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

Background: Evaluating safety of emerging interventions is important in clinical trials. To support reporting of safety outcomes, a harms extension of the Consolidated Standards of Reporting Trial (CONSORT) guidelines was published in 2004.

Objective: To examine safety reporting in pivotal trials of disease-modifying therapies (DMTs) in patients with multiple sclerosis (MS).

Methods: Published phase III clinical trials from 1995 to 2022 included in FDA approval material for MS DMTs were compiled and reviewed by two independent examiners. Criteria derived from the CONSORT harms extension were used to evaluate safety reporting. Linear regression was applied to examine associations between quality of safety reporting and study level factors.

Results: 30 publications were included in the analysis. Overall, safety reporting quality was fair with an average score of 10.2 out of 15. Trials examining small molecule versus biologic interventions (p = 0.001) and recent publication (p = 0.005) were associated with higher quality reporting. Items related to laboratory-defined toxicity and defining adverse events were among reporting items notably lacking (present in 53% and 40% of publications, respectively).

Conclusion: While the reporting of phase III clinical trials for DMTs for the treatment of MS has improved with time, there remain gaps and opportunities for further improvement.

Objectives and aims: Ocrelizumab (OCR) is disease-modifying therapy that depletes B cells for the treatment of patients with relapsing and progressive multiple sclerosis (MS). The aim of this study was to evaluate occurrence of hypogammaglobulinemia and infection rates in patients with MS treated with OCR for up to 5.9 years in a real-world, single-center study.

Methods: We assessed immunoglobulins IgG, IgM, IgA; CD19, CD4, CD8 cell counts, anti-JCV antibodies, at baseline and every six months prior to each OCR infusion. Mixed effects regression models controlling for random patient intercept were used to analyze immunological trends. Infections requiring oral or intravenous antibiotics were also recorded and analyzed.

Results: A total of 238 patients were followed for up to 5.9 years and received a mean of 7.6 (range, 2-13) OCR infusions. IgG declined on average by 3.7% (p < .001) and IgM by 11.8% (p < .001) annually. At last follow-up, 14.6% of patients had IgG < 600 mg/dL and 51.1% had IgM M < 40 mg/dL. Patients with IgG < 600 mg/dL experienced higher rates of infections requiring oral antibiotics (1.17 vs 0.99 per year, p = .004) and IV antibiotics (0.147 vs 0.066 per year, p = .009) compared to those with normal IgG. White race was associated with reduced IgG (p = .008) and IgA (p < .001) levels, while female sex was associated with increased CD4 (p < .001) and CD8 (p = .015) counts. Anti-JCV antibody index declined by 1.9% annually (p < .001). Linear trend analysis predicted that 14.9 years of treatment would be required for at least 50% of patients to have IgG levels <600 mg/dL.

Conclusions: Continuous OCR treatment results in increasing hypogammaglobulinemia associated with increasing risk of moderate and severe infections. The clinical significance of these immunological findings and the influences of demographic characteristics highlight the importance of regular, personalized immunoglobulin monitoring during long-term OCR therapy.

Background: Early life stress (ELS) has been implicated in the risk of developing autoimmune disorders including multiple sclerosis (MS), but less is known about its relationship to the clinical course of MS.

Objective: Investigate the relationship between ELS and MS patient-reported outcomes (PRO).

Methods: In a single-center, cross-sectional study, persons with MS completed a composite of surveys assessing ELS and PRO including the adverse childhood experiences (ACE) survey, the Childhood Trauma Questionnaire, MS Performance Scales, MS Impact Scale (MSIS-29) and MS Quality of Life (MSQOL-54). Multiple linear regression models were used to assess the associations between ELS and outcomes while adjusting for potential confounding variables.

Results: A total of 133 persons with MS completed the study. ELS was significantly associated with worse outcomes on the MSQOL-54. Persons with MS with ACE score ≥ 4 were 25.6 points lower (95% CI -15.7 to -35.6) on the Mental Health Composite and 24.6 points lower (95% CI -14.4 to -34.8) on the Physical Health Composite scores of the MSQOL-54. ELS was also associated with worse outcomes on the MS Performance Scale and the MSIS-29.

