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

Background: Excessive daytime sleepiness (EDS) in multiple sclerosis (MS) can be a significant source of disability. Despite this, its prevalence as a patient-reported outcome in this condition has not been well established, and its causes are not well understood.

Methods: We prospectively assessed EDS as part of an observational study for patients referred for diagnostic neuro-ophthalmological testing. EDS was evaluated by the Epworth Sleepiness Scale (ESS), and visual data were also collected as part of a research protocol. Analysis with patient data was performed following the exclusion of patients with known primary sleep disorders.

Results: A total of 69 patients with MS were included in the analysis. The mean ESS was 6.5 with a SD of 4.3. ESS ≥ 10 was present in 23% of the cohort even in the presence of minimal mean neurological disability (Patient Determined Disease Steps (PDDS) = 1.5). The ESS score was not associated with age, sex, disease-related disability, retinal nerve fiber layer (RNFL), or optic neuritis (ON), but displayed an association with visual dysfunction.

Conclusions: There is an increased prevalence of EDS in MS. The increased values of the ESS are not explained by other sleep disorders, suggesting separate mechanisms. Further study of the underlying mechanisms is warranted.

Background: The imaging g-ratio, estimated from axonal volume fraction (AVF) and myelin volume fraction (MVF), is a novel biomarker of microstructural tissue integrity in multiple sclerosis (MS).

Objective: To assess axonal and myelin changes and their inter-relationship as measured by g-ratio in the optic radiations (OR) in people with MS (pwMS) with and without previous optic neuritis (ON) compared to healthy controls (HC).

Methods: Thirty pwMS and 17 HCs were scanned on a 3Tesla Connectom scanner. AVF and MVF, derived from a multi-shell diffusion protocol and macromolecular tissue volume, respectively, were measured in normal-appearing white matter (NAWM) and lesions within the OR and used to calculate imaging g-ratio.

Results: OR AVF and MVF were decreased in pwMS compared to HC, and in OR lesions compared to NAWM, whereas the g-ratio was not different. Compared to pwMS with previous ON, AVF and g-ratio tended to be higher in pwMS without prior ON. AVF and MVF, particularly in NAWM, were positively correlated with retinal thickness, which was more pronounced in pwMS with prior ON.

Conclusion: Axonal measures reflect microstructural tissue damage in the OR, particularly in the setting of remote ON, and correlate with established metrics of visual health in MS.

Background: Relapsing-remitting multiple sclerosis (RRMS) affects predominantly young women within reproductive years. As an increased risk of relapses is known to occur during the post-partum period, it is important to consider treatment options.

Aim: Evaluate the effects of intravenous immunoglobulins (IVIg) to prevent post-partum relapses.

Methods: We prospectively followed 198 pregnant female RRMS patients, 67 treated with IVIg during pregnancy and the three months post-partum, and 131 untreated patients that served as controls.

Results: During the pre-gestation year, 41.4% were treated with immunomodulatory drugs, and 28.3% experienced a relapse. During pregnancy and the post-partum period, the number of relapsing patients significantly decreased in the IVIg group (37.3%, 10.4%, 8.9%, respectively, p = 0.0003), while no significant change was observed in the untreated group (23.7%, 17.6%, and 22.1%). During the three-month post-partum period, there were only mild and moderate relapses in the IVIg group, while in the untreated group, there were also severe relapses. Stepwise logistic regression that assessed the relation between three-month post-partum relapse and explanatory variables demonstrated that untreated patients had increased risk for post-partum relapse (odds ratio = 4.6, 95% CI [1.69, 12.78], p = 0.033).

Conclusions: IVIg treatment proved efficient to reduce the rate and severity of relapses during pregnancy and the three-month post-partum.

Background: Sleep disorders are common in patients with multiple sclerosis and have a bidirectional interplay with fatigue and depression.

Objective: To evaluate the effect of treatment with oral dimethyl fumarate on the quality of sleep in relapsing-remitting multiple sclerosis.

