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Multiple Sclerosis (Houndmills,... Jul 2023With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy. (Review)
Review
BACKGROUND
With the new highly active drugs available for people with multiple sclerosis (pwMS), vaccination becomes an essential part of the risk management strategy.
OBJECTIVE
To develop a European evidence-based consensus for the vaccination strategy of pwMS who are candidates for disease-modifying therapies (DMTs).
METHODS
This work was conducted by a multidisciplinary working group using formal consensus methodology. Clinical questions (defined as population, interventions, and outcomes) considered all authorized DMTs and vaccines. A systematic literature search was conducted and quality of evidence was defined according to the Oxford Centre for Evidence-Based Medicine Levels of Evidence. The recommendations were formulated based on the quality of evidence and the risk-benefit balance.
RESULTS
Seven questions, encompassing vaccine safety, vaccine effectiveness, global vaccination strategy and vaccination in sub-populations (pediatric, pregnant women, elderly and international travelers) were considered. A narrative description of the evidence considering published studies, guidelines, and position statements is presented. A total of 53 recommendations were agreed by the working group after three rounds of consensus.
CONCLUSION
This first European consensus on vaccination in pwMS proposes the best vaccination strategy according to current evidence and expert knowledge, with the goal of homogenizing the immunization practices in pwMS.
Topics: Aged; Child; Female; Humans; Pregnancy; Consensus; Evidence-Based Medicine; Immunization; Multiple Sclerosis; Vaccination
PubMed: 37293841
DOI: 10.1177/13524585231168043 -
Journal of Comparative Effectiveness... Jul 2023To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod,... (Meta-Analysis)
Meta-Analysis
To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) were conducted. For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR).
Topics: Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Alemtuzumab; Network Meta-Analysis; Bayes Theorem; Recurrence
PubMed: 37265062
DOI: 10.57264/cer-2023-0016 -
The Cochrane Database of Systematic... Jan 2024Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators,... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Different therapeutic strategies are available for the treatment of people with relapsing-remitting multiple sclerosis (RRMS), including immunomodulators, immunosuppressants and biological agents. Although each one of these therapies reduces relapse frequency and slows disability accumulation compared to no treatment, their relative benefit remains unclear. This is an update of a Cochrane review published in 2015.
OBJECTIVES
To compare the efficacy and safety, through network meta-analysis, of interferon beta-1b, interferon beta-1a, glatiramer acetate, natalizumab, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate, alemtuzumab, pegylated interferon beta-1a, daclizumab, laquinimod, azathioprine, immunoglobulins, cladribine, cyclophosphamide, diroximel fumarate, fludarabine, interferon beta 1-a and beta 1-b, leflunomide, methotrexate, minocycline, mycophenolate mofetil, ofatumumab, ozanimod, ponesimod, rituximab, siponimod and steroids for the treatment of people with RRMS.
SEARCH METHODS
CENTRAL, MEDLINE, Embase, and two trials registers were searched on 21 September 2021 together with reference checking, citation searching and contact with study authors to identify additional studies. A top-up search was conducted on 8 August 2022.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that studied one or more of the available immunomodulators and immunosuppressants as monotherapy in comparison to placebo or to another active agent, in adults with RRMS.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies and extracted data. We considered both direct and indirect evidence and performed data synthesis by pairwise and network meta-analysis. Certainty of the evidence was assessed by the GRADE approach.
