly favoured the twice a week HIRT (group A). As an exploratory endpoint, changes in plasma inflammatory protein markers were associated with reduced FSMC scores in the pooled material.

      Conclusion

      The finding that HIRT in fatigued PwMS leads to clinically relevant reductions in self-reported fatigue, associated with changes in plasma inflammatory protein levels, provide evidence for recommending HIRT for fatigued PwMS.

      Keywords

      Abbreviations:

      DMT (Disease Modifying Therapy), EDSS (Expanded Disability Status Scale), EQ-5D-5L (5-level EQ-5D version), EQ-VAS (EuroQoL Visual Analogue Scale), FDR (False Discovery Rate), FSMC (Fatigue Scale for Motor and Cognitive Functions), FSS (Fatigue Severity Scale), HADS (Hospital Anxiety and Depression Scale), HIRT (High-Intensity Resistance Training), HRQL (Health-Related Quality of Life), ITT (Intention To Treat), MD (Mean Difference), MSIS-29 (Multiple Sclerosis Impact Scale), NPX (Normalized Protein Expression), OGQ (Occupational Gaps Questionnaire), PPMS (Primary Progressive Multiple Sclerosis), PwMS (Persons with Multiple Sclerosis), RCT (Randomised Controlled Trial), RM (Repetition Maximum), RRMS (Relapsing Remitting Multiple Sclerosis), SDMT (Symbol Digit Modalities Test), SPMS (Secondary Progressive Multiple Sclerosis)

      1. Introduction

      Multiple sclerosis (MS) is one of the most frequent causes of neurological disability and loss of work capacity among young and middle-aged adults. Although the symptom spectrum experienced by persons with MS (PwMS) is very wide, both in terms of qualitative aspects and severity, fatigue is often cited as one of the most frequently reported and disabling impairments (
      • Broch L.
      • Simonsen C.S.
      • Flemmen H.
      • Berg-Hansen P.
      • Skardhamar Å.
      • Ormstad H.
      • Celius E.G.
      High prevalence of fatigue in contemporary patients with multiple sclerosis.
      ).
      Fatigue can be described as a subjective feeling of exhausted physical and/or mental energy reserves to an extent that it restricts normal activities of daily living. It is present in approximately two-thirds of PwMS (
      • Rooney S.
      • Wood L.
      • Moffat F.
      • Paul L.
      Prevalence of fatigue and its association with clinical features in progressive and non-progressive forms of Multiple Sclerosis.
      ) and displays a strong correlation to health-related quality of life (HRQL) scores (
      • Rooney S.
      • Wood L.
      • Moffat F.
      • Paul L.
      Prevalence of fatigue and its association with clinical features in progressive and non-progressive forms of Multiple Sclerosis.
      ). The underlying aetiology of fatigue is not known, although both central and peripheral mechanisms have been suggested (
      • Langeskov-Christensen M.
      • Bisson E.J.
      • Finlayson M.L.
      • Dalgas U.
      Potential pathophysiological pathways that can explain the positive effects of exercise on fatigue in multiple sclerosis: a scoping review.
      ). These may be related directly to the MS disease, e.g., inflammation, demyelination and/or neurodegeneration; or to non-disease specific factors (
      • Langeskov-Christensen M.
      • Bisson E.J.
      • Finlayson M.L.
      • Dalgas U.
      Potential pathophysiological pathways that can explain the positive effects of exercise on fatigue in multiple sclerosis: a scoping review.
      ). Soluble inflammatory mediators such as pro-inflammatory cytokines like tumour necrosis factor (TNF) and Interleukin-6 (IL-6) have also been proposed to be involved in the pathophysiology of MS fatigue (
      • Langeskov-Christensen M.
      • Bisson E.J.
      • Finlayson M.L.
      • Dalgas U.
      Potential pathophysiological pathways that can explain the positive effects of exercise on fatigue in multiple sclerosis: a scoping review.
      ).
      The evidence base for physical exercise as a therapeutic intervention for inflammatory diseases is growing both regarding its beneficial clinical effects and mechanism of action (
      • Pedersen B.K.
      • Saltin B.
      Exercise as medicine - evidence for prescribing exercise as therapy in 26 different chronic diseases.
      ). This is in line with research identifying skeletal muscles as a secretary organ producing and releasing contraction dependent anti-inflammatory mediators (
      • Pedersen B.K.
      Muscle as a secretory organ.
      ), where intensity level is subject to a dose-response effect (
      • Calle M.C.
      • Fernandez M.L.
      Effects of resistance training on the inflammatory response.
      ). Moderate-intensity resistance training is well tolerated in PwMS and can reduce self-reported fatigue (
      • Heine M.
      • van de Port I.
      • Rietberg M.B.
      • van Wegen E.E.
      • Kwakkel G.
      Exercise therapy for fatigue in multiple sclerosis.
      ). However, the lack of high-quality studies including only fatigued PwMS and using fatigue reduction as a primary endpoint has been highlighted (
      • Heine M.
      • van de Port I.
      • Rietberg M.B.
      • van Wegen E.E.
      • Kwakkel G.
      Exercise therapy for fatigue in multiple sclerosis.
      ). Furthermore, the optimal dose, i.e., the combination of duration, frequency, and intensity, is not known (
      • Heine M.
      • van de Port I.
      • Rietberg M.B.
      • van Wegen E.E.
      • Kwakkel G.
      Exercise therapy for fatigue in multiple sclerosis.
      ).
      It has been shown that supervised exercise training is accompanied with better effects in PwMS (
      • Snook E.M.
      • Motl R.W.
      Effect of exercise training on walking mobility in multiple sclerosis: a meta-analysis.
      ). Adults with other chronic conditions are, in general, recommended muscle-strengthening activities twice a week (Physical Activity Guidelines Advisory
      • Committee Physical Activity Guidelines Advisory
      Physical Activity Guidelines Advisory Committee Scientific Report.
      ). However, frequent supervised exercise sessions over extended periods of time are resource demanding, which may constitute a problem when translating clinical study protocols to real world contexts.
      We previously conducted a pilot-study of a 12-week supervised high-intensity resistance training (HIRT) programme in patients with relapsing remitting MS (RRMS), indicating clinically relevant improvements in fatigue, a decrease in anxiety and depression scores, improved HRQL and reduced levels of TNF in blood (
      • Kierkegaard M.
      • Lundberg I.E.
      • Olsson T.
      • Johansson S.
      • Ygberg S.
      • Opava C.
      • Holmqvist L.W.
      • Piehl F.
      High-intensity resistance training in multiple sclerosis - an exploratory study of effects on immune markers in blood and cerebrospinal fluid, and on mood, fatigue, health-related quality of life, muscle strength, walking and cognition.
      ). However, to serve as an evidence base these preliminary findings need to be corroborated by a larger high-quality randomised controlled trial (RCT) in fatigued PwMS. Thus, the objectives here were to evaluate the effects of HIRT on functioning and HRQL in fatigued PwMS, and to explore associations between changes in fatigue with serum inflammatory protein markers, and to compare HIRT twice a week with once a week and using a matched non-randomised cohort as non-intervention control group.

