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The Cochrane Database of Systematic... Nov 2021Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, with an unpredictable course. Current MS therapies such as disease-modifying... (Review)
Review
BACKGROUND
Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, with an unpredictable course. Current MS therapies such as disease-modifying therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. Siponimod (BAF312) is an oral treatment, a selective sphingosine-1-phosphate (S1P) receptor modulator, for the treatment of adults with relapsing forms of MS including active, secondary progressive MS with relapses.
OBJECTIVES
To assess the benefits and adverse effects of siponimod as monotherapy or combination therapy versus placebo or any active comparator for people diagnosed with MS.
SEARCH METHODS
On 18 June 2020, we searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Trials Register, which contains studies from CENTRAL, MEDLINE and Embase, and the trials registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). We also handsearched relevant journals and screened the reference lists of published reviews and retrieved articles and searched reports (2004 to June 2020) from the MS societies in Europe and America.
SELECTION CRITERIA
We included randomised parallel controlled clinical trials (RCTs) that evaluated siponimod, as monotherapy or combination therapy, versus placebo or any active comparator in people with MS. There were no restrictions on dose or administration frequency.
DATA COLLECTION AND ANALYSIS
We used standard methodological procedures expected by Cochrane. We discussed disagreements and resolved them by consensus among the review authors. Our primary outcomes wereworsening disability , relapse and adverse events, and secondary outcomes were annualised relapse rate, gadolinium-enhancing lesions, new lesions or enlarged pre-existing lesions and mean change of brain volume. We independently evaluated the certainty of evidence using the GRADE approach. We contacted principal investigators of included studies for additional data or confirmation of data.
MAIN RESULTS
Two studies (1948 participants) met our selection criteria, 608 controls and 1334 treated with siponimod. The included studies compared siponimod with placebo. Overall, all studies had a high risk of bias due to selective reporting and attrition bias. Comparing siponimod administered at a dose of 2 mg to placebo, we found that siponimod may reduce the number of participants with disability progression at six months (56 fewer people per 1000; risk ratio (RR) 0.78, 95% confidence interval (CI) 0.65 to 0.94; 1 study, 1641 participants; low-certainty evidence) and annualised relapse rate (RR 0.43, 95% CI 0.34 to 0.56; 2 studies, 1739 participants; low-certainty evidence). But it might lead to little reduction in the number of participants with new relapse (166 fewer people per 1000; RR 0.38, 95% CI 0.15 to 1.00; 1 study, 94 participants; very low-certainty evidence). We observed no evidence of a difference due to adverse events for siponimod at 2 mg compared to placebo (14 more people per 1000; RR 1.52, 95% CI 0.85 to 2.71; 2 studies, 1739 participants, low-certainty evidence). In addition, due to the high risk of inaccurate magnetic resonance imaging (MRI) data in the two included studies, we could not combine data for active lesions on MRI scans. Both studies had high attrition bias resulting from the unbalanced reasons for dropouts among groups and high risk of bias due to conflicts of interest. Siponimod may reduce the number of gadolinium-enhancing T1-weighted lesions at two years of follow-up (RR 0.14, 95% CI 0.10 to 0.19; P < 0.0001; 1 study, 1641 participants; very low-certainty evidence). There may be no evidence of a difference between groups in the number of participants with at least one serious adverse event excluding relapses (113 more people per 1000; RR 1.80, 95% CI 0.37 to 8.77; 2 studies, 1739 participants; low-certainty evidence) at six months. No data were available regarding cardiac adverse events. In terms of safety profile, the most common adverse events associated with siponimod were headache, back pain, bradycardia, dizziness, fatigue, influenza, urinary tract infection, lymphopenia, nausea, alanine amino transferase increase and upper respiratory tract infection. These adverse events have dose-related effects and rarely led to discontinuation of treatment.
