Multiple Sclerosis Journal - Experimental, Translational and Clinical最新文献

Background: To recover normal functions, remyelination in multiple sclerosis is crucial. Although endogenous remyelination occurs, it is often insufficient, and finding molecules promoting repair of demyelinated lesions is needed.

Objectives: To compare the remyelination potential of evobrutinib, an inhibitor of Bruton's tyrosine kinase and clemastine, an antagonist of M1 muscarinic acetylcholine receptor.

Methods: Remyelination was investigated in lysolecithin demyelinated organotypic mouse cerebellar slices and a transgenic Xenopus model of inducible-demyelination.

Results: Evobrutinib (100 nM) and clemastine (200 nM) potentiated remyelination of mouse cerebellar slices by a factor of 2.9 and 1.76, respectively. In conditionally demyelinated Xenopus, evobrutinib and clemastine increased remyelination by a factor of 1.61 and 1.92, respectively. Evobrutinib targets Bruton's tyrosine kinase expressed by microglia, and we showed that the increase in number of myeloid cells following demyelination is due to an extravasation from nearby vessels of macrophages migrating toward the optic nerve. In contrast, clemastine is expected to antagonize muscarinic receptor 1 expressing cells of the oligodendroglial lineage. We investigated a possible synergistic effect on remyelination by adding simultaneously both molecules. In both experimental models tested no significative improvement on remyelination of co-treatment with evobrutinib plus clemastine was observed.

Discussion: While evobrutinib increased 1.59 fold the number of microglia/macrophages, in the presence of clemastine the number of innate immune cells was decreased by 0.39 fold, therefore counteracting the beneficial effect of microglia/macrophages on remyelination.

Background: Multiple sclerosis (MS) is characterized by impairment of physical function that is often linked to neuromuscular and cardiovascular deficits. However, the specific contributions of muscle strength and aerobic capacity to physical function in MS are not fully understood.

Objective: This study aimed to investigate the independent roles of maximal muscle strength (MVC) and aerobic capacity (VO₂peak) on lower extremity physical function, as measured by the 6-minute walk test (6MWT) and five-time sit-to-stand test (5STS) in people with MS (pwMS).

Methods: In a cross-sectional study, 150 pwMS underwent assessment of VO₂peak, maximal voluntary contraction (MVC), and physical function (6MWT and 5STS). Regression analyses were conducted to explore the associations between physiological parameters and physical function.

Results: MVC and VO₂peak were moderately associated with (i.e., explained) 6MWT (R² = 0.40, p < 0.001), yet with VO₂peak (β = 7.9, std. β = 0.45, p < 0.001) having a preferential influence compared to MVC (β = 48.2, std. β = 0.26, p < 0.001). MVC and VO₂peak were weakly associated with (i.e., explained) 5STS (R² = 0.14, p < 0.001), yet with MVC (β = 0.06, std. β = 0.28, p = 0.004) having a preferential influence compared to VO₂peak (β = 0.00, std. β = 0.16, p = 0.101).

Conclusion: Both maximal muscle strength and aerobic capacity to physical function in pwMS. Maximal muscle strength was preferentially linked to performance in the 5STS test, whereas aerobic capacity was preferentially linked to performance in the 6MWT. These findings support the need for tailored exercise interventions to target specific physiological deficits during MS rehabilitation.

Objectives: To characterize patient-perceived fatigue by using the Finnish Multiple Sclerosis (MS) registry data.

Materials & methods: Fatigue was assessed with the Fatigue Severity Scale (FSS), the Fatigue Scale for Motor and Cognitive Functions (FSMC), and the Visual Analogue Scale-Fatigue. Disease severity was evaluated with the Expanded Disability Status Scale and symptoms with the Visual Analogue Scales. Patient reported outcomes (PROs) included the Multiple Sclerosis Neuropsychological Questionnaire, the Euro Quality of Life - 5 dimensions, the 15 D, and the Multiple Sclerosis Impact Scale. For the purposes of the study, patients were classified to those without (FSS ≤ 4) and those with (FSS ≥ 5) fatigue. The FSS scores were correlated with the results of other PROs.

Results: Based on the 512 FSS scores, 47% of the patients reported fatigue (FSS ≥ 5). Fatigue was related to higher disability, lower education, and smoking. FSS correlated significantly with other measures of fatigue, cognitive, and mood symptoms, and was associated with lower Quality of Life.

Conclusions: As an invisible and debilitating symptom fatigue should be evaluated systematically. In the screening, it is important to recognize the characteristics of the different scales. Whereas the FSS may serve as an overall screen, the FSMC may help to identify aspects of cognitive and motor fatigue separately.