MAIN RESULTS
We included 50 studies involving 36,541 participants (68.6% female and 31.4% male). Median treatment duration was 24 months, and 25 (50%) studies were placebo-controlled. Considering the risk of bias, the most frequent concern was related to the role of the sponsor in the authorship of the study report or in data management and analysis, for which we judged 68% of the studies were at high risk of other bias. The other frequent concerns were performance bias (34% judged as having high risk) and attrition bias (32% judged as having high risk). Placebo was used as the common comparator for network analysis. Relapses over 12 months: data were provided in 18 studies (9310 participants). Natalizumab results in a large reduction of people with relapses at 12 months (RR 0.52, 95% CI 0.43 to 0.63; high-certainty evidence). Fingolimod (RR 0.48, 95% CI 0.39 to 0.57; moderate-certainty evidence), daclizumab (RR 0.55, 95% CI 0.42 to 0.73; moderate-certainty evidence), and immunoglobulins (RR 0.60, 95% CI 0.47 to 0.79; moderate-certainty evidence) probably result in a large reduction of people with relapses at 12 months. Relapses over 24 months: data were reported in 28 studies (19,869 participants). Cladribine (RR 0.53, 95% CI 0.44 to 0.64; high-certainty evidence), alemtuzumab (RR 0.57, 95% CI 0.47 to 0.68; high-certainty evidence) and natalizumab (RR 0.56, 95% CI 0.48 to 0.65; high-certainty evidence) result in a large decrease of people with relapses at 24 months. Fingolimod (RR 0.54, 95% CI 0.48 to 0.60; moderate-certainty evidence), dimethyl fumarate (RR 0.62, 95% CI 0.55 to 0.70; moderate-certainty evidence), and ponesimod (RR 0.58, 95% CI 0.48 to 0.70; moderate-certainty evidence) probably result in a large decrease of people with relapses at 24 months. Glatiramer acetate (RR 0.84, 95%, CI 0.76 to 0.93; moderate-certainty evidence) and interferon beta-1a (Avonex, Rebif) (RR 0.84, 95% CI 0.78 to 0.91; moderate-certainty evidence) probably moderately decrease people with relapses at 24 months. Relapses over 36 months findings were available from five studies (3087 participants). None of the treatments assessed showed moderate- or high-certainty evidence compared to placebo. Disability worsening over 24 months was assessed in 31 studies (24,303 participants). Natalizumab probably results in a large reduction of disability worsening (RR 0.59, 95% CI 0.46 to 0.75; moderate-certainty evidence) at 24 months. Disability worsening over 36 months was assessed in three studies (2684 participants) but none of the studies used placebo as the comparator. Treatment discontinuation due to adverse events data were available from 43 studies (35,410 participants). Alemtuzumab probably results in a slight reduction of treatment discontinuation due to adverse events (OR 0.39, 95% CI 0.19 to 0.79; moderate-certainty evidence). Daclizumab (OR 2.55, 95% CI 1.40 to 4.63; moderate-certainty evidence), fingolimod (OR 1.84, 95% CI 1.31 to 2.57; moderate-certainty evidence), teriflunomide (OR 1.82, 95% CI 1.19 to 2.79; moderate-certainty evidence), interferon beta-1a (OR 1.48, 95% CI 0.99 to 2.20; moderate-certainty evidence), laquinimod (OR 1.49, 95 % CI 1.00 to 2.15; moderate-certainty evidence), natalizumab (OR 1.57, 95% CI 0.81 to 3.05), and glatiramer acetate (OR 1.48, 95% CI 1.01 to 2.14; moderate-certainty evidence) probably result in a slight increase in the number of people who discontinue treatment due to adverse events. Serious adverse events (SAEs) were reported in 35 studies (33,998 participants). There was probably a trivial reduction in SAEs amongst people with RRMS treated with interferon beta-1b as compared to placebo (OR 0.92, 95% CI 0.55 to 1.54; moderate-certainty evidence).
AUTHORS' CONCLUSIONS
We are highly confident that, compared to placebo, two-year treatment with natalizumab, cladribine, or alemtuzumab decreases relapses more than with other DMTs. We are moderately confident that a two-year treatment with natalizumab may slow disability progression. Compared to those on placebo, people with RRMS treated with most of the assessed DMTs showed a higher frequency of treatment discontinuation due to AEs: we are moderately confident that this could happen with fingolimod, teriflunomide, interferon beta-1a, laquinimod, natalizumab and daclizumab, while our certainty with other DMTs is lower. We are also moderately certain that treatment with alemtuzumab is associated with fewer discontinuations due to adverse events than placebo, and moderately certain that interferon beta-1b probably results in a slight reduction in people who experience serious adverse events, but our certainty with regard to other DMTs is lower. Insufficient evidence is available to evaluate the efficacy and safety of DMTs in a longer term than two years, and this is a relevant issue for a chronic condition like MS that develops over decades. More than half of the included studies were sponsored by pharmaceutical companies and this may have influenced their results. Further studies should focus on direct comparison between active agents, with follow-up of at least three years, and assess other patient-relevant outcomes, such as quality of life and cognitive status, with particular focus on the impact of sex/gender on treatment effects.
