Predictors and treatment of fatigue in multiple sclerosis

Fatigue is a self-reported symptom, often described as an extreme lack of energy, which is common across many medical conditions. In multiple sclerosis (MS), it is frequently reported as the most prevalent and debilitating symptom, with significant impact on quality of life and daily functioning. Underlying causes of fatigue in MS are still elusive, which impedes development of effective therapeutic strategies. The objectives of my thesis were to investigate associations between fatigue among people with MS and a range of demographic and disease-related measures, as well as to explore potential effects of symptomatic pharmaceutical and non-pharmaceutical interventions. To this end, we conducted three nationwide cohort studies using data from the Swedish MS Register and other national registers, as well as a smaller randomized controlled trial (RCT) evaluating the effect of resistance training.

Study I was a register-based, cross-sectional study to assess the association between fatigue and a range of demographic and disease-related measures. We included 3,179 Fatigue Scale for Motor and Cognitive Functions (FSMC) scores obtained from 2,165 individuals with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) between 2012 and 2018, all of which were or had been undergoing disease-modifying therapy (DMT) for MS. Of these, 40.7% reported no or low fatigue, 12.7% mild, 14.0% moderate, and 32% severe fatigue. Expanded Disability Status Scale (EDSS) score and information processing speed, measured with Symbol Digit Modalities Test (SDMT), were the only objective MS- related measures displaying a clinically meaningful differences across fatigue severity levels; FSMC scores were 17.6 points higher with severe (EDSS ≥6) vs mild disability (EDSS 0-2.5; 95% CI: 13.1-22.2), and 10.7 points higher in the lowest vs highest SDMT quartiles (95% CI: 8.0-13.4), respectively. However, self- reported impact of MS and quality of life showed even greater differences across fatigue severity levels. Additionally, fatigue severity was associated with work loss, psychiatric comorbidities, and treatments for depression, anxiety, and fatigue-related symptoms.

Study II was a register-based cohort study in which we identified and compared fatigue and disability trajectories, measured with FSMS and EDSS, respectively, in individuals with RRMS. Additionally, we investigated associations between potential predictors of fatigue and the identified fatigue trajectories. We included 1,587 individuals followed for a mean (SD) of 7.1 (2.2) years from initiation of a first DMT (first DMT cohort), and 1,818 people with MS followed for a mean (SD) of 7.3 (1.9) years from initiation of a second DMT (DMT switch cohort). Using group-based trajectory modeling, we identified five fatigue trajectories in the first DMT cohort, and six in the DMT switch cohort. All fatigue trajectories displayed stable trends over time, except for one trajectory (20.1% of participants, moderate fatigue at treatment initiation) of the first DMT cohort, who reported an 11.5-point increase in FSMC during follow-up. A strong association was observed between fatigue and disability trajectories in both cohorts. Apart from fatigue severity at DMT initiation, few other covariates independently predicted membership in the higher stable or increasing fatigue trajectories.

Study III was a two-armed RCT exploring the effect of group-based high- intensity resistance training (HIRT) for 12 weeks, supervised by a physiotherapist, in people with MS reporting at least moderate fatigue. Seventy-one participants were randomized 1:1 to HIRT once or twice a week, with an additional 69 individuals with similar characteristics serving as an uncontrolled, non- intervention control group. Based on intention-to-treat, mean changes in FSMC scores were -9.8 (95% CI: - 13.2 to -6.3) and -10.9 (95% CI: - 14.8 to -6.9) in the once and twice weekly HIRT groups, respectively, indicating clinically relevant improvements, but with no significant difference between the two groups. Corresponding values for the combined HIRT group and the non-intervention control group were -10.3 (95% CI: - 12.9 to -7.7) and 1.5 (95% CI: - 0.6 to 3.6), respectively.

Study IV was a register-based cohort study to explore the use of central stimulants and amantadine as symptomatic off-label treatments for fatigue in MS, and to evaluate their impact on work loss. We identified 29,257 people with MS through the Swedish MS and National Patient Registers. To assess annual prescription rates, we created yearly cohorts of individuals alive and residing in Sweden from January to December of each year between 2006 and 2023. For additional analyses, we included 2,162 new modafinil users, 462 new amantadine users, and 424 new users of attention deficit hyperactivity disorder (ADHD) drugs, who were followed for 12 months before and 24 months after their first filled prescription (index date). We also identified a cohort of 9,762 individuals with no prior fatigue treatment, using risk-set sampling, matched on first modafinil start. Modafinil was the most prescribed treatment, with an annual prevalence of 8.5% in 2006 and 7% in 2023. All cohorts showed increasing work loss in the year preceding the index date, followed by no change in work loss rates during the subsequent 24 months. Modafinil users demonstrated a significantly greater reduction in the trajectory of average monthly work loss compared to the untreated cohort (-0.17 days; 95% CI: - 0.22 to -0.12). No significant differences were observed between the modafinil group and the other treated cohorts.

In conclusion, fatigue in MS is associated with greater disability and slower cognitive processing speed, while other MS-related characteristics show weak or no associations. Fatigue severity remains relatively stable in the years following both the first and second initiation of DMT, except for a clinically meaningful increase among a minority with moderate fatigue at first DMT start. Moreover, HIRT is associated with clinically meaningful reductions in fatigue among fatigued individuals with MS, although a definitive causal relationship could not be established due to the lack of a randomized non-intervention control group. Over the past two decades in Sweden, modafinil has been the most commonly prescribed off-label pharmacological treatment for fatigue in MS. Modafinil and other stimulants may help mitigate the progression of work loss in people with MS, although no single treatment appears to be superior in effectiveness.

List of scientific papers

I. Predictors of patient-reported fatigue symptom severity in a nationwide multiple sclerosis cohort. Simon Englund, Marie Kierkegaard, Joachim Burman, Katharina Fink, Anna Fogdell-Hahn, Martin Gunnarsson, Jan Hillert, Annette Langer- Gould, Jan Lycke, Petra Nilsson, Jonatan Salzer, Anders Svenningsson, Johan Mellergård, Tomas Olsson, Elisa Longinetti, Thomas Frisell, Fredrik Piehl. Mult Scler Relat Disord. 2023;70:104481. https://doi.org/10.1016/j.msard.2022.104481

II. Trajectories of self-reported fatigue following initiation of multiple sclerosis disease-modifying therapy. Simon Englund, Thomas Frisell, Ying Qu, Kavita Gandhi, Annika Hultén, Marie Kierkegaard, Fredrik Piehl, Elisa Longinetti. J Neurol Neurosurg Psychiatry. 2024;95:1012-1020. https://doi.org/10.1136/jnnp-2024-333595

III. High-intensity resistance training in people with multiple sclerosis experiencing fatigue: A randomised controlled trial. Simon Englund, Fredrik Piehl, Marie Kierkegaard. Mult Scler Relat Disord. 2022;68:104106. https://doi.org/10.1016/j.msard.2022.104106

IV. Use of symptomatic drug treatment for fatigue in multiple sclerosis and its impact on work loss: a register-based Swedish cohort study. Simon Englund, Johan Reutfors, Thomas Frisell, Fredrik Piehl. [Manuscript]