Multiple sclerosis (MS) is a chronic immune-mediated disease. Persons with MS (pwMS) are likely to experience complex disabilities, including a decline in physical and cognitive function, as well as progressive depression and fatigue (1). A growing body of literature confirms positive effects of regular physical activity and exercise on disease-specific symptoms of MS (2–4). Recently, a comprehensive non-systematic review summarised the role of physical activity and exercise as tertiary (i.e., reducing symptoms appearance), secondary (i.e., provoking disease-modification), and even primary (i.e., reducing the risk of developing MS) prevention method of MS (5). The authors introduced a theory-based model that shows physical activity to reduce inflammatory disease activity and progression in pwMS (exercise-induced postponement theory). This theoretical framework is subject by preclinical animal models showing adaptations at the cellular level, such as attenuation of cellular infiltration and inhibition of pro-inflammatory mediators in the central nervous system (6, 7). Although an increasing number of exercise intervention studies focuses on the effects of acute physical activity on symptoms such as fatigue and cognition or motor impairments in pwMS only a few investigations with heterogeneous study quality have been conducted so far assessing disease-modifying effects (8). Even less is known about the disease-modifying effects of regular lifestyle physical activity, which also covers unplanned and unstructured physical movements in daily life (5, 9).

With this background, the objective of the current study was to investigate a potential relation between physical activity and disease severity, fatigue and relapse rate in persons with relapsing remitting multiple sclerosis (RRMS).

This cross-sectional study was approved by the ethics committee of the German Sport University Cologne (028/2019), registered in the German Clinical Trials Register (DRKS00016624) and was performed according to the latest Declaration of Helsinki. All participants provided written informed consent, and data was collected anonymized.

Assessing the relation between physical activity and disease severity, relapse rate and fatigue in pwMS, this study confirms negative relationship between a self-reported physical activity level, disability severity and fatigue. In addition, multiple regression analyses explain 12.6% and 5.2% of the variances in PDDS and FSMC scores, respectively. When all theoretical predictors of disease progression were considered and depending on the measured outcome, MS duration, gender, and BMI were significant whereas current physical activity was the most consistent. It is displayed that increased current physical activity is related with lower disability severity and fatigue. In this regard, our data confirm the proposed exercise-induced postponement theory by Dalgas et al. (4). This is in line with results from most cross-sectional (23–26) and longitudinal (27, 28) studies that investigate the relationship between physical activity level and disease progression expressed by symptom exacerbations such as fatigue, or neurological and motor impairment.

On the contrary, our findings do not support a correlation between physical activity and the annualised relapse rate. The rate of relapses represents a common measure to quantify inflammatory disease activity in MS clinical trials (27). In line with our results, Tallner et al., report inconsistent results regarding the relationship between physical activity and the relapse rate (28). Groups categorised according to their physical activity level did not differ significantly for annualised relapse rate. Yet, when these variables were considered in a correlation, a significant inverse relationship emerged (28). It is worth mentioning that the disease duration was not considered in the analyses. However, it is an important parameter as the accuracy of the relapse rate as a prognostic factor has been discussed, especially for long-term disability (20, 27). As the number of relapses decreases over time, its rate seems to be most reliable in the first years of the disease (20). Thus, the results presented by Tallner et al., might not represent the full potentials of physical activity (28). In our investigation, we analysed the relapse rate only for those patients who reported a disease duration of a maximum of 10 years at the time of study participation. We could not compute the relapse rate for patients diagnosed within the last 2 years as it led to an overestimation of their relapse rate. However, the relapse rate might be a more sensible prognostic value for this patient group.

This study has limitations that need to be taken into account when interpreting the results. First, data is restricted to self-reported outcomes, also including disability-scale and number of relapses. Patients with MS might not be aware of their total number of relapses. Future studies might assess both factors using objective measurements such as radiological diagnostic via MRI examination. Furthermore pwMS probably misjudge their level of disability. The PDDS may not be detailed enough and could be supplemented with accelerometer data.

Second, a selection bias may have potentially affected the study sample, as study participants are characterized as highly educates and suffer from a rather benign disease course, which may have impacted the study’s results. Third, the results of our study cannot explain the direction of the relationship between current physical activity level and disease activity or progression. It seems logical that pwMS with a pronounced disability status or fatigue are less capable and/or motivated to perform long-lasting or intense physical activity. Therefore we recalculated the correlation with including only ambulatory pwMS (i.e., PDDS 0-2). After changing the including criteria there is no significant inverse correlation between PDDS (0-2) and GLTEQ-HCT (p = 0.12). This confirms that pwMS with a physical impairment are less physical active justified by their impairment itself. The disability is therefore the conditioning factor for physical activity. The most important point could be the subjective perception. Physical activity is often connected to exercise including endurance training (running/walking) or weight training. Physical movements where the heartbeat rises are often not perceived as physical activity or exercise, rather than everyday movement. Probably it needs more enlightenment in relation to physical activity and sports exercise. Nevertheless we believe it is important to establish studies that consider the individual subjective perception related to physical activity and the individual physical possibilities in pwMS. In terms of fatigue, excluding pwMS with a PDDS 3-8 seems not to have an impact on GLTEQ-HCT. There is still a significant inverse correlation between the physical activity level and fatigue (p = 0.008). More longitudinal and interventional studies remain essential to conclude whether changes in physical activity behaviour provoke changes in disease activity and/or progression. Additionally, mechanistically supported investigations can deepen the knowledge concerning the causality within these relationships. Furthermore a prospective randomized and controlled trial should be carried out over the time comparing those who undergo physical activity in the placebo group.

Finally, the restriction imposed by the COVID-19 pandemic might potentially have influenced participants´ physical activity assessment. Especially at the beginning of the COVID-19 pandemic, there was a major uncertainty about dealing with the disease. To analyze the effect in self-reported physical activity levels between pwMS recruited before versus after March 2020, where the first Covid-related lockdown in Germany took place. There is no significant difference in the self-reported physical activity level between pwMS who conducted the survey before the Corona-related lockdown in Germany in March 2020 and pwMS who conducted the survey after March 2020 (unpaired t-test: p = 0.485). The corona-pandemic situation seems not to have an impact on the physical activity levels in pwMS during the first months of the government ordered lockdown.

Our results suggest that self-reported physical activity is related to disease severity and fatigue in pwMS. However, self-reported physical activity does not significantly affect the annualised relapse rate. By excluding non-ambulatory pwMS there is no significant relation between physical activity level and disease severity. The physical disability could be the conditioning factor for self-reported physical activity. To assess whether changes in physical activity behaviour lead to changes in disease activity, more high evidence quality interventional studies are needed.

The datasets presented in this study can be found in online repositories: https://github.com/MaritSchlagheck/MS-survey. Any further enquiries can be directed to the corresponding author.

MLS: conceptualization, methodology, formal analysis, writing - original draft. SH: methodology, writing - original draft. NJ, DW, AR, and FW: conceptualization, methodology, writing - review & editing. JB: conceptualization, resources, writing - review & editing. CW: conceptualization, writing - review & editing. PZ: conceptualization, methodology, supervision, writing - review & editing. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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