Multiple sclerosis (MS) has entered an era of immunomodulatory drug treatment, the impact of which on long-term disease progression remains controversial. The increasing use of these therapies has ...intensified our need to understand the true natural history of MS. The MS community is poised to establish whether the immunomodulatory drugs exhibit long-term benefits, with a suitable untreated natural history cohort likely the most practical and ethical comparator group. Thus, a thorough understanding of the natural history of MS is fundamental. In this review, we highlight recent advances in MS natural history over the last 5 years, with a focus on long-term population-based cohorts and factors associated with disease progression. Survival in MS has increased and longer times to irreversible disability have been reported in contemporary studies, indicating a slower accumulation of disability. Wide variation in the MS disease trajectory is evident within and between natural history studies, reflecting both methodologic considerations related to data collection and heterogeneity of disease activity. Recent publications have indicated that a younger age at disease onset is no longer indicative of a favorable outcome and further evidence supports the dissociation between relapses and long-term disability, although windows of opportunity may exist for some patients. We are now perhaps faced with our last chance to examine the true natural history of MS, so whether the reader is a practicing physician, health care provider, or researcher, or engaged in the pharmaceutical industry or in clinical trial design, recent advances in our understanding of the natural history of MS are of key significance.
Primary progressive multiple sclerosis (PPMS) carries the worst prognosis of the multiple sclerosis (MS) subtypes and is currently untreatable. A previous analysis of the British Columbia MS database ...challenged the view that disability progression is rapid in PPMS, but identified few predictors of disease progression. Here, we extend previous analyses in an updated PPMS retrospective cohort study of prevalent cases.
We used Kaplan-Meier survival analyses and Cox regression models to investigate the influence of gender, age at onset, and onset symptoms on time to and age at Expanded Disability Status Scale (EDSS) 6.0 in patients with PPMS.
Of 5,779 patients with definite MS, 552 (10%) had PPMS. Median time to EDSS 6.0 was 14.0 years (95% confidence interval CI 11.3-16.7), reached at a median age of 58.6 years (95% CI 56.8-60.3). Sensory onset symptoms were associated with a longer time to and an older age at EDSS 6.0 (multivariable hazard ratios 0.55 95% CI 0.35-0.87 and 0.54 0.35-0.85). Younger age at disease onset was associated with a longer time to but a younger age at EDSS 6.0. Gender and other onset symptoms were not associated with these outcomes. Fifty patients with PPMS (9%) fulfilled criteria for benign MS (EDSS < or =3.0 after 10 years' disease duration).
We identified 2 predictors of a slower disease progression in primary progressive multiple sclerosis. Sensory onset symptoms were associated with both a longer time to and a higher age at Expanded Disability Status Scale (EDSS) 6.0. A younger age at disease onset was associated with a longer time to EDSS 6.0, but patients with an early disease onset reached EDSS 6.0 at a younger age.
Persons with multiple sclerosis frequently report increased levels of fatigue and fatigability. However, behavioral surrogates that are strongly associated with self-reports are lacking, which limits ...research and treatment.
The aim of this study was to derive distinct behavioral syndromes that are reflected by self-reports concerning fatigue and fatigability.
We collected actigraphic data of 30 persons with multiple sclerosis over a period of 1 week during an inpatient stay at a neurorehabilitation facility. Further, participants completed the German fatigue severity scale. A principal component analysis of actigraphic parameters was performed to extract the latent component levels of behaviors that reflect fatigue (quantity of activity) and fatigability (fragmentation of activity). The resulting components were used in a cluster analysis.
Analyses suggested 3 clusters, one with high activity (d=0.65-1.57) and low clinical disability levels (d=0.91-1.39), one with high levels of sedentary behavior (d=1.06-1.58), and one with strong activity fragmentation (d=1.39-1.94). The cluster with high levels of sedentary behavior further revealed strong differences from the other clusters concerning participants' reported levels of fatigue (d=0.99-1.28).
Cluster analysis data proved to be feasible to meaningfully differentiate between different behavioral syndromes. Self-reports reflected the different behavioral syndromes strongly. Testing of additional domains (eg, volition or processing speed) and assessments during everyday life seem warranted to better understand the origins of reported fatigue symptomatology.
Abstract
Finger tapping tests have been shown feasible to assess motor performance in multiple sclerosis (MS) and were observed to be strongly associated with the estimated clinical severity of the ...disease. Therefore, tapping tests could be an adequate tool to assess disease status in MS. In this study we examined potential influencing factors on a maximum tapping task with the whole upper-limb for 10 s in 40 MS patients using linear mixed effects modelling. Patients were tested in three sessions with two trials per body-side per session over the course of 4–27 days of inpatient rehabilitation. Tested factors were the expanded disability scale (EDSS) score, laterality of MS, age, sex, hand dominance, time of day, session, trial (first or second), time between sessions, and the reported day form. A second model used these factors to examine the self-reported day form of patients. Linear mixed effects modelling indicated the tapping test to have a good inter-trial (proportional variance < 0.01) and inter-session reliability (non-significant; when controlling for time between sessions), an influence of hand-dominance (proportional variance 0.08), to be strongly associated with the EDSS (eta
2
= 0.22, interaction with laterality of MS eta
2
= 0.12) and to be not associated with the reported day form. The model explained 87% (p < 0.01) of variance in tapping performance. Lastly, we were able to observe a positive effect of neurologic inpatient rehabilitation on task performance obvious from a significant effect of the time between sessions (eta
2
= 0.007; longer time spans between sessions were associated with higher increments in performance). Day form was only impacted by EDSS and the time of the day (p < 0.01, R
2
= 0.57, eta
2
TIME
= 0.017, eta
2
EDSS
= 01.19). We conclude that the tapping test is a reliable and valid assessment tool for MS.
