Over the last decade, clinical registries have significantly contributed to the pool of evidence that supports management decisions in patients with multiple sclerosis. Being the largest ...international registry of multiple sclerosis and neuroimmunological disorders, MSBase collects demographic, clinical and limited paraclinical information from patients managed in different regions and under various circumstances. In this review, we will provide an overview of its published output, with focus on the information with impact on the management of multiple sclerosis.
The complexity of multiple sclerosis (MS) treatment means that doctors and decision-makers need the best available evidence to make the best decisions for patient care. Randomized controlled trials ...(RCTs) are accepted as the gold standard for assessing the efficacy and safety of any new drug, but conclusions of these trials do not always aid in daily decision-making processes. Indeed, RCTs are usually conducted in ideal conditions, so can measure efficacy only in restricted and unrepresentative populations. In the past decade, a growing number of MS databases and registries have started to produce long-term outcome data from large cohorts of patients with MS treated with disease-modifying therapies in real-world settings. Such observational studies are addressing issues that are otherwise difficult or impossible to study. In this Review, we focus on the most recently published observational studies designed to identify predictors of poor outcome and treatment response or failure, and to evaluate the relative and long-term effectiveness of currently used MS treatments. We also outline the statistical approaches that are most commonly used to reduce bias and limitations in these studies, and the challenges associated with the use of 'big MS data' to facilitate the implementation of personalized medicine in MS.
Objective
There is an association between latitude, relative vitamin D deficiency and risk of multiple sclerosis (MS), and an association between vitamin D and disease progression. We have performed ...a meta-analysis with the aim of investigating the role of therapeutic vitamin D in MS.
Methods
A systematic search of databases was performed to identify clinical trials assessing vitamin D in patients with relapsing–remitting MS. Studies were selected based on inclusion and exclusion criteria. Analysis was performed using RevMan 5.3 software.
Results
Twelve studies involving 950 patients were included in the final analysis. Studies were divided into four groups because of heterogeneity in study design. Studies were judged to be at low or unclear risk of bias, except in three studies, and this was confirmed by funnel plots. No statistically significant difference was seen for any of the outcome measures. There were non-significant trends in favour of vitamin D for all outcome measures, particularly when only placebo-controlled studies were included. Dose comparison studies showed a significant increase in annualised relapse rate (mean difference 0.15 95%CI 0.01–0.30) and non-significant trends of increased Expanded Disability Status Scale and gadolinium-enhancing lesions for the higher-dose arms.
Conclusion
These findings suggest that vitamin D supplementation may have a therapeutic role in the treatment of MS. However, there is uncertainty with regard to the most appropriate dose, with high doses potentially being associated with worse outcomes. There remains the need for further well-performed randomised, dose-ranging, placebo-controlled trials of vitamin D in MS.
Background:
Confirmed Expanded Disability Status Scale (EDSS) progression occurring after a fixed-study entry baseline is a common measure of disability increase in relapsing-remitting multiple ...sclerosis (RRMS) studies but may not detect all disability progression events, especially those unrelated to overt relapses.
Objective:
To evaluate possible measures of disability progression unrelated to relapse using EDSS data over ≈5.5 years from the Tysabri® Observational Program (TOP).
Methods:
TOP is an ongoing, prospective, open-label study in RRMS patients receiving intravenous 300 mg natalizumab every 4 weeks. Measures of increasing disability were assessed using as a reference either study baseline score or a “roving” system that resets the reference score after ⩾24- or ⩾48-week confirmation of a new score.
Results:
This analysis included 5562 patients. Approximately 70% more EDSS progression events unrelated to relapse and 50% more EDSS worsening events overall were detected with a roving reference score (cumulative probability: 17.6% and 29.7%, respectively) than with a fixed reference baseline score (cumulative probability: 10.1% and 20.3%, respectively).
Conclusion:
In this long-term observational RRMS dataset, a roving EDSS reference value was more efficient than a study baseline EDSS reference in detecting progression/worsening events unrelated to relapses and thus the transition to secondary progressive disease.
Summary Background The human monoclonal antibody opicinumab (BIIB033, anti-LINGO-1) has shown remyelinating activity in preclinical studies. We therefore assessed the safety and tolerability, and ...efficacy of opicinumab given soon after a first acute optic neuritis episode. Methods This randomised, double-blind, placebo-controlled, phase 2 study (RENEW) was done at 33 sites in Australia, Canada, and Europe in participants (aged 18–55 years) with a first unilateral acute optic neuritis episode within 28 days from study baseline. After treatment with high-dose methylprednisolone (1 g/day, intravenously, for 3–5 days), participants were assigned with a computer-generated sequence with permuted block randomisation (1:1) using a centralised interactive voice and web response system to receive 100 mg/kg opicinumab intravenously or placebo once every 4 weeks (six doses) and followed up to week 32. All study participants and all study staff, including the central readers, were masked to treatment assignment apart from the pharmacist responsible for preparing the study treatments and the pharmacy monitor at each site. The primary endpoint was remyelination at 24 weeks, measured as recovery of affected optic nerve conduction latency using full-field visual evoked potential (FF-VEP) versus the unaffected fellow eye at baseline. Analysis was by intention-to-treat (ITT); prespecified per-protocol (PP) analyses were also done. This study is registered with ClinicalTrials.gov , number NCT01721161. Findings The study was done between Dec 21, 2012, and Oct 21, 2014. 82 participants were enrolled, and 41 in each group comprised the ITT population; 33 participants received opicinumab and 36 received placebo in the PP population. Adjusted mean treatment difference of opicinumab versus placebo was −3·5 ms (17·3 vs 20·8 95% CI −10·6 to 3·7; 17%; p=0·33) in the ITT population, and −7·6 ms in the PP population (14·7 vs 22·2 −15·1 to 0·0; 34%; p=0·050) at week 24 and −6·1 ms (15·1 vs 21·2 −12·7 to 0·5; 29%; p=0·071) in the ITT population and −9·1 ms (13·2 vs 22·4 −16·1 to −2·1; 41%; p=0·011) in the PP population at week 32. The overall incidence (34 83% of 41 in each group) and severity of adverse events (two 5% of 41 severe adverse events with placebo vs three 7% of 41 with opicinumab) were similar between groups and no significant effects on brain MRI measures were noted in either group (mean T2 lesion volume change, 0·05 mL SD 0·21 for placebo vs 0·20 mL 0·52 with opicinumab; 27 77% of 35 participants with no change in gadolinium-enhancing Gd+ lesion number with opicinumab vs 27 79% of 34 with placebo; mean 0·4 SD 0·79 for the placebo group and 0·85 for the opicinumab group new Gd+ lesions per participant in both groups). Treatment-related serious adverse events were reported in three (7%) of 41 participants in the opicinumab group (hypersensitivity n=2, asymptomatic increase in transaminase concentrations n=1) and none of the participants in the placebo group. Interpretation Remyelination did not differ significantly between the opicinumab and placebo groups in the ITT population at week 24. However, results from the prespecified PP population suggest that enhancing remyelination in the human CNS with opicinumab might be possible and warrant further clinical investigation. Funding Biogen.
