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

Background: Trials of disease-modifying therapies (DMTs) for multiple sclerosis (MS) often include patients with minimal disability. Patient-reported outcome instruments used in these trials have often not captured physical and psychological treatment effects concomitant with observed clinical benefits.

Objective: To examine whether the Multiple Sclerosis Impact Scale-29 (MSIS-29) captures changes in the impact of MS in a sample of patients enrolled in the Phase 3 ASCLEPIOS studies (ofatumumab vs. teriflunomide).

Methods: Measurement properties (i.e. item fit, reliability, and targeting) of the MSIS-29 were analyzed using Rasch measurement theory (RMT) in data from two phase 3 ofatumumab clinical trials including patients with relapsing-remitting or secondary progressive MS (N = 1882). Targeting of the MSIS-29 items to the patient population was explored within groups categorized by Expanded Disability Status Scale (EDSS) scores.

Results: Under RMT analyses, both the Physical and Psychological Impact scales of the MSIS-29 were not appropriately targeted to the overall sample of patients. In particular, 49% and 30% of patients with an EDSS score ≤ 2.5 had fewer physical and psychological impacts, respectively, than would typically be captured by these MSIS-29 items compared to patients with EDSS scores of ≥ 3.

Conclusion: The MSIS-29 is commonly used to evaluate the patient-reported physical and psychological impact of MS. However, it may be limited in evaluating changes associated with DMTs in patients with minimal disability.

Background: Although upper respiratory infections (URIs) are linked to multiple sclerosis (MS) attacks, SARS-COV2 has not been compared to URIs for attack rates.

Objectives: This study aimed to evaluate the attack rate and the results of neuroimaging in MS patients with URIs caused by COVID-19 and non-COVID-19 infections (NC-URI).

Methods: From May 2020 to April 2021, we followed 362 patients with relapsing-remitting MS in a prospective cohort design. Patients were monitored regularly every 12 weeks; an magnetic resonance imaging (MRI) scan was performed at enrollment and every time a relapse occurred. Poisson analysis was used to determine exacerbation rate ratios (RR) and the MRI parameters were tested using chi-square analysis.

Results: 347 patients with an average age of 38 and a female ratio of 86% were included. A RR of 2.24 (p < 0.001) was observed for exacerbations during the at-risk period (ARP). Attacks related to COVID-19 (RR = 2.13, p = 0.001) and NC-URIs (RR = 2.39, p < 0.001) were comparable regarding the increased risk of exacerbation (p = 0.62). Exacerbations within or outside the ARP did not significantly alter the number of baseline GAD-enhancing lesions (p > 0.05 for both).

Conclusion: COVID-19 has been shown to increase the risk of MS exacerbations, like other viral URIs.

Introduction: Gait impairment is common in multiple sclerosis (MS), but difficult to evaluate in clinical practice. In this proof-of-concept observational study, we compared walking ability recorded by Google Maps Timeline to conventional clinical measures in people with MS.

Methods: We used open-access Google Maps Timeline to record the total number of days with walking activity, walking distance, walking time, and walking speed. Each Google Maps Timeline variable was included in a different stepwise linear regression model including all conventional clinical variables.

Results: We included nine people with MS (age 43.1 ± 6.6 years; females 55.6%; disease duration 12.7 ± 3.1 years; median Expanded Disability Status Scale 3.0 (range 1.0-5.5)). Higher percentage of days with recorded walking was associated with lower Fatigue Severity Scale (p = 0.01), and higher MS Walking Scale (p = 0.04). Longer average daily walking distance was associated with shorter Timed-25 Foot Walking Test (p = 0.02), lower Expanded Disability Status Scale (p = 0.01), and higher Euro-Quality of Life (p = 0.04). Longer average daily walking time was associated with shorter Timed-25 Foot Walking Test (p = 0.03). Higher walking speed was associated with lower Fatigue Severity Scale (p = 0.04).

Conclusion: Google Maps Timeline parameters provide actual estimates of daily walking activities in MS.

Background: Multiple sclerosis (MS) comparative effectiveness research needs to go beyond average treatment effects (ATEs) and post-host subgroup analyses.

Objective: This retrospective study assessed overall and patient-specific effects of dimethyl fumarate (DMF) versus teriflunomide (TERI) in patients with relapsing-remitting MS.

Methods: A novel precision medicine (PM) scoring approach leverages advanced machine learning methods and adjusts for imbalances in baseline characteristics between patients receiving different treatments. Using the German NeuroTransData registry, we implemented and internally validated different scoring systems to distinguish patient-specific effects of DMF relative to TERI based on annualized relapse rates, time to first relapse, and time to confirmed disease progression.

Results: Among 2791 patients, there was superior ATE of DMF versus TERI for the two relapse-related endpoints (p = 0.037 and 0.018). Low to moderate signals of treatment effect heterogeneity were detected according to individualized scores. A MS patient subgroup was identified for whom DMF was more effective than TERI (p = 0.013): older (45 versus 38 years), longer MS duration (110 versus 50 months), not newly diagnosed (74% versus 40%), and no prior glatiramer acetate usage (35% versus 5%).

Conclusion: The implemented approach can disentangle prognostic differences from treatment effect heterogeneity and provide unbiased patient-specific profiling of comparative effectiveness based on real-world data.

Background: In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in the pipeline for relapsing MS: ocrelizumab, ofatumumab (both registered), ublituximab (awaiting registration) and rituximab (off-label). List prices differ significantly between registered and off-label drugs.

Objective: Comparing differences in benefits between anti-CD20 mAbs from a health-economic and societal perspective.