Methods: This was a multicentre observational study with 223 relapsing-remitting multiple sclerosis subjects starting treatment with dimethyl fumarate (n=177) or beta interferon (n=46). All patients underwent subjective (Pittsburgh Sleep Quality Index) and objective (wearable tracker) measurements of quality of sleep. Fatigue, depression, and quality of life were also investigated and physical activity was monitored.

Results: Patients treated with dimethyl fumarate had significant improvement in the quality of sleep as measured with the Pittsburgh Sleep Quality Index (p<0.001). At all-time points, no significant changes in Pittsburgh Sleep Quality Index score were observed in the interferon group. Total and deep sleep measured by wearable tracker decreased at week 12 with both treatments, then remained stable for the total study duration. Depression significantly improved in patients treated with dimethyl fumarate. No significant changes were observed in mobility, fatigue and quality of life.

Conclusion: In patients with relapsing-remitting multiple sclerosis, the treatment with dimethyl fumarate was associated with improvements in patient-reported quality of sleep. Further randomised clinical trials are needed to confirm the benefits of long-term treatment with dimethyl fumarate.

Background: We aimed to determine the proportion of highly active multiple sclerosis patients under high-efficacy therapies (HETs) achieve no evidence of disease activity-3 (NEDA-3) at 1 and 2 years, and to identify factors associated with failing to meet no evidence of disease activity 3 at 2 years.

Methods: This retrospective cohort study based on Argentina Multiple Sclerosis patient registry (RelevarEM), includes highly active multiple sclerosis patients who received HETs.

Results: In total, 254 (78.51%) achieved NEDA-3 at year 1 and 220 (68.12%) achieved NEDA-3 at year 2. Patients who achieved NEDA-3 at 2 years had a shorter duration of multiple sclerosis (p < 0.01) and a shorter time between first treatment and current treatment (p = 0.01). Early high-efficacy strategy patients reached NEDA-3 more frequently (p < 0.01). Being a naïve patient (odds ratio: 3.78, 95% confidence interval 1.50-9.86, p < 0.01) was an independent predictor to reach NEDA-3 at 2 years. No association was found between type of HETs and NEDA-3 at 2 years when adjusted for potential confounders (odds ratio: 1.73; 95% confidence interval 0.51-6.06, p 0.57).

Conclusion: We found a high proportion of patients who achieved NEDA-3 at 1 and 2 years. Early high-efficacy strategy patients had a higher probability of achieving NEDA-3 at 2 years.

Background: To assign a course of secondary progressive multiple sclerosis (MS) (SPMS) may be difficult and the proportion of persons with SPMS varies between reports. An objective method for disease course classification may give a better estimation of the relative proportions of relapsing-remitting MS (RRMS) and SPMS and may identify situations where SPMS is under reported.

Materials and methods: Data were obtained for 61,900 MS patients from MS registries in the Czech Republic, Denmark, Germany, Sweden, and the United Kingdom (UK), including date of birth, sex, SP conversion year, visits with an Expanded Disability Status Scale (EDSS) score, MS onset and diagnosis date, relapses, and disease-modifying treatment (DMT) use. We included RRMS or SPMS patients with at least one visit between January 2017 and December 2019 if ≥ 18 years of age. We applied three objective methods: A set of SPMS clinical trial inclusion criteria ("EXPAND criteria") modified for a real-world evidence setting, a modified version of the MSBase algorithm, and a decision tree-based algorithm recently published.

Results: The clinically assigned proportion of SPMS varied from 8.7% (Czechia) to 34.3% (UK). Objective classifiers estimated the proportion of SPMS from 15.1% (Germany by the EXPAND criteria) to 58.0% (UK by the decision tree method). Due to different requirements of number of EDSS scores, classifiers varied in the proportion they were able to classify; from 18% (UK by the MSBase algorithm) to 100% (the decision tree algorithm for all registries). Objectively classified SPMS patients were older, converted to SPMS later, had higher EDSS at index date and higher EDSS at conversion. More objectively classified SPMS were on DMTs compared to the clinically assigned.