AUTHORS' CONCLUSIONS
Based on the findings of the RCTs included in this review, we are uncertain whether siponimod interventions are beneficial for people with MS. There was low-certainty evidence to support that siponimod at a dose of 2 mg orally once daily as monotherapy compared with placebo may reduce the annualised relapse rate and the number of participants who experienced disability worsening, at 6 months. However, the certainty of the evidence to support the benefit in reducing the number of people with a relapse is very low. The risk of withdrawals due to adverse events requires careful monitoring of participants over time. The duration of all studies was less than 24 months, so the efficacy and safety of siponimod over 24 months are still uncertain, and further exploration is needed in the future. There is no high-certainty data available to evaluate the benefit on MRI outcomes. We assessed the certainty of the body of evidence for all outcomes was low to very low, downgraded due to serious study limitations, imprecision and indirectness. We are uncertain whether siponimod is beneficial for people with MS. More new studies with robust methodology and longer follow-up are needed to evaluate the benefit of siponimod for the management of MS and to observe long-term adverse effects. Also, in addition to comparing with placebo, more new studies are needed to evaluate siponimod versus other therapeutic options.
Topics: Adult; Azetidines; Benzyl Compounds; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive
PubMed: 34783010
DOI: 10.1002/14651858.CD013647.pub2 -
Nutrients Jun 2023Vitamin D supplementation has been considered a possible treatment to reduce the risk of disease activity and progression in people with multiple sclerosis (MS).... (Meta-Analysis)
Meta-Analysis Review
Vitamin D supplementation has been considered a possible treatment to reduce the risk of disease activity and progression in people with multiple sclerosis (MS). However, its effect on disease symptoms remains unclear. The aim of this meta-analysis was to conduct a systematic review to assess the effect of vitamin D on fatigue in this population. The systematic review was conducted using the MEDLINE, Cochrane Library, Embase and Web of Science databases from inception to May 2023. Randomized controlled trials (RCTs) reporting pre-post changes in fatigue after vitamin D supplementation were included. Pooled effect sizes and 95% confidence intervals (95% CIs) were calculated by applying a random effects model with Stata/SE (Version 16.0; StataCorp., College Station, TX, USA). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. A total of five studies with 345 individuals (271 females; age range: 25.4-41.1 years) were included. A significant reduction in fatigue was perceived when vitamin D supplementation was compared with a control group: -0.18 (95% CI: -0.36 to -0.01; I = 0%). Thus, our findings show that the therapeutic use of vitamin D on fatigue in people with MS could be considered. Nevertheless, due to the lack of agreement on the dose to be applied, it is recommended to use it under medical prescription.
Topics: Adult; Female; Humans; Dietary Supplements; Fatigue; Multiple Sclerosis; Vitamin D; Male
PubMed: 37447189
DOI: 10.3390/nu15132861 -
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 -
European Addiction Research 2021Although the recreational cannabis use is expressive worldwide, the literature about medical potential of cannabis extracts, including its anti-inflammatory properties,...
INTRODUCTION
Although the recreational cannabis use is expressive worldwide, the literature about medical potential of cannabis extracts, including its anti-inflammatory properties, remains inconclusive.
METHODS
We screened all articles, published on the PubMed database, on inflammatory mediators and any information about cannabis use from 1980 to March 2019.
RESULTS
Six studies were included, and the main findings were as follows: (i) among healthy volunteers and cannabis users, cannabinoids seemed to decrease the inflammatory response, thus decreasing the immune response, which led to a higher risk of infections; (ii) among patients with multiple sclerosis, cannabinoids seemed to have little impact on the inflammatory markers' levels.
DISCUSSION
Although cannabis use can produce immune inflammatory suppression in healthy people, this effect is not robust enough to change inflammatory mediators' levels in situations of highly dysfunctional inflammatory activation. Nevertheless, the impact of cannabinoids in clinical outcomes of these conditions remains to be determined.
