Highlighting Progress, Addressing Unmet Needs in MS Rehabilitation Trials

The closing day of the Americas Committee for Research and Treatment in Multiple Sclerosis (ACTRIMS) Forum 2024 featured multiple presentations on current data regarding rehabilitation efforts in multiple sclerosis (MS) and future directions in this area, also highlighting challenges in advancing such research.

Lara Pilutti, PhD, associate professor in the Interdisciplinary School of Health Sciences at the University of Ottawa, overviewed the concept of exercise as a form of therapy in MS; and Robert Motl, PhD, professor in the department of kinesiology and nutrition at the University of Illinois at Chicago, surveyed the unmet needs and barriers in MS rehabilitation clinical trials.

Breaking Barriers in MS ACTRIMS Forum 2024 | image credit: forum.actrims.org

Prescribing Exercise: A Promising Therapy in MS?

Pilutti’s discussion on the role of exercise in MS therapeutics reviewed data from tertiary intervention efforts to manage MS symptoms, the influence of secondary interventions on disability progression, and then primary interventions and associated risks for developing MS.

Data on the effects of exercise in MS symptom management and rehabilitation were gathered from systematic reviews and meta-analyses that span the last 30 years. Throughout these studies, the most beneficial and consistent outcomes related to disease management included improvements in depressive symptoms¹, fatigue², and lower-body mobility.³ Additionally, Pilutti et al's analysis found that there were not as many studies reporting on effects related to anxiety, pain, upper body mobility, or cognition.

“So it's not that there may not be potential for benefits in terms of exercise training on these outcomes, but rather, these have been much less studied, they have often not been the primary outcome of interest when we are looking at exercise interventions, and often patients haven't been selected with these symptoms in mind,” Pilutti explained.

Over the last 5-10 years, Pilutti continues, research has shifted focus more primarily to understanding the potential impact of exercise on disease activity and progression, as well as MRI outcomes. She cited a 2023 systematic review and meta-analysis that evaluated 40 randomized controlled trials (RTCs) from the last year. These RTCs included exercise cohorts and compared them to non-exercise control cohorts, finding that there was no significant difference in relapse risk between groups (P = .82).⁴ Regarding disability markers, Pilutti points to another review that summarized results from 13 RTCs or control trials that measured the influence of exercise on Expanded Disability Status Scale (EDSS) or the Multiple Sclerosis Functional Composite (MSFC). These results did not show any EDSS score changes; however, MSFC scores were seen to improve in participants.⁵

Imaging outcomes, however, have not produced coherent conclusions. High degrees of variability in imaging results suggest potential benefits but ultimately the lack of clarity in whole-brain volumetrics and lesion outcomes led Pilutti to argue that there is a need for exploring different imaging outcomes.⁶

Touching on the role of primary prevention, Pilutti referred to additional studies containing large cohorts that utilize registry-based data on aerobic capacity and physical fitness. These factors were explored for any associations with MS risk and reviewed the risk throughout adolescence and early adulthood. In these studies, vigorous physical activity correlated with reduced risk for MS (OR = 0.74, P = < .001)⁷, as did higher degrees of aerobic fitness (relapse risk [RR] = 0.69, P = .003)⁸.

Pilutti concluded by sharing recent “prescribed” exercise guidelines that, in accordance with decades of evidence on the benefits of exercise in MS management, were published in 2020.⁹ With the availability of these guidelines for the benefit of patients with MS, Pilutti also called attention to the limited scope of studies that investigate the influence of exercise to modify MS. While there is potential, she reemphasized the need to rethink about the outcomes investigators are exploring in this area.

Unmet Needs in Rehabilitation Clinical

To bring the session to a close, Motl took the stage to focus on issues in the field that affect the application and translation of knowledge, negatively impact individuals in need of rehabilitation interventions, and undermine the value of the field. To discuss these issues, Motl identified 7 key problems in MS research: poor quality of RTCs, choice of interventions, end-points and sample targets, outcome heterogeneity, compliance and adherence concerns, mechanism identification in experimental medicine, and factors such as race, ethnicity, and aging.

Regarding the quality of RTCs in MS, Motl said that “feasibility studies have to be done first . . . to know if and how an intervention can be undertaken in a target population.” He went on to identify 4 key metrics for successful feasibility studies. These metrics include the feasibility of factors such as successful recruitment rates, knowledge about one’s resources such as retention rates and eligibility, management of components such as site capacity and monetary costs, as well as scientific factors such as safety, burden of data collection, outcome selection, and more.

“I get the feeling oftentimes that we design trials and we throw as many possible outcome measures as we can at our participants. And it creates quite a burden on our participants," Motl said. "And sometimes that creates this position where we ultimately receive garbage data from our participants.”

Motl then discussed the importance of discovery models that inform researchers’ choices of interventions. By curating a targeted approach to the design of a study, ultimately more effective and focused trials can be created.