      2. Materials and methods

      2.1 Study design and participants

      This was a single-blinded RCT of HIRT in fatigued PwMS comparing HIRT twice a week with once a week, with an additional comparison of change in fatigue with a contemporary non-intervention control group.
      Study participants were recruited during two screening epochs, in August 2020 and January 2021 respectively, at the largest MS clinic in Sweden; Center of Neurology (CfN), Stockholm. Inclusion criteria were age ≥ 18 years, a diagnosis of MS according to the revised 2017 McDonald Criteria, scoring at least moderate fatigue (score ≥ 53) on the Fatigue Scale for Motor and Cognitive Functions (FSMC) (
      • Penner I.K.
      • Raselli C.
      • Stocklin M.
      • Opwis K.
      • Kappos L.
      • Calabrese P.
      The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue.
      ), ability to understand and communicate in Swedish, and not practicing high-intensity training within 6 months prior to the trial. Key exclusion criteria were comorbidity interfering with the possibility to engage in HIRT or to evaluate the endpoints, and pregnancy or breastfeeding. Participants were provided with both oral and written study information, and all provided a signed informed consent before study start. Approval was obtained from the Swedish Ethical Review Authority (2019-05105, 2020-05614) and procedures were conducted in accordance with the Helsinki Declaration. The study was registered with ClinicalTrials.gov (NCT04562376).
      The contemporary non-intervention control group consisted of PwMS included in the prospective observational Combat-MS study (ClinicalTrials.gov NCT03193866) with a FSMC score ≥ 53 at assessments in September-October 2020 and who were re-assessed with the FSMC within 2-4 months.

      2.2 Intervention

      The HIRT programme followed the current guidelines concerning resistance training. The training consisted of a 5–10-minute warm-up on a stationary bicycle, four upper body exercises (pull down, push up, chest press, latissimus pull) and three lower body exercises (leg extension, leg curl, leg press) performed in training machines (HUR machines, https://www.hur.fi/en), and one whole body exercise (plank position), followed by a 5-10-minute cool down of stretching exercises. A progressive resistance training model was applied (Table 1). At the start of the intervention period, 1 repetition maximum (RM) for each machine-exercise was calculated after performance of 10RM tests, i.e., the load a person can manage for 10, but not 11 consecutive repetitions. This load is considered to represent 70% of 1RM. The maximum time for holding the plank position was considered 1RM for this exercise.
      Table 1Description and progression of the intervention.
      Load (repetition maximum)15 (week 1–2), 10 (week 3–4), 7 (week 5–12)
      Number of repetitions15 (week 1–2), 10 (week 3–4), 7 (week 5–12)
      Number of sets3
      Rest in-between repetitionsNone
      Rest between sets (minute)1-3
      Sessions per week Group A2
      Sessions per week Group B1
      Duration of training period (weeks)12
      Contraction modesConcentric and eccentric
      Contraction failure in each setFailure or near failure (week 3–12)
      Recovery time in-between sessions (hours)≥48
      Participants had a 60 minutes HIRT session twice a week (group A) or once a week (group B) for 12 weeks at the Karolinska University Hospital, Stockholm, Sweden, under the supervision of a physiotherapist. Participants were provided with different options for HIRT sessions to increase adherence and they trained alone or in groups of maximum five persons/session.