Methods: To reflect lifetime use of DMTs, we used a treatment-sequence model to compare ocrelizumab/ofatumumab and eight other drug classes in terms of health (lifetime relapses, time to Expanded Disability Status Scale [EDSS] 6, lifetime quality-adjusted life years) and cost-effectiveness (net health benefit). To become cost-effective compared to ocrelizumab, we modelled the list price of ublituximab and desired effect on EDSS progression of rituximab.

Results: Although drug sequences with ocrelizumab in first- and second-line were more cost-effective than ofatumumab, our probabilistic analysis suggests this outcome was very uncertain. To be more cost-effective than ocrelizumab, ublituximab needs to be about 25% cheaper whilst rituximab needs to equal the effect on disability progression seen with first-line treatments.

Conclusions: Our model showed no clear difference in cost-effectiveness between ocrelizumab and ofatumumab. Hence, prescribing the least costly anti-CD20 mAb can democratise MS care without a loss in health benefits.

Background: Computerized training in persons with multiple sclerosis (PwMS) seems to enhance working memory (WM)/information processing (IP), but factors associated with the efficacy of the treatment have not been sufficiently explored. Objective: To identify clinical and radiological characteristics associated with positive WM/IP training responses.

Methods: Radiological and neuropsychological assessments were carried out on a sample of 35 PwMs who were divided into "WM/IP-impaired" and "WM/IP-preserved." All participants underwent adaptive n-back training for 10 days and were assessed post-training. Between-group differences ("WM/IP-impaired" vs. "WM/IP-preserved") in training-induced cognitive improvement were assessed and exploratory correlational/ regression-based methods were employed to assess the relationship between cognitive improvement and clinical and radiological variables.

Results: All PwMS exhibited WM/IP benefits after training, but those with preserved WM/IP functions showed greater positive effects as well as transfer effects to other WM/IP tests when compared to the impaired group. Additional analyses revealed that positive response to treatment was associated with WM/IP baseline capabilities and greater gray matter volume (GMVOL) in relevant areas such as the thalamus.

Conclusions: Restorative cognitive training is suitable to improve cognition in PwMS but its effective outcome differs depending on the baseline WM/IP capabilities and GMVOL.

Sleep disturbance is common in people with multiple sclerosis and may worsen fatigue; however, the assessment of sleep-fatigue relationships varies across studies. To better understand sleep-fatigue relationships in this population, we conducted a systematic review and random effects meta-analyses for the associations between fatigue and 10 sleep variables: Sleep-disordered breathing, daytime sleepiness, sleep quality, insomnia, restless legs, number of awakenings, sleep efficiency, sleep latency, sleep duration, and wake after sleep onset. Of the 1062 studies screened, 46 met inclusion criteria and provided sufficient data for calculating Hedges' g. Study quality was assessed using the Newcastle-Ottawa Scale. Sample characteristics did not differ between the 10 analyses. Results indicated that sleep quality and insomnia (assessed via self-report or diagnostic criteria) were strongly associated with fatigue (all gs ≥ 0.80 and all ps < .001). In contrast, the number of awakenings and sleep duration (assessed objectively) were not significantly associated with fatigue. Remaining sleep variables yielded moderate, significant effects. Most effects did not vary based on study quality or sample demographics. Results highlight that insomnia and perceptions of poor sleep have a stronger link than objective sleep duration to fatigue in multiple sclerosis and may represent a more effective target for intervention.

Background: Multiple sclerosis (MS) is a progressively debilitating neurologic disease that poses significant costs to the healthcare system and workforce.

Objective: To evaluate the impact of MS disease progression on societal costs and quality of life (QoL) using data from the German NeuroTransData (NTD) MS registry.

Methods: Cross-sectional cohort study. The cost cohort included patients with MS disability assessed using Expanded Disability Status Scale (EDSS) in 2019 while the QoL cohort included patients assessed using EDSS and EuroQol-5 Dimension 5-Levels between 2009 and 2019. Direct and indirect medical, and non-medical resource use was quantified and costs derived from public sources.

Results: Within the QoL cohort (n = 9821), QoL worsened with increasing EDSS. Within the cost cohort (n = 7286), increasing resource use with increasing EDSS was observed. Societal costs per patient, excluding or including disease-modifying therapies, increased from €5694 or €19,315 at EDSS 0 to 3.5 to €25,419 or €36,499 at EDSS 4 to 6.5, and €52,883 or €58,576 at EDSS 7 to 9.5. In multivariate modeling, each 0.5-step increase in EDSS was significantly associated with increasing costs, and worsening QoL.

Conclusion: This study confirms the major socioeconomic burden associated with MS disability progression. From a socioeconomic perspective, delaying disability progression may benefit patients and society.

Background: People over age 50-55 have historically been excluded from randomized clinical trials for multiple sclerosis (MS). However, more than half of those living with an MS diagnosis are over 55.

Objective: Explore the unique considerations of treating older people with MS (PwMS) using an iterative and structured Delphi-based assessment to gather expert opinions.

Methods: Eight MS neurologists with an interest in older PwMS developed a 2-round survey. Survey respondents were qualified neurologists with ≥3 years' experience, personally responsible for treatment decisions, and treating ≥20 patients per month, of whom ≥10% were ≥50 years old. Consensus was defined as ≥75% agreement on questions with categorical responses or as a mean score ≥4 on questions with numerical responses.

Results: In Survey 1, 224 neurologists responded; 180 of these completed Survey 2. Limited consensus was reached with varying levels of agreement on several topics including identification and assessment of older patients; factors relating to treatment decisions including immunosenescence and comorbidities; considerations for high-efficacy treatments; de-escalation or discontinuation of treatment; effects of COVID-19; and unmet needs for treating this population.

Conclusion: The results of this Delphi process highlight the need for targeted studies to create guidance for the care of older PwMS.