Topics: Adult; Humans; Immunosuppressive Agents; Multiple Sclerosis, Relapsing-Remitting; Glatiramer Acetate; Interferon beta-1a; Fingolimod Hydrochloride; Natalizumab; Interferon beta-1b; Cladribine; Alemtuzumab; Dimethyl Fumarate; Daclizumab; Network Meta-Analysis; Immunologic Factors; Recurrence
PubMed: 38174776
DOI: 10.1002/14651858.CD011381.pub3 -
Neurological Sciences : Official... Sep 2023Previously, several studies investigated the effect of cladribine among patients with multiple sclerosis (MS) as a treatment option. Due to the contradictory results of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Previously, several studies investigated the effect of cladribine among patients with multiple sclerosis (MS) as a treatment option. Due to the contradictory results of previous studies regarding the efficacy and safety of cladribine in the MS population, we aimed to conduct a systematic review and meta-analysis by including clinical trials and observational studies in terms of having more confirmative results to make a general decision.
METHODS
The three databases including PubMed, Scopus, and Web of Science were comprehensively searched in May 2022. We included the studies that investigated the efficacy and safety of cladribine in patients with MS. Eligible studies have to provide sufficient details on MS diagnosis and appropriate follow-up duration. We investigated the efficacy of cladribine with several outcomes including Expanded Disability Status Scale (EDSS) change, progression-free survival (PFS), relapse-free survival (RFS), and MRI-free activity survival (MFAS).
RESULTS
After two-step reviewing, 23 studies were included in our qualitative and quantitative synthesis. The pooled SMD for EDSS before and after treatment was - 0.54 (95%CI: - 1.46, 0.39). Our analysis showed that the PFS after cladribine use is 79% (95%CI 71%, 86%). Also, 58% of patients with MS who received cladribine remained relapse-free (95%CI 31%, 83%). Furthermore, the MFAS after treatment was 60% (95%CI 36%, 81%). Our analysis showed that infection is the most common adverse event after cladribine treatment with a pooled prevalence of 10% (95%CI 4%, 18%). Moreover, the pooled prevalence of infusion-related adverse events was 9% (95%CI 4%, 15%). Also, the malignancies after cladribine were present in 0.4% of patients (95%CI 0.25%, 0.75%).
CONCLUSION
Our results showed acceptable safety and efficacy for cladribine for the treatment of MS except in terms of reducing EDSS. Combination of our findings with the results of previous studies which compared cladribine to other disease-modifying therapies (DMTs), cladribine seems to be a safe and effective drug in achieving better treatment for relapsing-remitting MS (RRMS) patients.
Topics: Humans; Cladribine; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Clinical Trials as Topic; Observational Studies as Topic
PubMed: 37062787
DOI: 10.1007/s10072-023-06794-w -
Journal of Neurology Mar 2024Case-reports/series and cohorts of Guillain-Barré syndrome (GBS) associated with COVID-19 vaccination have been reported. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Case-reports/series and cohorts of Guillain-Barré syndrome (GBS) associated with COVID-19 vaccination have been reported.
METHODS
A systematic review and meta-analysis of cohort studies of GBS after COVID-19 vaccination was carried out. Incidence and incidence rate ratio for a number of vaccine doses and risk of GBS, also considering the specific vaccine technology, were calculated in a random-effects model.
RESULTS
Of 554 citations retrieved, 518 were discarded as irrelevant. We finally included 15 studies. The random effect model yielded, regardless of the vaccine technology, 1.25 (95%CI 0.21; 2.83) GBS cases per million of COVID-19 vaccine doses, 3.93 (2.54; 5.54) cases per million doses for adenovirus-vectored vaccines and 0.69 (0.38; 1.06) cases per million doses for mRNA vaccines. The GBS risk was 2.6 times increased with the first dose. Regardless of the vaccine technology, the GBS risk was not increased but disaggregating the data it was 2.37 (1.67; 3.36) times increased for adenovirus-vectored vaccines and 0.32 (0.23; 0.47) for mRNA vaccines. Mortality for GBS after vaccination was 0.10 per million doses and 4.6 per GBS cases.
CONCLUSIONS
Adenovirus-vectored vaccines showed a 2.4 times increased risk of GBS that was about seven times higher compared with mRNA-based vaccines. The decreased GBS risk associated with mRNA vaccines was possibly due to an elicited reduction of infections, including SARS-CoV-2, associated with GBS during the vaccination period. How adenovirus-vectored COVID-19 vaccines may trigger GBS is unclear and further studies should investigate the relationship between vaccine technologies and GBS risk.