      2.3 Measures

      Participant characteristics and disease-related data were collected for descriptive purposes. The primary endpoint was change in fatigue measured with the FSMC (
      • Penner I.K.
      • Raselli C.
      • Stocklin M.
      • Opwis K.
      • Kappos L.
      • Calabrese P.
      The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue.
      ). A change of 10 points was considered a clinically meaningful difference (
      • D'Hooghe M.
      • Van Gassen G.
      • Kos D.
      • Bouquiaux O.
      • Cambron M.
      • Decoo D.
      • Lysandropoulos A.
      • Van Wijmeersch B.
      • Willekens B.
      • Penner I.K.
      • Nagels G.
      Improving fatigue in multiple sclerosis by smartphone-supported energy management: the MS TeleCoach feasibility study.
      ;
      • Oervik M.S.
      • Sejbaek T.
      • Penner I.K.
      • Roar M.
      • Blaabjerg M.
      Validation of the fatigue scale for motor and cognitive functions in a danish multiple sclerosis cohort.
      ). Secondary endpoints comprised fatigue measured with the Fatigue Severity Scale (FSS) (
      • Krupp L.B.
      • LaRocca N.G.
      • Muir-Nash J.
      • Steinberg A.D.
      The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus.
      ), mood measured with the Hospital Anxiety and Depression Scale (HADS) (
      • Zigmond A.
      • Snaith R.
      The hospital anxiety depression scale.
      ), participation in everyday occupations measured with the Occupational Gaps Questionnaire (OGQ) (
      • Eriksson G.
      • Tham K.
      • Kottorp A.
      A cross-diagnostic validation of an instrument measuring participation in everyday occupations: the Occupational Gaps Questionnaire (OGQ).
      ), HRQL measured with the MS Impact Scale-29 (MSIS-29) (
      • Hobart J.
      • Lamping D.
      • Fitzpatrick R.
      • Riazi A.
      • Thompson A.
      The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure.
      ) and the 5-level EQ-5D version (EQ-5D-5L) including the EQ visual analogue scale (EQ-VAS) (
      • Herdman M.
      • Gudex C.
      • Lloyd A.
      • Janssen M.
      • Kind P.
      • Parkin D.
      • Bonsel G.
      • Badia X.
      Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Quality of life research : an international journal of quality of life aspects of treatment.
      ).
      As an exploratory endpoint, change of inflammatory protein markers in serum was measured using a highly sensitive multiplex technique (Olink Target 96 Inflammation, ref no. 95302, Uppsala, Sweden). A detailed description of the assay methodology and processing has previously been described (
      • Assarsson E.
      • Lundberg M.
      • Holmquist G.
      • Björkesten J.
      • Thorsen S.B.
      • Ekman D.
      • Eriksson A.
      • Rennel Dickens E.
      • Ohlsson S.
      • Edfeldt G.
      • Andersson A.C.
      • Lindstedt P.
      • Stenvang J.
      • Gullberg M.
      • Fredriksson S.
      Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability.
      ). In short, the panel includes 92 immune-related proteins (Supplementary Table S1), and the assay utilizes epitope-specific binding and hybridization of a set of paired antibodies linked to oligonucleotide probes, which subsequently can be amplified using a quantitative polymerase chain reaction to quantify relative protein concentrations in terms of log base-two normalized protein expression (NPX) values.

      2.4 Procedures

      Data collections were performed at the CfN by a registered nurse, blinded to allocation, before (baseline) and after the 12-week intervention. Standard EDTA tubes were used for blood samples, which were spun down at 1500G for 15 min within 15-120 min directly after sampling. Serum samples were aliquoted and stored at -80◦C until analyses.
      Randomisation was performed after baseline assessments by an independent nurse using a computer-generated random scheme (Sealed Envelope Ltd). A 1:1 allocation ratio of blocks of ten without stratification was used and implementation was done by means of sequentially numbered sealed opaque envelopes.

      2.5 Data analysis

      The sample size calculation was based on reported clinically relevant change in the primary endpoint fatigue and a standard deviation (SD) in a similar sample of fatigued PwMS (
      • D'Hooghe M.
      • Van Gassen G.
      • Kos D.
      • Bouquiaux O.
      • Cambron M.
      • Decoo D.
      • Lysandropoulos A.
      • Van Wijmeersch B.
      • Willekens B.
      • Penner I.K.
      • Nagels G.
      Improving fatigue in multiple sclerosis by smartphone-supported energy management: the MS TeleCoach feasibility study.
      ;
      • Oervik M.S.
      • Sejbaek T.
      • Penner I.K.
      • Roar M.
      • Blaabjerg M.
      Validation of the fatigue scale for motor and cognitive functions in a danish multiple sclerosis cohort.
      ). A total of 45 participants in each group were needed to detect a difference of 10 points in FSMC assuming a common SD of 11, with a power of 90%, at α=0.01 and a drop-out rate of 20%.
      The cut-off for session adherence was set to attendance ≥75% of the sessions. Mean percentage increase in muscle strength for the seven body exercises performed in training machines were calculated for each participant and used as a parameter for adherence to the exercise protocol, i.e., content adherence. The cut-off for content adherence was set to a mean percentage increase ≥10%.
      Descriptive statistics were used to present data. An intention to treat (ITT) approach was used for data analysis. The primary endpoint was after the 12-week intervention period. Linear repeated-measurement analyses were used for evaluating within-group (time) and between-group (time x group) effects for FSMC, FSS, HADS, OGQ, MSIS-29 and EQ-VAS. Drop-out analyses were performed with non-parametric methods. Based on FSMC scores participants were categorised as having no (20-42), mild (43-52), moderate (53-62) or severe (63-100) fatigue (
      • Penner I.K.
      • Raselli C.
      • Stocklin M.
      • Opwis K.
      • Kappos L.
      • Calabrese P.
      The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue.
      ). Data from the 30-item OGQ identifying occupational gaps in the areas of instrumental activities of daily living, leisure, socialising, and work were summarized by calculation of the total number of identified gaps. Data from the EQ-5D-5L questionnaire were only presented with descriptive statistics.
      Changes in inflammatory protein markers were analysed with paired samples t-tests. Analyses of associations between change in FSMC and immune-related protein levels were analysed using multivariable linear regression models adjusting for age, sex, and days between last HIRT session and follow-up sampling. In all analyses, only proteins with a call rate ≥75% were included, with additional corrections for potential effects of pre-analytical variability relating to handling procedures (see supplementary information). Volcano-plots were used to illustrate mean difference in NPX values and significance (P-values) from paired samples t-tests and multivariable linear regression analyses.
      The significance level was set at P<0.05 for primary and secondary endpoints. For statistical analyses of inflammatory protein markers, a direct false discovery rate (FDR) correction of P-values with a significance cut-off of PFDR <0.05 were performed and an exploratory significance cut-off of P=0.05 were used. Analyses were performed using IBM SPSS Statistics 28 and SAS version 9.4 (SAS Institute).