Topics: Analgesics; Cannabis; Humans; Inflammation Mediators; Multiple Sclerosis
PubMed: 32726782
DOI: 10.1159/000508840 -
Neuropsychology Review Sep 2022Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic... (Meta-Analysis)
Meta-Analysis Review
Fatigue is one of the most debilitating symptoms for people with multiple sclerosis (PwMS). By consolidating a diverse and conflicting evidence-base, this systematic review and meta-analysis aimed to gain new insights into the neurobiology of MS fatigue. MEDLINE, ProQuest, CINAHL, Web of Science databases and grey literature were searched using Medical Subject Headings. Eligible studies compared neuroimaging and neurophysiological data between people experiencing high (MS-HF) versus low (MS-LF) levels of perceived MS fatigue, as defined by validated fatigue questionnaire cut-points. Data were available from 66 studies, with 46 used for meta-analyses. Neuroimaging studies revealed lower volumetric measures in MS-HF versus MS-LF for whole brain (-22.74 ml; 95% CI: -37.72 to -7.76 ml; p = 0.003), grey matter (-18.81 ml; 95% CI: -29.60 to -8.03 ml; p < 0.001), putamen (-0.40 ml; 95% CI: -0.69 to -0.10 ml; p = 0.008) and acumbens (-0.09 ml; 95% CI: -0.15 to -0.03 ml; p = 0.003) and a higher volume of T1-weighted hypointense lesions (1.10 ml; 95% CI: 0.47 to 1.73 ml; p < 0.001). Neurophysiological data showed reduced lower-limb maximum voluntary force production (-19.23 N; 95% CI: -35.93 to -2.53 N; p = 0.02) and an attenuation of upper-limb (-5.77%; 95% CI:-8.61 to -2.93%; p < 0.0001) and lower-limb (-2.16%; 95% CI:-4.24 to -0.07%; p = 0.04) skeletal muscle voluntary activation, accompanied by more pronounced upper-limb fatigability (-5.61%; 95% CI: -9.57 to -1.65%; p = 0.006) in MS-HF versus MS-LF. Results suggest that MS fatigue is characterised by greater cortico-subcortical grey matter atrophy and neural lesions, accompanied by neurophysiological decrements, which include reduced strength and voluntary activation. Prospero registration Prospero registration number: CRD42016017934.
Topics: Brain; Cross-Sectional Studies; Fatigue; Humans; Multiple Sclerosis; Organ Size
PubMed: 33961198
DOI: 10.1007/s11065-021-09508-1 -
Reviews in the Neurosciences Aug 2021Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the... (Meta-Analysis)
Meta-Analysis
Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes.
Topics: Biomarkers; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Neurodegenerative Diseases; Neuroglia
PubMed: 33594840
DOI: 10.1515/revneuro-2020-0145 -
Nutrients Apr 2023The link between vitamin D and multiple sclerosis (MS) has been suggested in epidemiological, genetic, immunological, and clinical studies. The aim of the present... (Review)
Review
The link between vitamin D and multiple sclerosis (MS) has been suggested in epidemiological, genetic, immunological, and clinical studies. The aim of the present systematic review of the literature was to assess the effects of vitamin D supplementation on clinical and imaging outcomes in patients with MS. The outcomes we assessed included relapse events, disability progression, and magnetic resonance imaging (MRI) lesions. The search was conducted using PubMed, ClinicalTrials.gov, and EudraCT databases, and it included records published up until 28 February 2023. The systematic review was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 guidelines. Nineteen independent clinical studies (corresponding to 24 records) were included in the systematic review. The risk of bias in randomized controlled trials (RCTs) was analyzed using the Cochrane risk-of-bias tool. Fifteen trials investigated relapse events, and most of them reported no significant effect of vitamin D supplementation. Eight of 13 RCTs found that vitamin D supplementation had no effect on disability [assessed by Expanded Disability Status Scale (EDSS) scores] compared to controls. Interestingly, recent RCTs reported a significant reduction in new MRI lesions in the central nervous system of MS patients during supplementation with vitamin D3.
Topics: Humans; Vitamins; Vitamin D; Multiple Sclerosis; Dietary Supplements; Recurrence
PubMed: 37111166
DOI: 10.3390/nu15081945 -
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 -
Neurological Sciences : Official... May 2023To exp lore changes in immunoglobulin (Ig) levels for people with relapsing-multiple sclerosis (RMS) treated with ocrelizumab or ofatumumab and the relationship between... (Review)
Review
OBJECTIVE
To exp lore changes in immunoglobulin (Ig) levels for people with relapsing-multiple sclerosis (RMS) treated with ocrelizumab or ofatumumab and the relationship between Ig levels and infections.
METHODS
A systematic literature review (SLR) was conducted to identify clinical trials and real-world evidence (RWE) studies on Ig levels over time and studies on associations with infections for ocrelizumab and ofatumumab for people with RMS through 10 September 2021. Searches were conducted in Embase, MEDLINE, Cochrane Library, trial registries, and recent conference abstracts.
