UNASSIGNED: Currently, disease-modifying therapies (DMTs) for progressive multiple sclerosis (PMS) are widely used in clinical practice. At the same time, there are a variety of drug options for DMTs, but the effect of the drugs that can better relieve symptoms and improve the prognosis are still inconclusive.
UNASSIGNED: This systematic review aimed to evaluate the efficacy and safety of DMTs for PMS and to identify the best among these drugs.
UNASSIGNED: MEDLINE, EMBASE, the Cochrane Library, and clinicaltrials.gov were systematically searched to identify relevant studies published before 30 January, 2023. We assessed the certainty of the evidence using the confidence in the network meta-analysis (CINeMA) framework. We estimated the summary risk ratio (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes with 95% credible intervals (CrIs).
UNASSIGNED: We included 18 randomized controlled trials (RCTs) involving 9,234 patients in the study. DMT can effectively control the disease progression of MS. Among them, mitoxantrone, siponimod, and ocrelizumab are superior to other drug options in delaying disease progression (high certainty). Mitoxantrone was the best (with high certainty) for mitigating deterioration (progression of disability). Ocrelizumab performed best on the pre- and post-treatment Timed 25-Foot Walk test (T25FW; low certainty), as did all other agents (RR range: 1.12-1.05). In the 9-Hole Peg Test (9HPT), natalizumab performed the best (high certainty), as did all other agents (RR range: 1.59-1.09). In terms of imaging, IFN-beta-1b performed better on the new T2 hypointense lesion on contrast, before and after treatment (high certainty), while siponimod performed best on the change from baseline in the total volume of lesions on T2-weighted image contrast before and after treatment (high certainty), and sWASO had the highest area under the curve (SUCRA) value (100%). In terms of adverse events (AEs), rituximab (RR 1.01), and laquinimod (RR 1.02) were more effective than the placebo (high certainty). In terms of serious adverse events (SAEs), natalizumab (RR 1.09), and ocrelizumab (RR 1.07) were safer than placebo (high certainty).
UNASSIGNED: DMTs can effectively control disease progression and reduce disease deterioration during the treatment of PMS.
UNASSIGNED: https://inplasy.com/?s=202320071, identifier: 202320071.

A systematic review and meta-analysis of the prognostic value of neurofilament light chain levels in multiple sclerosis treatment with natalizumab Relevant studies published before January 2022 were retrieved from the PubMed, Web of Science, and clinicaltrials.gov databases. Qualitative analysis and meta-analysis were included in 7 of the 46 papers. Differences in the Neurofilament light chain levels were used as the main efficacy measures, and the meta-analysis was performed using Review Manager version 5.3 software. Seven clinical trials were selected. Neurofilament light chain levels were lower in the 947 patients on natalizumab treatment than the 959 patients before therapy, with a moderate effect size of 0.73 (p < 0.00001). Mean Neurofilament light chain levels showed no significant difference between the remitting and relapsing phase of MS before and after natalizumab treatment. The EDSS scores of 41 MS patients in the relapsing phase after natalizumab treatment were significantly lower than those in 102 MS patients without therapy (MD = -0.45;95% CI = -0.85 to -0.05;P < 0.001). However, the EDSS scores in the remitting phase demonstrated no difference. The comparison of Neurofilament light chain across multiple groups demonstrates the potential of Nfl as a noninvasive biomarker of neurodegeneration, evaluating the efficacy of natalizumab in MS patients. We also investigated the relationship between different phases of relapsing-remitting MS with Neurofilament light chain levels. However, the value of Neurofilament light chain as a biomarker was hard to assess due to the limited number of studies. For clinical application, a comprehensive understanding of Neurofilament light chain concentrations in disease subtypes is required, and disease stages should be defined to develop standardized criteria.

Background High efficacy disease modifying therapies (DMT) in the management of Multiple Sclerosis (MS) have a favorable effect on relapse rate and disability progression; however, they can expose patients to significant risks, such as progressive multifocal leukoencephalopathy (PML). Objective The study aims to investigate prognostic factors that can determine outcome in MS-related PML patients. Methods We conducted a literature review and meta-analysis of 194 patients from 62 articles in PubMed, SCOPUS and EMBASE. Results Out of 194 patients (66.5% women, 33.5% men), 81% had progression in their EDSS score by at least 1 point from the time of PML diagnosis (EDSS-P group). The remaining patients had either stable or improved EDSS (EDSS-S group). In univariate analysis, older age at the time of PML diagnosis was associated with higher probability of disability accumulation and worsening of EDSS by at least 1 point (mean age = 44.8, p = 0.046). After adjusting for other variables, age at time of PML diagnosis remained a significant predictive variable in the multivariable logistic model (OR = 0.93, 95% CI: 0.88-0.99, p = 0.037). Natalizumab is the most commonly associated DMT linked to PML, followed by fingolimod and others including dimethyl fumarate, ocrelizumab, alemtuzumab. Among the different treatments used, no therapeutic agent was found to be superior in improving post-PML EDSS. Conclusions Younger age and lower JCV viral load at the time of PML diagnosis were associated with better outcome in MS-associate PML, while none of the PML therapies was superior over the others or associated with favorable outcome.