Background: Recent studies support the need for early and intensive disease-modifying treatment (DMT) for patients with multiple sclerosis (PWMS). Abrupt DMT withdrawal may risk disease reactivation. Recent studies showed that MS disease activity was not rare after DMT withdrawal for PWMS aged >45/55 y. Immune reconstitution therapy (IRT) with cladribine tablets (CladT), may be an option for older PWMS who wish to stop DMT.

Objective: We retrospectively analysed PWMS aged >45 y who initiated CladT in 6 MS centers in Europe.

Results: One hundred and twenty nine PWMS (95 women/34 men, mean age 55.0 +/-7.5y initiated CladT; 83 (64.3%) previously received platform DMT, 35 (27.2%) previously received high efficacy DMT and 11 (8.5%) received CladT as a 1^st DMT due to a late onset of MS or to a delayed therapy decision. Mean follow-up was 2.4 y (1-5) on CladT. Only three patient experienced 4 relapses. The first one had 2 relapses after switching from fingolimod with a 2-month interval between treatments. The 2 remaining were naïve patients that had a relapse between the 2 courses of CladT.

Conclusion: Last/exit therapy with CladT seems to avoid MS disease reactivation in older PWMS and may be an interesting alternative solution to continue immunosuppression/immunomodulation.

Background: This scoping review aimed to identify existing information and gaps in knowledge regarding the diversity characteristics of the multiple sclerosis (MS) population in Canada.

Methods: We searched MEDLINE, EMBASE, Cumulated Index in Nursing and Allied Health Literature (CINAHL), SCOPUS and ProQuest's global dataset of theses and dissertations from 2010 to January 12, 2024. Data sources were case reports/series, cohort studies, case-control studies, analytical cross-sectional studies, randomized clinical trials, qualitative, mixed methods, participatory studies and systematic reviews conducted in Canada, published in English or French, that included participants with clinically isolated syndrome or MS. Sample characteristics were extracted applying Cochrane's PROGRESS-Plus framework.

Results: We included 259 studies, most often studying disease-modifying therapy (24.3%) and access to care (20.9%). Among primary data collection studies 40% used one recruitment strategy, usually MS Clinics and MS Canada. Age (92.7%) and sex (86.9%) were reported most often, ≤10% of studies reported race or ethnicity; religion, sexual orientation and language were not reported.

Conclusions: We lack an understanding of characteristics of people living with MS in Canada relevant to health equity. Existing research has been insufficiently inclusive. Better reporting of diversity characteristics is needed, along with specific efforts to recruit and retain more diverse samples.

Background: Impact of changing diagnostic criteria for the population-based incidence of multiple sclerosis (MS) has not been investigated.

Objective: To assess the effect of changing diagnostic criteria on national MS incidence and prevalence in Finland from 1974 to 2021.

Methods: We identified patients with MS (pwMS) through the National MS registry and the national Care Register for Healthcare and divided them into four groups based on the year of MS diagnosis: 1) Schumacher criteria (1974-1982), 2) Poser criteria (1983-2000), 3) Earlier McDonald criteria (2001-2016), and 4) Current McDonald criteria (2017-2021). Age-adjusted incidence and prevalence were calculated.

Results: Age-adjusted incidence per 10⁵ person years increased from 3.7 (95% CI 3.5-3.8) during the Schumacher criteria period to 9.2 (95% CI 9.0-9.4) during the earlier McDonald criteria. During the Current McDonald criteria incidence stabilized to 8.6 (95% CI 8.3-9.0). Prevalence increased from 24.3 (95% CI 22.8-25.8) to 241.5 (95% CI 237.3-245.6) per 10⁵ person years.

Conclusion: Both incidence and prevalence of MS increased significantly. Incidence showed a sharp increase when entering the twenty-first century, after which it stabilized. Increasing incidence was likely related to incorporation of MRI in the diagnostic criteria. Current diagnostic criteria did not further increase the incidence.

Objective: To determine the efficacy of a safety program designed for monitoring infusion disease-modifying therapies (DMTs) prescribed for multiple sclerosis (MS).

Background: Infusion-based high-efficacy DMTs represent a major advance in the treatment of MS. However, safe administration requires close monitoring. Non-adherence to safety monitoring can lead to DMT-related complications.

Methods: A safety nurse navigator reviewed charts for infusion DMT patients from November 2020 to December 2022, and contacted them to address incomplete safety monitoring. Patients were screened for the primary outcome of incomplete safe infusion, including outdated safety labs, imaging, and/or recent follow-up with their neurologist. Logistic regression was performed for predictors of incomplete safety monitoring and of successful safety intervention.

Results: Three hundred and forty-three patients were on infusible DMTs over the study time period: 75 natalizumab, 31 rituximab, and 237 ocrelizumab. Two hundred and eighty-six (83%) patients did not meet the criteria for safe infusion; 64% lacked safety labs, 47% prescriber follow-up, and 26% an MRI. The nurse succeeded in 82% of interactions. B-cell depletion was linked to outdated lab monitoring, whereas natalizumab use was associated with outdated appointments and imaging.