RESULTS
Of 1,580 articles identified, 30 reporting on 11 trials and 5 RWE studies were included. Ocrelizumab trials (n = 4) had 24-336 weeks of follow-up and reported decreasing Ig G (IgG) levels, while RWE (n = 5) had 52-78 weeks of follow-up and reported IgG to be stable or decrease only slightly. IgG levels were stable in ofatumumab trials (n = 5; 104-168 weeks of follow-up), but no RWE or longer-term studies were identified. No apparent association between decreased Ig levels and infections was observed during ofatumumab treatment (ASCLEPIOS I/II), while for ocrelizumab, the only data on apparent associations between decreased IgG levels and serious infection rates were for a pooled population of people with RMS or primary progressive MS.
CONCLUSION
Decreasing IgG levels have been correlated with increased infection risk over time. IgG levels appeared to decrease over time in ocrelizumab trials but remained relatively stable over time in ofatumumab trials. Additional research is needed to understand differences between ocrelizumab and ofatumumab and identify people at risk of decreasing IgG levels and infection.
Topics: Humans; Multiple Sclerosis; Antibodies, Monoclonal; Antineoplastic Agents; Immunoglobulin G; Multiple Sclerosis, Relapsing-Remitting
PubMed: 36648561
DOI: 10.1007/s10072-022-06582-y -
Cureus May 2023CANOMAD, characterized by chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M (IgM) paraprotein, cold agglutinins, and disialosyl antibodies, encompasses a... (Review)
Review
CANOMAD, characterized by chronic ataxic neuropathy, ophthalmoplegia, immunoglobulin M (IgM) paraprotein, cold agglutinins, and disialosyl antibodies, encompasses a clinical, radiological, and laboratory diagnosis. CANOMAD is a rare condition, with fewer than 100 cases reported in the literature. The understanding and diagnosis of the disease have improved in the last few years, but the treatment of CANOMAD is mainly unknown, and there is not a clear consensus about it. We conducted a systematic review regarding the efficacy of rituximab in CANOMAD's treatment to investigate the clinical and biological response of CANOMAD in patients treated with rituximab. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-Analyses of Observational Studies in Epidemiology (MOOSE) reporting guidelines for this systematic review. To analyze the bias of the study, we used the Joanna Briggs Institute's (JBI) Critical Appraisal Checklist to analyze the bias of the case reports, and we used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for the observational studies. We only included case reports, case series, and observational studies written in English with patients formally diagnosed with CANOMAD and treated with rituximab. We excluded systematic reviews, literature reviews, and meta-analyses. We investigated the clinical and biological responses of the patients to rituximab. The clinical response was classified as complete recovery (CR), partial response (PR), stable disease (SD), and non-response (NR). We gathered 34 patients. The literature uses a modified Rankin score to define complete improvement (CR), partial response (PR), stable disease (SD), and progression. Clinically, there were three patients with CR, five with PR, 15 with SD, and 11 with progression. The biological response was assessed by measuring the decrease in antibody titers in 27 patients. Among those, six patients had CR, 12 had PR, eight had SD, and one had progression. Among 15 patients with neurological evaluation, 10 had ocular symptoms, and two presented with bulbar symptoms. Seven of the ten patients with ocular symptoms had SD, two had PR, and one had progression. Only 14 patients had a report of demyelinating features. Three had an axonal pattern, six had a demyelinating pattern, and five had a mixed pattern. Among patients with an axonal pattern, three had an SD. Among patients with a demyelinating pattern, three had a PR, two had an SD, and one had progression. Among patients with a mixed pattern, four had SD, and one had progression. We concluded that patients with CR have a shorter disease duration than patients with PR, SD, or progression. In addition, patients with CR had longer follow-ups than the other groups, suggesting that being treated early with rituximab improves the clinical outcome and has a sustained effect. There were no differences in the frequency of ocular and bulbar symptoms among patients with CANOMAD. The axonal pattern is more common in patients with SD, suggesting that axonal and mixed patterns could be markers of a bad prognosis.
PubMed: 37337500
DOI: 10.7759/cureus.39237