      3. Results

      In the two screening epochs in August 2020 and January 2021, 81 and 63 potentially eligible PwMS, respectively, were screened, out of which 71 were enrolled in the study, 35 were allocated to HIRT twice a week (group A) and 36 to once HIRT a week (group B) (Fig. 1). Forty-four PwMS started their training period in September 2020 and 27 in February 2021. The contemporary non-intervention control group consisted of 69 PwMS. Descriptive baseline characteristics are presented in Table 2. Nineteen participants had been prescribed symptomatic pharmacological treatment for fatigue within one-year prior to baseline assessments and 16 had prescriptions of antidepressants.
      Fig. 1
      Fig. 1Consort diagram giving an overview of the participant flow in the study.
      Table 2Baseline characteristics of participants receiving high-intensity resistance training by group allocation, for all participants and for contemporary non-intervention control group.
      CharacteristicsGroup A (twice/week) n=35Group B (once a week) n=36All participants N=71Non-intervention control group N=69
      Age, mean (SD), years40.5 (9.7)43.6 (9.6)42.1 (9.7)43.6 (10.3)
      Female, n (%)28 (80.0)34 (94.4)62 (87.3)53 (76.8)
      MS subtype, n (%)
       RRMS35 (100.0)35 (97.2)70 (98.6)64 (92.8)
       PPMS/SPMS0 (0.0)/0 (0.0)1 (2.8)/0 (0.0)1 (1.4)/0 (0.0)0 (0.0)/5 (7.2)
      Time since diagnosis, mean (SD), years7.7 (5.1)9.4 (8.0)8.6 (6.7)8.6 (5.6)
      EDSS, median (IQR)2.0 (1.5-2.5)2.3 (1.5-3.0)2.0 (1.5-3.0)2.5 (1.5-3.5)
      EDSS, n (%)
       Mild (0-2.5)28 (80.0)22 (61.1)50 (70.4)46 (66.7)
       Moderate (3-5.5)5 (14.3)12 (33.3)17 (23.9)21 (30.4)
       Severe (≥6)2 (5.7)2 (5.6)4 (5.6)2 (2.9)
      DMT, n (%)
       Rituximab22 (62.9)28 (77.8)50 (70.4)46 (66.7)
       Natalizumab5 (14.3)2 (5.6)7 (9.9)3 (4.3)
       Fingolimod2 (5.7)1 (2.8)3 (4.2)3 (4.3)
       Ocrelizumab1 (2.9)0 (0.0)1 (1.4)0 (0.0)
       Dimethyl Fumarate0 (0.0)1 (2.8)1 (1.4)4 (5.8)
       Untreated5 (14.3)4 (11.1)9 (12.7)6 (8.7)
       Other0 (0.0)0 (0.0)0 (0.0)7 (10.1)
      BMI, mean (SD), kg/m227.6 (5.1)24.9 (5.0)26.2 (5.2)NA
      SDMT score, mean (SD)58.5 (11.9)56.9 (9.4)13 (18.3)NA
      Civil status, n (%)
       Married, partner26 (74.3)20 (55.6)46 (64.8)NA
       Single9 (25.7)16 (44.4)25 (35.2)NA
      Educational level, n (%)
       >12 years27 (77.1)26 (72.2)53 (74.6)NA
       ≤12 years8 (22.9)10 (27.8)18 (25.4)NA
      Employment status, n (%)
       Working full-time, studying20 (57.1)17 (47.2)37 (52.1)NA
       Working part-time11 (31.4))13 (36.1)24 (33.8)NA
       Sick leave, disability pension4 (11.4)6 (16.7)10 (14.1)NA
      Heat intolerance, n (%)21 (60.0)26 (72.2)47 (66.2)NA
      Smoking (current), n (%)7 (20.0)6 (16.7)13 (18.3)NA
      Snuff-taking (current), n (%)3 (8.6)7 (19.4)10 (14.1)NA
      Physical activity
      Defined as minutes per week of aerobic physical activity according to the recommendation of physical activity for health benefits by the World Health Organization.
      , n (%)
       ≥ 150 activity min/week18 (51.4)23 (63.9)41 (57.7)NA
       < 150 activity min/week17 (48.6)13 (36.1)30 (42.3)NA
      Sleeping in general, n (%)
      Fair to excellent19 (54.3)21 (58.3)40 (56.3)NA
      Very  or fairly poor16 (45.7)15 (41.7)31 (43.7)NA
      Abbreviations: BMI=body mass index; DMT=disease modulatory therapies; EDSS=expanded disability status scale; IQR=interquartile range; MS=multiple sclerosis; PPMS=primary progressive MS; RRMS=relapsing remitting MS; SD=standard deviation; SPMS=secondary progressive MS; SDMT=symbol digit modalities test.