Topics: Humans; COVID-19; COVID-19 Vaccines; Guillain-Barre Syndrome; mRNA Vaccines; Vaccination
PubMed: 38233678
DOI: 10.1007/s00415-024-12186-7 -
Multiple Sclerosis Journal -... 2023Comorbidity is a current area of interest in multiple sclerosis (MS) and is essential for multidisciplinary management. Although recent studies suggest that patients... (Review)
Review
BACKGROUND
Comorbidity is a current area of interest in multiple sclerosis (MS) and is essential for multidisciplinary management. Although recent studies suggest that patients with MS have an elevated risk of developing inflammatory bowel diseases (IBD), this systematic review and meta-analysis aimed to estimate the overall risk of developing ulcerative colitis (UC), specifically in patients with MS.
METHODS
In 2021, a comprehensive literature search was performed on PubMed, Scopus, Embase, and Web of Science to identify studies investigating the association between UC and MS. The selected papers were utilized to estimate the associations, risk ratios (RRs), and a 95% confidence interval (CI).
RESULTS
The analysis revealed a slightly elevated risk of UC incidence in patients with MS compared to controls, but this finding was not statistically significant (RR: 1.27 [95% CI: 0.96-1.67]). In contrast, the study found that patients with UC have a significantly higher risk of developing MS than controls (RR: 1.66 [95% CI: 1.15-2.40]).
CONCLUSION
Our findings highlight that the presence of UC increases the risk of developing MS by more than 50%, whereas the presence of MS does not increase the risk of UC occurrence. These results underscore the importance of considering the potential development of UC in the clinical management and early diagnosis of patients with MS, as it may contribute to better therapeutic outcomes.
PubMed: 37483528
DOI: 10.1177/20552173231186516 -
Orphanet Journal of Rare Diseases Aug 2023To understand the benefit-risk profile for historical and current treatments for MLD. (Review)
Review
A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel.
OBJECTIVE
To understand the benefit-risk profile for historical and current treatments for MLD.
METHODS
A systematic review was conducted on the effectiveness, safety, and costs of MLD treatments: allogeneic haematopoietic stem cell transplantation (HSCT) and atidarsagene autotemcel (arsa-cel) according to best practice.
RESULTS
A total of 6940 titles and abstracts were retrieved from the literature searches and 26 from other sources. From these, 35 manuscripts reporting on a total of 12 studies were selected for inclusion in the review. There were no controlled multi-armed trials. However, we provide observations comparing two interventional therapies (alloHSCT and arsa-cel) and each of these to standard/supportive care (natural history). There were no benefits for survival, gross motor function and cognitive function for LI patients receiving alloHSCT, as patients experienced disease progression similar to LI natural history. For juvenile patients receiving alloHSCT, no differences in survival were observed versus natural history, however stabilisation of cognitive and motor function were reported for some patients (particularly for pre- or minimally-symptomatic LJ patients), while others experienced disease progression. Furthermore, alloHSCT was associated with severe complications such as treatment-related mortality, graft versus host disease, and re-transplantation in both LI and EJ treated patients. Most LI and EJ patients treated with arsa-cel appeared to have normal development, preservation, or slower progression of gross motor function and cognitive function, in contrast to the rapid decline observed in natural history patients. A survival benefit for arsa-cel versus natural history and versus alloHSCT was observed in LI patients.LI and EJ patients treated with arsa-cel had better gross motor function and cognitive function compared to alloHSCT, which had limited effect on motor and cognitive decline. No data has been reported for arsa-cel treatment of LJ patients.
CONCLUSIONS
Overall, this systematic review indicates that compared to NHx and HSCT, treatment with arsa-cel results in clinically relevant benefits in LI and EJ MLD patients by preserving cognitive function and motor development in most patients, and increased survival for LI patients. Nevertheless, further research is required to confirm these findings, given they are based on results from non-RCT studies.