OBJECTIVE: To compare the efficacy and compliance of up-to-date disease modifying therapies (DMTs) in patients with remitting-relapsing MS (RRMS).
METHODS: We searched PubMed, EMBASE and Cochrane Library for eligible studies. Annualized relapse rate, discontinuation due to adverse events (AEs) were assessed as primary outcomes. Sensitivity analysis and inconsistency detection were performed to evaluated whether exclusion of high-risk studies affected the validity. Risk of bias was assessed using Cochrane\'s Risk-of-Bias Tool 2. Surface under the cumulative ranking curve (SUCRA) was used to estimate the rankings among different DMTs.
RESULTS: 21 studies were included for main report. Seven studies were evaluated as \"high risk\" and were therefore excluded. Exclusion of high-risk studies did not affect the validity of evidence. The risk of relapses for most DMTs except Betaseron 50 μg was significantly lower comparing to placebo. Incompliance in patients treated with DMTs was not significantly increased comparing to placebo. Dimethyl fumarate and ocrelizumab had superiority in improving MRI outcomes. Ocrelizumab and ofatumumab had the largest reduction of risk in disability progression at 3 months. Referring to SUCRA, ofatumumab, alemtuzumab and natalizumab showed the best efficacy and compliance.
CONCLUSIONS: The present study demonstrated the hierarchy of DMTs treating RRMS. Ofatumumab, alemtuzumab and natalizumab have superiority with respect to effectiveness and compliance. More studies are required to explore the long-term effect of DMTs. Our findings could provide helpful information and contribute to clinical treatment decision-making.

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BACKGROUND: Several monoclonal antibodies have been licensed for relapsing remitting multiple sclerosis (RRMS). It is still unclear which treatment regimen should be recommended due to the lack of head-to-head randomized controlled trials (RCTs). This study aims to investigate the relative efficacy and safety of existing monoclonal antibody therapies in treating RRMS.
METHODS: We searched PubMed, Embase, and the Cochrane Library for RCTs of monoclonal antibodies for treatment of RRMS. We performed a network meta-analysis to identify evidence comparing monoclonal antibodies with one another, interferon beta-1a (INFβ-1a), or placebo in adult patients with RRMS. The primary efficacy outcome was annualized relapse rate and the primary safety outcome was incidence rate of serious adverse events.
RESULTS: A total of 14 eligible studies containing 9412 patients treated with 7 regimens were analyzed. INFβ-1a was the most common comparison treatment and showed an annualized relapse rate of 45.3%. All monoclonal antibody regimens, including natalizumab, natalizumab plus INFβ-1a, alemtuzumab, daclizumab, and ocrelizumab, were associated with significant reduction in annualized relapse rate and similar risks of serious adverse events. Cluster analysis showed that natalizumab plus INFβ-1a and alemtuzumab performed best in terms of high efficacy and safety. Natalizumab and daclizumab were characterized by high efficacy but relatively high risk of serious adverse events. Ocrelizumab was differentiated by high safety but relatively poor efficacy.
CONCLUSIONS: This network meta-analysis provided a comprehensive summary of efficacy and safety of monoclonal antibodies for RRMS, which might provide a reference for treatment. More direct comparison studies are warranted.

BACKGROUND: Natalizumab (NAT), a humanized monoclonal antibody, which binds in both α4β1 integrins and α4β7 integrins, is approved for the treatment of multiple sclerosis (MS) and Crohn\'s disease (CD). An uncommon but serious adverse event from NAT treatment is known as progressive multifocal leukoencephalopathy (PML). However, clinical comprehensive safety evidence of NAT is limited.
METHODS: We will search Medline, Embase, Cochrane library, and ClinicalTrials.gov website from inception to May 9, 2018. Double-blind, randomized placebo-controlled trials reporting safety data of NAT will be eligible for inclusion. Outcome variables will include adverse events (AEs) varying degrees and AEs occurring in ≥ 5% patients with NAT or placebo. STATA software (version 12, Statacorp, College Station, TX) will be utilized to assess risk of bias and synthesize data. Outcomes will be reported by weight mean difference (WMD), risk ratios (RRs), and their 95% confidence intervals (95% CIs). I statistic will be used to evaluate heterogeneity among studies.
RESULTS: This systemic review and meta-analysis will evaluate serious AEs and AEs of NAT as compared to placebo.
CONCLUSIONS: Our study will provide a comprehensive picture of AEs of NAT.