      a Defined as minutes per week of aerobic physical activity according to the recommendation of physical activity for health benefits by the World Health Organization.
      Eleven participants (15.5%) dropped-out of the study (Fig. 1), although only three (4%) were completely lost to follow-up (another five could not attend the follow-up meeting in person but sent in questionnaires by post). These 11 participants scored significantly higher fatigue (FSMC, p=0.016), anxiety (HADS, p=0.030) and HRQL (MSIS-29 physical, p=0.009) at baseline compared to participants who remained in the study.
      Session adherence ranged between 25-100% in group A and between 33-100% in group B with 26 (74%) and 24 (67%) participants in group A and B, respectively, who completed at least 75% of the stipulated HIRT sessions. Thus, 50 (70%) participants fulfilled the criteria for session adherence. As for content adherence, 52 (73%) participants showed adherence to the exercise protocol. There were two reported adverse events: one patient dropped-out due to unpleasant sensory sensations, another patient reported chest pain which was diagnosed as Tietze's syndrome and who remained in the study.
      The results of HIRT are shown in Table 3. There was no significant between-group difference in the primary endpoint with mean FSMC change score being reduced with approximately 10 points in both groups, i.e., representing a clinically meaningful change. A total of 28 participants (15 in group A and 13 in group B) decreased their FSMC score ≥ 10 points. The reduction in FSMC scores in the merged HIRT groups was larger than the non-intervention control, who retained similar scores between baseline and follow-up (Fig. 2, Table 3). At baseline, 66 HIRT participants were categorized as having severe fatigue and five as having moderate. At follow-up, 43 participants had severe fatigue, 16 moderate, five mild and four were categorized as having no fatigue. As for the secondary endpoints, there was a significant time effect for all except OGQ, and only HADS anxiety and MSIS-29 psychological showed a significant between-group difference in favour of group A (twice a week). Results from EQ-5D-5L questionnaire ratings of perceived problems are presented in Fig. 3.
      Table 3Results of primary and secondary outcome measures, P-values are from intention to treat linear repeated-measurement analyses.
      Group A (twice/week) n=34Group B (once a week), n=34Effects
      BaselineFollow-upBaselineFollow-upTimeTime x Group
      Outcome measureMean (SD)Mean (SD)MD (95% CI)Mean (SD)Mean (SD)MD (95% CI)P-valueP-value
      FSMC (20-100)
      Lower score represents better outcome
      78.1 (9.4)67.2 (16.0)-10.9 (-14.8; -6.9)76.4 (9.7)66.6 (10.7)-9.8 (-13.2; -6.3)<0.0010.676
      FSS (1-7)
      Lower score represents better outcome
      5.6 (0.8)4.7 (1.3)-0.9 (-1.2; -0.6)5.3 (0.9)
      n=33
      4.3 (1.2)
      n=33
      -1.0 (-1.4; -0.5)
      n=33
      <0.0010.746
      HADS anxiety (0-21)
      Lower score represents better outcome
      8.4 (4.4)6.5 (4.1)-1.9 (-3.1; -0.7)7.7 (4.0)7.5 (3.8)-0.2 (-1.3; 1.0)0.0130.039
      HADS depression (0-21)
      Lower score represents better outcome
      6.6 (3.4)4.9 (3.4)-1.7 (-2.8; -0.6)6.8 (4.1)5.8 (4.0)-1.0 (-2.0; -0.1)<0.0010.365
      OGQ (number of gaps)
      Lower score represents better outcome
      8.4 (5.1)7.6 (4.9)-0.7 (-2.0; 0.6)7.1 (5.8)6.4 (4.6)-0.7 (-1.9; 0.5)0.1111.000
      MSIS-29
       physical (0-100)
      Lower score represents better outcome
      34.6 (15.8)
      n=33
      21.9 (14.9)
      n=33
      -12.7 (-17.2; -8.2)