Topics: Humans; Child; Leukodystrophy, Metachromatic; Treatment Outcome; Cognition; Cognitive Dysfunction; Disease Progression
PubMed: 37644601
DOI: 10.1186/s13023-023-02814-2 -
Cells Jun 2023Multiple sclerosis (MS) is a chronic, progressive neuroinflammatory disease with a complex pathophysiological background. A variety of diverse factors have been... (Review)
Review
Multiple sclerosis (MS) is a chronic, progressive neuroinflammatory disease with a complex pathophysiological background. A variety of diverse factors have been attributed to the propagation of inflammation and neurodegeneration in MS, mainly genetic, immunological, and environmental factors such as vitamin D deficiency, infections, or hormonal disbalance. Recently, the importance of the gut-brain axis for the development of many neurological conditions, including stroke, movement disorders, and neuroinflammatory disorders, has been postulated. The purpose of our paper was to summarize current evidence confirming the role of the gut microbiome in the pathophysiology of MS and related disorders, such as neuromyelitis optica spectrum disorder (NMO-SD). For this aim, we conducted a systematic review of the literature listed in the following databases: Medline, Pubmed, and Scopus, and were able to identify several studies demonstrating the involvement of the gut microbiome in the pathophysiology of MS and NMO-SD. It seems that the most relevant bacteria for the pathophysiology of MS are those belonging to , , , , , , , and , while and have been demonstrated to play a role in the pathophysiology of NMO-SD. Following this line of evidence, there is also some preliminary data supporting the use of probiotics or other agents affecting the microbiome that could potentially have a beneficial effect on MS/NMO-SD symptoms and prognosis. The topic of the gut microbiome in the pathophysiology of MS is therefore relevant since it could be used as a biomarker of disease development and progression as well as a potential disease-modifying therapy.
Topics: Humans; Multiple Sclerosis; Gastrointestinal Microbiome; Neuromyelitis Optica; Vitamin D Deficiency; Inflammation
PubMed: 37443793
DOI: 10.3390/cells12131760 -
Global Epidemiology Dec 2023Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy that affects the peripheral nervous system. The study aimed to describe the... (Review)
Review
INTRODUCTION
Guillain-Barré syndrome (GBS) is an acute inflammatory demyelinating polyradiculoneuropathy that affects the peripheral nervous system. The study aimed to describe the incidence of GBS in the world up to the year 2020.
METHODS
A systematic review was conducted. Searches were done in four databases, PUBMED, EMBASE, EBSCO and , and in grey literature and manual search in the reference lists of eligible studies.
RESULTS
A total of 72 studies were included. The incidence of GBS among the cohort studies varied from 0.30 to 6.08 cases per 100.000 habitants and 0.42 to 6.58 cases per 100.000 person-years. Among the self-controlled studies, the risk incidence ranged from 0.072 to 1 case per 100.000 habitants and 1.73 to 4.30 cases per 100.000 person-years.
CONCLUSIONS
The reported incidence of GBS in the world among the studies included in the review is slightly higher than that reported in previous studies. The highest incidence rates were associated with public health events of international concern.
PubMed: 37638372
DOI: 10.1016/j.gloepi.2023.100098 -
Multiple Sclerosis and Related Disorders Jul 2023Aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare... (Review)
Review
A systematic literature review to examine the considerations around pregnancy in women of child-bearing age with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) or aquaporin 4 neuromyelitis optica spectrum disorder (AQP4+ NMOSD).
BACKGROUND
Aquaporin-4 antibody positive (AQP4+) neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are rare autoimmune diseases with overlapping phenotypes. Understanding their clinical manifestation prior to, during and after pregnancy may influence the management of women of child-bearing age (WOCBA) with these diseases.
METHODS
This systematic review identified relevant MEDLINE-indexed publications dated between 01 January 2011 and 01 November 2021, and congress materials from key conferences between 01 January 2019 and 01 November 2021. These were manually assessed for relevance to AQP4+ NMOSD and/or MOGAD in WOCBA, with selected data extracted and considered.
RESULTS
In total, 107 articles were retrieved and reviewed for relevancy, including 65 clinical studies. Limited evidence was found regarding a conclusive impact of either disease on female fertility, sexual function or menarche, and impact on maternal outcomes requires further investigation in both conditions to establish risk for pre-eclampsia, gestational diabetes and other complications relative to the general population. Collated data for pregnancy outcomes show clear risks in AQP4+ NMOSD to healthy delivery and a rise in annualised relapse rate postpartum that may require adaptation of treatment regimens. Disease activity appears to be attenuated during pregnancy in MOGAD patients with an increased risk of relapse during the postpartum months, but strong conclusions cannot be made due to a paucity of available data.
CONCLUSIONS
This review brings together the literature on AQP4+ NMOSD and MOGAD in WOCBA. The potential impact of pregnancy and the postpartum period on disease activity suggest a proactive management strategy early on may improve maternal and infant outcomes, but more clinical data are needed, particularly for MOGAD.
Topics: Female; Humans; Pregnancy; Aquaporin 4; Neuromyelitis Optica; Myelin-Oligodendrocyte Glycoprotein; Autoantibodies; Autoimmune Diseases
PubMed: 37224631
DOI: 10.1016/j.msard.2023.104760