Background:
The optimal timing of treatment starts for achieving the best control on the long-term disability accumulation in multiple sclerosis (MS) is still to be defined.
Objective:
The aim of ...this study was to estimate the optimal time to start disease-modifying therapies (DMTs) to prevent the long-term disability accumulation in MS, using a pooled dataset from the Big Multiple Sclerosis Data (BMSD) network.
Methods:
Multivariable Cox regression models adjusted for the time to first treatment start from disease onset (in quintiles) were used. To mitigate the impact of potential biases, a set of pairwise propensity score (PS)-matched analyses were performed. The first quintile, including patients treated within 1.2 years from onset, was used as reference.
Results:
A cohort of 11,871 patients (median follow-up after treatment start: 13.2 years) was analyzed. A 3- and 12-month confirmed disability worsening event and irreversible Expanded Disability Status Scale (EDSS) 4.0 and 6.0 scores were reached by 7062 (59.5%), 4138 (34.9%), 3209 (31.1%), and 1909 (16.5%) patients, respectively. The risk of reaching all the disability outcomes was significantly lower (p < 0.0004) for the first quintile patients’ group.
Conclusion:
Real-world data from the BMSD demonstrate that DMTs should be commenced within 1.2 years from the disease onset to reduce the risk of disability accumulation over the long term.
Abstract Introduction We present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used ...widely among those committed to creating a better future for people with MS and their families. Methods Structured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs). Results Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services. We recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and disability progression should be included in the definition of disease activity and monitored regularly when practical. On suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A shared decision-making process that embodies dialogue and considers all appropriate DMTs should be implemented. Monitoring data should be recorded formally in registries to generate real-world evidence. In many jurisdictions, access to DMTs is limited. To improve treatment access the relevant bodies should consider all costs to all parties when conducting economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models. Conclusions The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.
Background:
Multiple sclerosis (MS) quality of care guidelines are consensus-based. The effectiveness of the recommendations is unknown.
Objective:
To determine whether clinic-level quality of care ...affects clinical and patient-reported outcomes.
Methods:
This nationwide observational cohort study included patients with adult-onset MS in the Swedish MS registry with disease onset 2005–2015. Clinic-level quality of care was measured by four indicators: visit density, magnetic resonance imaging (MRI) density, mean time to commencement of disease-modifying therapy, and data completeness. Outcomes were Expanded Disability Status Scale (EDSS) and patient-reported symptoms measured by the Multiple Sclerosis Impact Scale (MSIS-29). Analyses were adjusted for individual patient characteristics and disease-modifying therapy exposure.
Results:
In relapsing MS, all quality indicators benefitted EDSS and physical symptoms. Faster treatment, frequent visits, and higher data completeness benefitted psychological symptoms. After controlling for all indicators and individual treatment exposures, faster treatment remained independently associated with lower EDSS (−0.06, 95% confidence interval (CI): −0.01, −0.10) and more frequent visits were associated with milder physical symptoms (MSIS-29 physical score: −16.2%, 95% CI: −1.8%, −29.5%). Clinic-level quality of care did not affect any outcomes in progressive-onset disease.
Conclusion:
Certain quality of care indicators correlated to disability and patient-reported outcomes in relapse-onset but not progressive-onset disease. Future guidelines should consider recommendations specific to disease course.
The autoimmune encephalitides are a group of autoimmune conditions targeting the central nervous system and causing severe clinical symptoms including drug-resistant seizures, cognitive dysfunction ...and psychiatric disturbance. Although these disorders appear to be antibody mediated, the role of innate immune responses needs further clarification. Infiltrating monocytes and microglial proliferation at the site of pathology could contribute to the pathogenesis of the disease with resultant blood brain barrier dysfunction, and subsequent activation of adaptive immune response. Both innate and adaptive immune cells can produce pro-inflammatory molecules which can perpetuate ongoing neuroinflammation and drive ongoing seizure activity. Ultimately neurodegenerative changes can ensue with resultant long-term neurological sequelae that can impact on ongoing patient morbidity and quality of life, providing a potential target for future translational research.
Objectives:
We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established ...relapsing–remitting multiple sclerosis (RRMS) and healthy controls (HCs).
Methods:
Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison.
Results:
CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI).
Interpretation:
Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.
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