      n=33
      29.2 (18.9)21.0 (17.3)-8.2 (-11.6; -4.8)<0.0010.110
       psychological (0-100)
      Lower score represents better outcome
      49.1 (23.0)
      n=33
      31.0 (17.9)
      n=33
      -18.1 (-25.5; -10.7)
      n=33
      43.4 (20.9)32.6 (19.8)-8.8 (-14.1; -3.6)<0.0010.041
      EQ-VAS (0-100)
      Higher score represents better outcome
      62.4 (17.0)72.2 (15.5)9.8 (4.7; 14.9)64.1 (14.9)69.5 (17.8)5.5 (0.9; 10.0)<0.0010.203
      High-intensity resistance training groups, n=68Non-intervention control group, n=69Effects
      BaselineFollow-upBaselineFollow-upTimeTime x Group
      Mean (SD)Mean (SD)MD (95% CI)Mean (SD)Mean (SD)MD (95% CI)P-valueP-value
      FSMC (20-100)
      Lower score represents better outcome
      77.3 (9.5)66.9 (13.5)-10.3 (-12.9; -7.7)72.0 (12.3)73.5 (12.6)1.5 (-0.6;3.6)<0.001<0.001
      Abbreviations: CI=Confidence Interval; EQ-VAS=Euroqol Visual Analogue Scale; FSMC=Fatigue Scale for Motor and Cognitive Function; FSS=fatigue severity scale; HADS=Hospital Anxiety and Depression Scale; MD=Mean Difference; MSIS-29=Multiple Sclerosis Impact Scale; OGQ=Occupational Gaps questionnaire; SD=standard deviation
      a Lower score represents better outcome
      b Higher score represents better outcome
      c n=33
      Fig. 2
      Fig. 2Mean Fatigue Scale for Motor and Cognitive Function (FSMC) scores and 95% confidence interval (CI) for combined high-intensity resistance training (HIRT) groups (n=68) and for the natural history cohort (n=69) at baseline and follow-up assessments.
      Fig. 3
      Fig. 3Baseline (T0) and follow-up (T1) results of ratings of perceived problems (no; slight; moderate; severe; extreme) on the 5-level EQ-5D version (EQ-5D-5L) in combined high-intensity resistance training (HIRT) groups.
      The median (interquartile range) time between last HIRT session and follow-up blood-sampling was 3 (2-10.5) days for group A, 6 (3-10) days for group B, and 5 (2-10) days for combined groups, n=63. As the change in FSMC was similar in both groups, results from the exploratory endpoint are reported from combined groups. Using a false discovery cut-off of 5% (PFDR <0.05) a significant up-regulation was found for 18 of 51 proteins, e.g., matrix metalloproteinase-1 (MMP-1), oncostatin-M (OSM) and vascular endothelial growth factor A (VEGF-A), in paired samples t-tests (Fig. 4). The multivariable linear regression model analyses showed that up-regulations in protein levels of TNF and Interleukin-17A (IL-17A) were significantly (PFDR <0.05) associated with improvement in FSMC (Fig. 4). Information on results in group A and B and exploratory analyses with significance cut-off of P=0.05 are presented in the supplementary information.
      Fig. 4
      Fig. 4[A] Mean differences and significance (P) from paired samples t tests comparing baseline and follow-up levels of inflammatory protein markers in all participants (n=63) after supervised high-intensity resistance training (HIRT) for 12 weeks. [B] Associations between change in plasma profile of immune markers and decrease in Fatigue Scale for Motor and Cognitive Functions (FSMC) after HIRT for 12 weeks in all participants (n=63). Figure [B] summarize the mean difference in protein markers and significance (P) for every ten-point decrease in FSMC from multivariable linear regression model analyses, which were adjusted for age, sex, and days between last HIRT session and follow-up sampling. The horizontal dashed line indicates an exploratory cut-off of P=0.05 and proteins highlighted with filled circles are direct false corrected (PFDR<0.05).