Conclusion: SPMS appears to be systematically underdiagnosed in MS registries. Reclassified patients were more commonly on DMTs.

Background: The traditional paper and pencil method for EDSS calculation (pEDSS) is the cornerstone of multiple sclerosis practice; however, it requires an expert for an accurate calculation, and it takes a lot of time to perform the function scores. A new algorithmic approach (aEDSS) has been developed for easier and faster assessment.

Objective: To determine if using aEDSS can achieve good inter-rater agreement and save time compared to pEDSS.

Subjects and methods: This study was conducted on 200 MS patients; EDSS was performed twice for each patient by two neurologists on the same day; one used the pEDSS, and the other used the aEDSS in a random order to test the inter-rater agreement regarding functional system scores and the final EDSS score and to detect the difference in the time needed for calculation between both methods.

Results: The new algorithmic approach achieved excellent agreement with the traditional method (Kappa > 0.81) with a shorter calculation time (16 ± 2.67 min for aEDSS vs 31 ± 4.3 min for pEDSS, P < 0.0001).

Conclusion: The new algorithmic approach could represent a suitable alternative to the traditional method, making EDSS calculation easier and faster.

Background: Treatment decisions for multiple sclerosis (MS) are influenced by many factors such as disease symptoms, comorbidities, and tolerability.

Objective: To determine how much relapsing MS patients were willing to accept the worsening of certain aspects of their MS in return for improvements in symptoms or treatment convenience.

Methods: A web-based discrete choice experiment (DCE) was conducted in patients with relapsing MS. Multinomial logit models were used to estimate relative attribute importance (RAI) and to quantify attribute trade-offs.

Results: The DCE was completed by 817 participants from the US, the UK, Poland, and Russia. The most valued attributes of MS therapy to participants were effects on physical fatigue (RAI = 22.3%), cognitive fatigue (RAI = 22.0%), relapses over 2 years (RAI = 20.7%), and MS progression (RAI = 18.4%). Participants would accept six additional relapses in 2 years and a decrease of 7 years in time to disease progression to improve either cognitive or physical fatigue from "quite a bit of difficulty" to "no difficulty."

Conclusion: Patients strongly valued improving cognitive and physical fatigue and were willing to accept additional relapses or a shorter time to disease progression to have less fatigue. The impact of fatigue on MS patients' quality of life should be considered in treatment decisions.

Background: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event.

Objective: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events.

Methods: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators.

Results: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar.

Conclusion: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients.ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553).

Background: Cladribine is a useful therapeutic option in RRMS with moderate to high disease activity. Its oral formulation and tolerability make it a useful alternative to infusion therapies. Cladribine is known to deplete CD19⁺ B lymphocytes, but its effect on immunoglobulin subsets is unclear.

Objective: To identify whether cladribine therapy in pwMS reduces immunoglobulin subset levels as a surrogate marker of infection risk.

Methods: A 'real-world' retrospective analysis of 341 pwMS presenting to a single tertiary centre between March 2017 and July 2021. Differences in immunoglobulin levels between cladribine, other disease-modifying therapies and no active treatment were assessed using a univariate ANOVA.

Results: Three hundred and forty-one patients had immunoglobulin levels assessed, with 29 patients treated with cladribine. The mean IgG, IgM and IgA levels on cladribine therapy were 10.44 ± 0.40, 0.99 ± 0.09 and 2.04 ± 0.18 g/L respectively. These were not significantly different from patients not on active treatment. There was a statistically significant reduction in IgG and IgM levels for patients treated with ocrelizumab (9.37 ± 0.19 and 0.68 ± 0.04 g/L) and natalizumab (8.72 ± 0.53 and 0.69 ± 0.12 g/L) compared to patients not on treatment.

Conclusion: Cladribine therapy for RRMS was not associated with immunoglobulin subset deficiencies. This is contrasted to ocrelizumab and natalizumab which demonstrate significant reductions in both IgG and IgM levels.