Conclusion: In persons with MS, a history of ELS is associated with significantly worse MS symptom burden and quality of life.

We present real-world data on patients switching from anti-CD20s to fumarates for various motivations in this retrospective observational study of 43 patients from three multiple sclerosis centers. Recurrent infections on anti-CD20s were the most common reason for switching to fumarates. Patients experienced limited disease activity on fumarates (83.7% were free from relapse and new MRI lesions), suggesting effectiveness was maintained. Of the 16.3% with disease activity on fumarates, 57.1% also had disease activity on anti-CD20s. Tolerability was the main reason for discontinuing fumarates. Future studies will provide additional insight into how to effectively and safely transition from anti-CD20s to fumarates.

Introduction: Multiple sclerosis (MS) is a central nervous system disorder and is frequently associated with fatigue. The Fatigue Scale for Motor and Cognitive Functions (FSMC) is an instrument to assess both motor and cognitive dimensions of fatigue in MS.

Methods: The study included 60 MS patients who completed the Persian version of the Modified Fatigue Impact Scale (MFIS) and a translated version of FSMC questionnaire. The FSMC was translated using standardized forward-backward translation, expert review, and patient feedback to ensure linguistic and conceptual validity. To evaluate test-retest reliability, participants completed the translated version of FSMC again after two weeks. Content validity was examined by a panel of eight experts.

Results: Sixty individuals with a mean age of 36.36 ± 9.7 years and an Expanded Disability Status Scale score of 3.00 ± 2.0 were enrolled in this study. Fifty-one (85%) of the participants were female. The Persian FSMC demonstrated strong content validity (Content Validity Index: 0.875-1.00; content validity ratio: 0.75-1.00). Internal consistency was excellent (Cronbach's alpha = 0.964). Test-retest reliability was strong for average scores (intraclass correlation coefficient (intraclass correlation coefficient (ICC) = 0.979), though fair to good for single measures (ICC = 0.540). Convergent validity was supported by strong correlations with MFIS scores (FSMC-total: r = 0.88; motor: r = 0.87; cognitive: r = 0.85; all p < .001). No floor/ceiling effects were observed.

Conclusions: The Persian version of the FSMC is a valid and reliable instrument for assessing fatigue in Iranian patients with MS. With strong psychometric properties, it is well-suited for clinical and research use in Persian-speaking populations.

Background: In relapsing-remitting multiple sclerosis (RRMS), smouldering inflammation at the rims of chronic active lesions is increasingly recognised as a key driver of disease progression. Paramagnetic rim lesions (PRLs), detected using susceptibility-weighted imaging, have emerged as a potential biomarker of this chronic inflammatory activity. However, their clinical relevance and relationship to lesion-specific features such as size and age remain poorly understood.

Objective: To investigate the association between PRL presence and clinical/radiological measures of disease progression, and to explore how PRLs relate to lesion size and age.

Methods: A retrospective study of 60 RRMS patients with over 5 years of magnetic resonance imaging data was conducted using susceptibility-weighted angiography. Lesions larger than 100 mm³ were analysed.

Results: PRLs were present in 48% of patients and represented 13% of lesions. PRLs were significantly larger and more structurally damaged, with volume correlating with EDSS change and brain atrophy. All lesions formed within 5 years of imaging were PRLs. This finding was validated in two independent international cohorts. Moreover, the proportion of rim-positive lesions decreased as lesion age increased.

Conclusion: PRLs are closely linked to lesion age and early development, supporting their role as a dynamic biomarker of lesion activity in multiple sclerosis.