      4. Discussion

      This is, as far as we know, the first single-blind RCT specifically designed to assess effects of progressive resistance training on MS-related fatigue in fatigued PwMS. We found a significant and clinically relevant reduction in the primary endpoint fatigue in both our training groups as well as in comparison to the non-intervention control group. In addition, secondary endpoints on anxiety, depression and HRQL were significantly changed to the better over time in both training groups. We had hypothesised that HIRT twice a week would be superior to once a week. This was, however, only found in measures of anxiety (HADS) and HRQL (MSIS-29 psychological subscale), which favoured a higher exercise frequency.
      Exercise RCTs having fatigue both as an inclusion criteria and primary endpoint in PwMS are rare. What has been studied previously are the effects of vestibular rehabilitation (
      • Hebert J.R.
      • Corboy J.R.
      • Manago M.M.
      • Schenkman M.
      Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial.
      ), multidisciplinary rehabilitation (
      • Rietberg M.B.
      • van Wegen E.E.
      • Eyssen I.C.
      • Kwakkel G.
      Effects of multidisciplinary rehabilitation on chronic fatigue in multiple sclerosis: a randomized controlled trial.
      ), aerobic training (
      • Heine M.
      • Verschuren O.
      • Hoogervorst E.L.
      • van Munster E.
      • Hacking H.G.
      • Visser-Meily A.
      • Twisk J.W.
      • Beckerman H.
      • de Groot V.
      • Kwakkel G.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ) and telephone-or internet-delivered programmes to promote physical activity (
      • Flachenecker P.
      • Bures A.K.
      • Gawlik A.
      • Weiland A.C.
      • Kuld S.
      • Gusowski K.
      • Streber R.
      • Pfeifer K.
      • Tallner A.
      Efficacy of an internet-based program to promote physical activity and exercise after inpatient rehabilitation in persons with multiple sclerosis: a randomized, single-blind, controlled study.
      ;
      • Kratz A.L.
      • Atalla M.
      • Whibley D.
      • Myles A.
      • Thurston T.
      • Fritz N.E.
      Calling out MS fatigue: feasibility and preliminary effects of a pilot randomized telephone-delivered exercise intervention for multiple sclerosis fatigue.
      ;
      • Plow M.
      • Finlayson M.
      • Liu J.
      • Motl R.W.
      • Bethoux F.
      • Sattar A.
      Randomized controlled trial of a telephone-delivered physical activity and fatigue self-management interventions in adults with multiple sclerosis.
      ). Only three of these RCTs used a fatigue outcome for power calculation (
      • Heine M.
      • Verschuren O.
      • Hoogervorst E.L.
      • van Munster E.
      • Hacking H.G.
      • Visser-Meily A.
      • Twisk J.W.
      • Beckerman H.
      • de Groot V.
      • Kwakkel G.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ;
      • Plow M.
      • Finlayson M.
      • Liu J.
      • Motl R.W.
      • Bethoux F.
      • Sattar A.
      Randomized controlled trial of a telephone-delivered physical activity and fatigue self-management interventions in adults with multiple sclerosis.
      ;
      • Rietberg M.B.
      • van Wegen E.E.
      • Eyssen I.C.
      • Kwakkel G.
      Effects of multidisciplinary rehabilitation on chronic fatigue in multiple sclerosis: a randomized controlled trial.
      ). Whereas multidisciplinary rehabilitation did not show any effect (
      • Rietberg M.B.
      • van Wegen E.E.
      • Eyssen I.C.
      • Kwakkel G.
      Effects of multidisciplinary rehabilitation on chronic fatigue in multiple sclerosis: a randomized controlled trial.
      ), aerobic training (
      • Heine M.
      • Verschuren O.
      • Hoogervorst E.L.
      • van Munster E.
      • Hacking H.G.
      • Visser-Meily A.
      • Twisk J.W.
      • Beckerman H.
      • de Groot V.
      • Kwakkel G.
      Does aerobic training alleviate fatigue and improve societal participation in patients with multiple sclerosis? A randomized controlled trial.
      ) and a self-management programme targeting both fatigue and physical activity (
      • Plow M.
      • Finlayson M.
      • Liu J.
      • Motl R.W.
      • Bethoux F.
      • Sattar A.
      Randomized controlled trial of a telephone-delivered physical activity and fatigue self-management interventions in adults with multiple sclerosis.
      ) reported statistically significant reductions in self-reported fatigue compared to control. In contrast to our results, the change in fatigue after aerobic training was below the predefined cut-off for a clinically relevant change and for the self-management programme the effect size was similarly small. It cannot be deduced from current data if HIRT might be more effective in reducing fatigue than these other interventions and future studies are therefore needed to explore how fatigued PwMS respond to different types of interventions.
      In addition to only include fatigued PwMS in our study, the limitation raised by Heijne et al (
      • Heine M.
      • van de Port I.
      • Rietberg M.B.
      • van Wegen E.E.
      • Kwakkel G.
      Exercise therapy for fatigue in multiple sclerosis.
      ) was addressed by choosing only validated outcome measures as primary and secondary endpoints. As recommended, fatigue was assessed by FSMC and FSS (
      • Elbers R.G.
      • Rietberg M.B.
      • van Wegen E.E.
      • Verhoef J.
      • Kramer S.F.
      • Terwee C.B.
      • Kwakkel G.
      Self-report fatigue questionnaires in multiple sclerosis, Parkinson's disease and stroke: a systematic review of measurement properties.
      ;
      • Paul L.
      • Coote S.
      • Crosbie J.
      • Dixon D.
      • Hale L.
      • Holloway E.
      • McCrone P.
      • Miller L.
      • Saxton J.
      • Sincock C.
      • White L.
      Core outcome measures for exercise studies in people with multiple sclerosis: recommendations from a multidisciplinary consensus meeting.
      ). A change ≥ 0.45 points in FSS constitutes a clinically relevant change (
      • Rooney S.
      • McFadyen D.A.
      • Wood D.L.
      • Moffat D.F.
      • Paul P.L.
      Minimally important difference of the fatigue severity scale and modified fatigue impact scale in people with multiple sclerosis.
      ). Thus, the mean reduction of approximately 1 point in FSS in both HIRT groups was not only statistically significant but also clinically relevant. Although the changes over time in the MSIS-29 subscales were significant and exceeded proposed change scores for moderate to high sensitivity and specificity for improvement (8 on the physical subscale and 6 on the psychological) (
      • Widener G.L.
      • Allen D.D.
      Measurement characteristics and clinical utility of the 29-item Multiple Sclerosis Impact Scale.