Studying focal end-points and targeted populations is a frustrating problem from Motl’s perspective. “I talked about this regularly, and people are dismayed by this, but oftentimes, our researchers don't focus on an outcome of interest.”

He encourages researchers pay attention to the relevancy of their outcomes and their chosen participants. Failure to do so will lead to anticlimactic, stifled results. “How do you improve cognition and someone who has high level cognitive function? You don't. How do you improve fatigue in a population of individuals who don't have fatigue? You don't.”

Heterogeneity should also be considered in any rehabilitation trial. Motl posited that heterogeneity, where some patients may demonstrate improvement, stagnation, or worsened outcomes, is predictable and explainable. “That matters because we can move beyond our current approach, which is we give all people 1 type of clinical rehabilitation and expect them all to have the same effect when they really don't.”

Issues with compliance and adherence reporting can drastically impact rehabilitation trials’ validity, especially in the context of, for example, an exercise training program in MS. Motl highlighted how the knowledge on what exactly to prescribe patients is severely altered when there isn’t transparency on who stuck with the study or who was doing what.

Motl then moved on to analyze what an experimental medicine model can offer for rehabilitation trials. Ultimately, the model he pointed to argues for a transition away from models of efficacy In favor of identifying bodily systems that could serve as mechanisms to explain outcomes. Motl noted, “once we can validate that these mechanisms are explaining outcomes, then we can begin to understand whether or not our interventions can change these mechanisms, and ultimately design these full-stage trials where mechanisms become part of the specific aims of the research, where we've looked at whether or not our interventions work, and by studying the specific mechanisms at play.”¹⁰

Lastly, Motl turned his attention to racial, ethnic, and age factors, pointing to the fact that “the face of MS” is changing as it is becoming more common in older adults and affecting various racial and ethnic groups at understudied rates. He points to the lack of racial and ethnic data reported in many trials, the prevalence of White participants in studies that do report these demographics, and the amount of studies reporting on young and middle-aged patients. This contributes to a problematic lack of knowledge in clinical rehabilitation in non-White groups and elderly populations.

“These are things that, if we can change the focus, we can put people with MS at the center for optimizing quality of life and promoting full participation and rehabilitation of outcomes,” Motl concluded.

References

1. Ensari I, Motl RW, Pilutti LA. Exercise training improves depressive symptoms in people with multiple sclerosis: results of a meta-analysis. J Psychosom Res. 2014;76(6):465-71. doi:10.1016/j.jpsychores.2014.03.014

2. Torres-Costoso A, Martínez-Vizcaíno V, Reina-Gutiérrez S, et al. Effect of exercise on fatigue in multiple sclerosis: A network meta-analysis comparing different types of exercise. Arch Phys Med Rehabil. 2022;103(5):970-987.e18. doi:10.1016/j.apmr.2021.08.008

3. Paltamaa J, Sjögren T, Peurala SH, Heinonen A. Effects of physiotherapy interventions on balance in multiple sclerosis: a systematic review and meta-analysis of randomized controlled trials. J Rehabil Med. 2012;44(10):811-23. doi:10.2340/16501977-1047

4. Learmonth YC, Herring MP, Russell DI, et al. Safety of exercise training in multiple sclerosis: An updated systematic review and meta-analysis. Mult Scler. 2023;29(13):1604-1631. doi:10.1177/13524585231204459

5. Proschinger S, Kuhwand P, Rademacher A, et al. Fitness, physical activity, and exercise in multiple sclerosis: a systematic review on current evidence for interactions with disease activity and progression. J Neurol. 2022;269(6):2922-2940. doi:10.1007/s00415-021-10935-6

6. Sandroff BM, Rafizadeh CM, Motl RW. Neuroimaging technology in exercise neurorehabilitation research in persons with MS: A scoping review. Sensors (Basel). 2023;23(9):4530. doi:10.3390/s23094530

7. Wesnes K, Myhr KM, Riise T, et al. Physical activity is associated with a decreased multiple sclerosis risk: The EnvIMS study. Mult Scler. 2018;24(2):150-157. doi:10.1177/1352458517694088

8. Cortese M, Riise T, Bjørnevik K, Myhr KM, et al. Body size and physical exercise, and the risk of multiple sclerosis. Mult Scler. 2018;24(3):270-278. doi:10.1177/1352458517699289

9. Kalb R, Brown TR, Coote S, et al. Exercise and lifestyle physical activity recommendations for people with multiple sclerosis throughout the disease course. Mult Scler. 2020;26(12):1459-1469. doi:10.1177/1352458520915629

10. Riddle M; Science of Behavior Change Working Group. News from the NIH: using an experimental medicine approach to facilitate translational research. Transl Behav Med. 2015;5(4):486-8. doi: 10.1007/s13142-015-0333-0