Background: Patients with neuromyelitis optica spectrum disorders (NMOSD) often experience significant functional limitation, high rates of disability, and cognitive impairment (CI). The objective of this study was evaluating the factors associated with CI in patients diagnosed with NMOSD in Mexico. Methods: The study was cross-sectional in design. We included 65 NMOSD patients (34 NMOSD with CI and 31 NMOSD without CI). We utilized the Brief International Cognitive Assessment for Multiple Sclerosis to identify CI in NMOSD patients. Logistic regression was applied to identify the factors associated with CI. Results: Factors associated with CI in the crude analysis were education level (⩽6 years of schooling; odds ratio (OR) 4.37, 95% confidence interval (CI) 1.41-13.52, p = 0.010), disease duration (⩾60 months; OR 8.22, 95% CI 2.68-25.20, p < 0.001), time from onset to diagnosis (⩾12 months; OR 3.70, 95% CI 1.21-11.31, p = 0.022), brain lesion (on magnetic resonance imaging before azathioprine or rituximab; OR 3.46, 95% CI 1.20-10.00, p = 0.022), and relapses by NMOSD diagnosis (⩾4; OR 4.48, 95% CI 1.57-12.76, p = 0.005). Factors associated with CI in the adjusted analyses were education (⩽6 years; OR 5.92, 95% CI 1.57-22.23, p = 0.008), disease duration (⩾60 months; OR 5.73, 95% CI 1.69-19.40, p = 0.005), and relapses by NMOSD diagnosis (⩾4; OR 5.79, 95% CI 1.70-19.72, p = 0.005). Conclusion: One of the biggest factors associated with CI was relapse by NMOSD, specifically those with lower education levels and those with longer disease duration.

Background: Progression independent of relapse activity (PIRA) may occur in patients with relapsing multiple sclerosis (MS) and is a major contributor to disability accumulation.

Objectives: We evaluated whether a panel of cerebrospinal fluid (CSF) biomarkers (neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), total-Tau (T-Tau), ubiquitin C-terminal hydrolase 1 (UCHL-1), and the phospho-Tau (P-Tau)181/T-Tau ratio) at diagnosis could discriminate patients who will develop PIRA in early disease phases.

Methods: CSF levels of NfL, GFAP, T-Tau, and UCHL-1 were measured with SIMOA, of P-Tau181, and the ratio P-Tau181/T-Tau with chemiluminescent immunoassay in 80 newly diagnosed MS patients who were followed up for three years with six-month Expanded Disability Status Scale (EDSS) assessments and yearly MRI scans.

Results: Nineteen participants developing PIRA exhibited elevated GFAP and UCHL-1 levels, and reduced P-Tau181/T-Tau ratio. These biomarkers remained significant predictors of the outcome after adjusting for confounders, particularly older age at onset and higher baseline EDSS. Additionally, we identified moderate positive correlations between NfL-GFAP, NfL-UCHL-1, and GFAP-UCHL-1 levels, and moderate negative correlations between P-Tau181/T-Tau ratio and NfL, GFAP, and UCHL-1 levels.

Conclusions: The elevation of GFAP and UCHL-1 likely reflects the role of astrocytic activation, while the reduction of the P-Tau181/T-Tau ratio may indicate disrupted Tau metabolism in individuals at risk of PIRA. Our findings suggest that combining these innovative biomarkers with clinical risk factors could improve early prognostic accuracy.

Background: In relapsing-remitting multiple sclerosis (RRMS), the assessment of clinical disease activity can be challenging.

Objectives: To determine the diagnostic potential of serum neurofilament light (sNfL) and glial fibrillary acidic protein (sGFAP) to distinguish a relapse from other causes of deterioration.

Methods: In this multicenter, prospective study, RRMS patients with new neurological symptoms in the last 14 days were followed for 12 weeks. A diagnosis was established by the treating physician or, when in doubt, a panel of experienced neurologists. Blood samples were taken at baseline and week 12.

Results: A total of 65 patients were included. At baseline, patients with a clear relapse had a significantly higher median sNfL (14.6 pg/mL) than those with a clear other cause (9.5 pg/mL, p = 0.004). Although not significant after correction for multiple testing, median sGFAP was also higher in relapse patients (73.0 vs 64.6 pg/mL, p = 0.036). An sNfL value below 6.0 pg/mL had a high sensitivity (67% at baseline (CI 22.3-95.7%) and 100% at follow-up (CI 54.1-100%)) to rule out a relapse.

Conclusions: Analysis of sNfL level can be useful as an add-on investigation to determine whether disease activity is present in patients with RRMS presenting with new symptoms.