BACKGROUND: Natalizumab (NAT), a humanized monoclonal antibody, binding in both α4β1 and α4β7 integrins, is approved for the treatment of Multiple Sclerosis (MS) and Crohn\'s Disease (CD). This review highlights the detailed Pharmacokinetics (PK) and Pharmacodynamics (PD) information of NAT, with the Pharmacogenomics (PG) properties of NAT.
METHODS: We undertake a systemic English-language search of Medline, EMBASE, Cochrane Library electronic databases to identify all potential studies with PK, PD or PG properties of NAT (up to October 2017).
RESULTS: Five papers contain detailed pharmacokinetic parameters are included in this review. Body weight is the most important factor associated with NAT concentration. Greater PK similarity and PD comparability is observed following Subcutaneous (SC) administration than Intramuscular (IM) administration. Initial difference in PK measures was observed between SC and Intravenous (IV) administration. However, trough NAT serum concentrations are similar between SC and IV administration after repeated dosing. Antibodies against NAT result in a low serum NAT concentration and cause a loss of efficacy of NAT. Gln-152, Lys-201, and Lys-256 are the three important point mutation on the α4 residues that NAT binds to. Syndecan-1 gene is a potential candidate gene for personalized approach for NAT use in MS.
CONCLUSIONS: As MS is a disease that affects young women most and NAT can pass placental barrier before delivery and into breast milk, a proper risk-benefit analysis of NAT therapy in lactating women are still needed. The relationship between Single Nucleotide Polymorphisms (SNPs) and NAT treatment are still not clear.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune disease, in which the insulating covers of nerve cells in the brain and spinal cord are demyelinated. This study was conducted to compare the efficacy of alemtuzumab and natalizumab in the treatment of different stages of MS patients.
METHODS: A total of 585 patients diagnosed with MS and hospitalized were included and analyzed after which they were divided into the primary progressive MS A and B groups, the relapsing-remitting MS (RRMS) C and D groups, and the secondary progressive MS E and F groups. Patients in A, C, and E groups were administered alemtuzumab while those in B, D, and F groups were administered natalizumab for the treatment. The expanded disability status scale (EDSS) scores and the EDSS difference were calculated before and after treatment. The number of head magnetic resonance imaging enhanced lesions in the patients, recurrence time and recurrence rate were measured before and after treatment.
RESULTS: The EDSS score of the RRMS group was significantly lower than that of the primary progressive MS group and the secondary progressive MS group. After 12 months of treatment, the EDSS score of RRMS patients treated with natalizumab was significantly lower compared with the patients with alemtuzumab, and the difference before and after treatment was significantly higher than alemtuzumab. The recurrence rate of the RRMS-D group was significantly lower than the RRMS-C group. After 12 months of treatment, compared with the RRMS-C group, a significant reduction was observed in the number of head magnetic resonance imaging enhanced lesions and longer recurrence time in the RRMS-D group.
CONCLUSIONS: The efficacy of natalizumab was better than alemtuzumab in the treatment of patients in the RRMS group, while there was no significant difference among other stages of MS patients, which provided the theoretical basis and clinical guidance for the treatment of different stages of MS.

Differentiation between progressive multifocal leukoencephalopathy (PML) and new multiple sclerosis (MS) lesions on brain MRI during natalizumab pharmacovigilance in the absence of clinical signs and symptoms is challenging but is of substantial clinical relevance. We aim to define MRI characteristics that can aid in this differentiation.
Reference and follow-up brain MRIs of natalizumab-treated patients with MS with asymptomatic PML (n=21), or asymptomatic new MS lesions (n=20) were evaluated with respect to characteristics of newly detected lesions by four blinded raters. We tested the association with PML for each characteristic and constructed a multivariable prediction model which we analysed using a receiver operating characteristic (ROC) curve.
Presence of punctate T2 lesions, cortical grey matter involvement, juxtacortical white matter involvement, ill-defined and mixed lesion borders towards both grey and white matter, lesion size of >3 cm, and contrast enhancement were all associated with PML. Focal lesion appearance and periventricular localisation were associated with new MS lesions. In the multivariable model, punctate T2 lesions and cortical grey matter involvement predict for PML, while focal lesion appearance and periventricular localisation predict for new MS lesions (area under the curve: 0.988, 95% CI 0.977 to 1.0, sensitivity: 100%, specificity: 80.6%).
The MRI characteristics of asymptomatic natalizumab-associated PML lesions proved to differ from new MS lesions. This led to a prediction model with a high discriminating power. Careful assessment of the presence of punctate T2 lesions, cortical grey matter involvement, focal lesion appearance and periventricular localisation allows for an early diagnosis of PML.