      ), the changes were below reported values for smallest detectable change (18 and 21) (
      • Smedal T.
      • Johansen H.H.
      • Myhr K.M.
      • Strand L.I.
      Psychometric properties of a Norwegian version of Multiple Sclerosis Impact Scale (MSIS-29).
      ).
      As proposed by Dennet et al (
      • Dennett R.
      • Madsen L.T.
      • Connolly L.
      • Hosking J.
      • Dalgas U.
      • Freeman J.
      Adherence and drop-out in randomized controlled trials of exercise interventions in people with multiple sclerosis: a systematic review and meta-analyses.
      ) we report important information for determining feasibility for HIRT from a service delivery perspective. The overall session and content adherence was 70% and 73%, respectively, marginally lower than reported pooled adherence of 77% (range 31-100%) for resistance interventions in MS. The drop-out rate of 15.5% was less than we had expected, but in line with other exercise interventions (
      • Dennett R.
      • Madsen L.T.
      • Connolly L.
      • Hosking J.
      • Dalgas U.
      • Freeman J.
      Adherence and drop-out in randomized controlled trials of exercise interventions in people with multiple sclerosis: a systematic review and meta-analyses.
      ). That the sessions were supervised by a physiotherapist might have contributed to the few adverse events. The fact that once weekly HIRT displayed the same effect as twice weekly facilitates clinical implementation. Based on our findings, we propose that healthcare providers should supply supervised HIRT for fatigued PwMS.
      We found an up-regulation in several proteins after HIRT, e.g., MMP-1 and VEGF-A. These proteins are involved in muscle remodelling and angiogenesis, respectively, and have previously been found to increase in concentration in serum after resistance training in healthy men (
      • Ross M.D.
      • Wekesa A.L.
      • Phelan J.P.
      • Harrison M.
      Resistance exercise increases endothelial progenitor cells and angiogenic factors.
      ;
      • Urso M.L.
      • Pierce J.R.
      • Alemany J.A.
      • Harman E.A.
      • Nindl B.C.
      Effects of exercise training on the matrix metalloprotease response to acute exercise.
      ). Interestingly, TNF and IL-17A did not significantly change over time but were found to be significantly up-regulated and associated to a decrease in FSMC. This was surprising and contradicted findings from our pilot study (
      • Kierkegaard M.
      • Lundberg I.E.
      • Olsson T.
      • Johansson S.
      • Ygberg S.
      • Opava C.
      • Holmqvist L.W.
      • Piehl F.
      High-intensity resistance training in multiple sclerosis - an exploratory study of effects on immune markers in blood and cerebrospinal fluid, and on mood, fatigue, health-related quality of life, muscle strength, walking and cognition.
      ), that higher levels of TNF are associated with worse fatigue (
      • Heesen C.
      • Nawrath L.
      • Reich C.
      • Bauer N.
      • Schulz K.H.
      • Gold S.M.
      Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?.
      ). Conflicting results concerning change in TNF and IL-17 levels after exercise are reported in both PwMS (
      • Wong V.L.
      • Holahan M.R.
      A systematic review of aerobic and resistance exercise and inflammatory markers in people with multiple sclerosis.
      ) and healthy adults (
      • Calle M.C.
      • Fernandez M.L.
      Effects of resistance training on the inflammatory response.
      ). These findings can be explained by differences in time since last training session and degree of rest before sampling as these factors represents important confounders when interpreting inflammatory protein markers (
      • Calle M.C.
      • Fernandez M.L.
      Effects of resistance training on the inflammatory response.
      ;
      • Wong V.L.
      • Holahan M.R.
      A systematic review of aerobic and resistance exercise and inflammatory markers in people with multiple sclerosis.
      ). Nevertheless, the findings reported here represent a biological correlate of training intensity, in turn correlating with impact on the primary endpoint.
      This study had certain limitations. The study was conducted during the COVID-pandemic which to some degree affected the recruitment of study participants and their possibility to attend training sessions. Thus, the planned number of 45 participants in each HIRT group was not achieved, which potentially might have masked HIRT group differences. The fact that the non-intervention control group was not randomised restricts the validity of detected differences as compared with intervention groups. However, this choice was motivated by ethical aspects, also considering that randomisation to a control arm might lead persons to engage in voluntary physical activity. Sampling of plasma was not conducted at a set time period after last exercise session, which likely introduced a technical bias as changes in protein levels with physical activity displays dynamic temporal changes that are difficult to control for. Finally, most of the study participants had RRMS, an EDSS score ≤ 2.5 and were receiving highly potent monoclonal DMTs, which may impact on the generalizability of our findings to other MS populations.
      In conclusion, we demonstrate that participation in once or twice weekly HIRT is associated with a clinically relevant reduction in self-reported fatigue scores among fatigued PwMS, with relevant improvements also in other patient-reported outcomes. In addition, improved fatigue scores were associated with changes in inflammatory protein levels in plasma. These findings provide evidence for recommending HIRT for fatigued PwMS.

      5. Funding

      Research reported in this article was partly funded through NEURO Sweden with additional framework support from the Swedish MRC (grant no. 2020-0270) and the Region of Stockholm. The funding sources had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

      CRediT authorship contribution statement

      S. Englund: Software, Formal analysis, Investigation, Writing – original draft, Visualization. F. Piehl: Conceptualization, Methodology, Resources, Writing – original draft, Visualization, Funding acquisition. M. Kierkegaard: Conceptualization, Methodology, Software, Formal analysis, Resources, Writing – original draft, Visualization, Project administration, Funding acquisition.

      Declaration of competing interest

      Simon Englund declare that there is no conflict of interest; Fredrik Piehl received research grants from Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck and Roche. Marie Kierkegaard has received honoraria for lectures from Novartis, Sanofi, Genzyme and Roche. There is no commercial entity relevant for potential conflicts.

      Appendix. Supplementary materials

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