Conclusions: This safety initiative identified gaps for managing infusion-based MS DMTs. Our safety nurse navigator successfully identified incomplete safety monitoring and intervened to avoid drug-related complications.

Background: Persistence to B cell depleting therapies (BCDT) like ocrelizumab and rituximab may be higher compared with other disease-modifying therapies (DMT) in multiple sclerosis (MS). Clinical trials directly comparing these treatments are lacking.

Objective: To compare the risk of treatment discontinuation, relapse, and confirmed disability worsening in patients starting BCDT vs other DMT within real-world settings.

Methods: In a longitudinal cohort study, patients with relapsing MS starting BCDT (ocrelizumab/rituximab, n = 269) after enrolment into the Swiss MS Cohort (SMSC) were evaluated for treatment discontinuation, occurrence of relapses, and disability worsening in comparison with platform (n = 57) and oral (n = 454) DMT, or natalizumab (n = 73) using Cox regression with double robust adjustment for baseline covariates.

Results: Patients starting BCDT were less likely to discontinue treatment than all other DMT combined (HR = 0.26, 95% CI = 0.18-0.36, p < .01), oral DMT (HR = 0.28, 95% CI = 0.20-0.39, p < .01) and natalizumab (HR = 0.35, 95% CI = 0.21-0.58, p < .01). BCDT were associated with lower risk of relapses as compared to oral DMT HR = 0.59, 95% CI = 0.39-0.88, p < .01), but not to natalizumab (HR = 0.90, 95% CI = 0.45-1.82, p = .778). Disability worsening was not significantly different between treatment groups.

Conclusion: We provide real-world evidence for patients being more persistent to BCDT than to other treatments, and better clinical outcomes may partly explain this.

Introduction: Fatigue is a highly prevalent symptom in people with multiple sclerosis. It demands careful assessment and prompt intervention to improve their quality of life and overall burden of disease. This scoping review aims to provide a comprehensive synthesis and update of the existing evidence on the effectiveness of different pharmacological and nonpharmacological interventions for multiple sclerosis (MS)-related fatigue.

Methods: To ensure the transparency and quality of the articles chosen for this scoping review, the Preferred Reporting Items for Systematic Reviews and Meta-analysis Protocols extension for Scoping Reviews was used. Exclusively randomized controlled trials published between 2016 and 2023 were included.

Results: Twenty-eight articles were analyzed. We found that pharmacological interventions are few and have included the use of Amantadine, Ondansetron, Methylphenidate, and Modafinil, with little effects on fatigue. Nonpharmacological interventions are diverse and include cognitive behavioral therapy, guided imagery, phototherapy, exercise, brain stimulation, and lavender administration with evidence of a statistically significant decrease in fatigue.

Conclusions and discussion: Current evidence on the effectiveness of pharmacological and nonpharmacological interventions is inconclusive. Lack of knowledge of the pathophysiology of fatigue limits its prevention, control, and management recommendations. A comprehensive and interdisciplinary approach is required to manage this symptom in patients with MS.

Background: Comorbidities in people with multiple sclerosis (PwMS) can affect disease course and quality of life.

Objectives: To investigate comorbidities in the five years after diagnosis, timing of comorbidity occurrence, age and sex effects, and differences between multiple sclerosis (MS) and other chronic autoimmune diseases (AIDs).

Methods: In this retrospective cohort study, we systematically assessed differences in diagnosis frequencies in newly diagnosed PwMS (n = 9,880) compared to matched controls (noAID, n = 29,640) and individuals with other AIDs (psoriasis, n = 29,640; Crohn's disease, n = 9,880).

Results: Some comorbidities of PwMS are similarly frequent in other AIDs, while others, such as depression, are more prevalent in PwMS (odds ratio (OR) vs noAID = 2.03(1.94-2.13)). We found that personality disorders are more frequently recorded in PwMS before (OR  = 1.34(1.21-1.49)) and after MS diagnosis (OR  = 1.32(1.16-1.5)), especially in women (OR  = 1.39(1.2-1.6)). PwMS are more frequently diagnosed with Lyme disease (OR  = 1.98(1.69-2.33)), which was predominantly recorded by general practitioners after presentation with neurological symptoms. We observed lower acute tonsillitis frequencies in PwMS (OR  = 0.8(0.75-0.85)).

Conclusions: Our results suggest that PwMS might have a generally increased risk for specific personality disorders. More frequent Lyme disease recordings for PwMS suggest misdiagnoses of MS symptoms. Lower tonsillitis frequencies suggest a link between MS and protection from specific infections.