Summary Background On the basis of various clinical and MRI measurements, the phase 3 Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) study in patients with relapsing–remitting ...multiple sclerosis (RRMS) showed that short-course oral treatment with cladribine at cumulative doses of 3·5 and 5·25 mg/kg over 96 weeks was more effective than placebo. Achieving sustained freedom from disease activity is becoming a viable treatment goal in RRMS; we therefore aimed to assess the effects of cladribine on this composite outcome measure by doing a post-hoc analysis of data from the CLARITY study. Methods Freedom from disease activity is composed of three components that are commonly used individually as endpoints in clinical trials; it is defined as the patient having no relapse, no 3-month sustained change in expanded disability status scale (EDSS) score, and no new MRI lesions (no T1 gadolinium-enhancing or active T2 lesions) over a specified period. We assessed the effect of two doses of cladribine tablets versus placebo on the proportion of patients who were free from disease activity based on the individual components, all pair-wise combinations, and the composite of the three components (freedom from disease activity). Freedom from disease activity was analysed at 24, 48, and 96 weeks, and in subgroups of patients stratified according to baseline demographic and disease characteristics (age, disease duration, previous treatment with disease-modifying therapy, T1 gadolinium-enhancing lesion number, T2 lesion volume, EDSS score, number of previous relapses, and highly active disease). Findings Of the 1326 patients randomly assigned to treatment in the CLARITY study, 1192 were assessable for freedom from disease activity at 96 weeks. Over 24 weeks, 266 (67%) of 395 patients in the cladribine 3·5 mg/kg group and 283 (70%) of 406 in the cladribine 5·25 mg/kg group were free from disease activity, versus 145 (39%) of 373 in the placebo group (odds ratio OR 3·31, 95% CI 2·46–4·46 for the 3·5 mg/kg group; and 3·68, 2·73–4·97 for the 5·25 mg/kg group; both p<0·0001). Over 48 weeks, 208 (54%) of 384 patients in the cladribine 3·5 mg/kg group and 222 (56%) of 396 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 86 (24%) of 360 patients in the placebo group (OR 3·80, 2·77–5·22 for the 3·5 mg/kg group; 4·13, 3·02–5·66 for the 5·25 mg/kg group; both p<0·0001). Over 96 weeks, 178 (44%) of 402 patients in the cladribine 3·5 mg/kg group and 189 (46%) of 411 patients in the cladribine 5·25 mg/kg group were free from disease activity, versus 60 (16%) of 379 patients in the placebo group (OR 4·28, 3·05–6·02 for the 3·5 mg/kg group; 4·62, 3·29–6·48 for the 5·25 mg/kg group; both p<0·0001). The effects of cladribine tablets on freedom from disease activity were significant across all patient subgroups. Interpretation Treatment with cladribine tablets significantly increased the proportion of patients with sustained freedom from disease activity over 96 weeks compared with placebo. Sustained freedom from disease activity could become an important measure of therapeutic response in RRMS. Funding Merck Serono SA–Geneva, Switzerland; an affiliate of Merck, Darmstadt, Germany.
Summary Background Siponimod is an oral selective modulator of sphingosine 1-phosphate receptor types 1 and type 5, with an elimination half-life leading to washout in 7 days. We aimed to determine ...the dose-response relation of siponimod in terms of its effects on brain MRI lesion activity and characterise safety and tolerability in patients with relapsing-remitting multiple sclerosis. Methods In this double-blind, adaptive dose-ranging phase 2 study, we enrolled adults (aged 18–55 years) with relapsing-remitting multiple sclerosis at 73 medical centres in Europe and North America. We tested two patient cohorts sequentially, separated by an interim analysis at 3 months. We randomly allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 2 mg, or 0·5 mg, or placebo for 6 months. We randomly allocated patients in cohort 2 (4:4:1) to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily for 3 months. Randomisation was done with a central, automated system and patients and investigators were masked to treatment assignment. The primary endpoint was dose-response, assessed by percentage reduction in monthly number of combined unique active lesions at 3 months for siponimod versus placebo; this endpoint was analysed by a multiple comparison procedure with modelling techniques in all patients with at least one MRI scan up to 3 months. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov , number NCT00879658. Findings Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation (p=0·0001) across the five doses of siponimod, with reductions in combined unique active lesions at 3 months compared with placebo of 35% (95% CI 17–57) for siponimod 0·25 mg (51 patients included in the primary endpoint analysis), 50% (29–69) for siponimod 0·5 mg (43 patients), 66% (48–80) for siponimod 1·25 mg (42 patients), 72% (57–84) for siponimod 2 mg (45 patients), and 82% (70–90) for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86%) of 43 patients who received siponimod 0·5 mg had adverse events (eight serious), as did 48 (98%) of 49 patients who received siponimod 2 mg (four serious), 48 (96%) of 50 patients who received siponimod 10 mg (three serious), and 36 (80%) of 45 controls (none serious). For individuals treated to 3 months, 38 (74%) of 51 patients who received siponimod 0·25 mg had adverse events (none serious), as did 29 (69%) of 42 patients who received siponimod 1·25 mg (two serious) and 13 (81%) of 16 controls (none serious). Interpretation Therapeutic effects of siponimod on MRI lesion activity in model-based analyses and its tolerability in relapsing-remitting multiple sclerosis warrant investigation in a phase 3 trial. Funding Novartis Pharma AG.
Abstract
Background
Wearable technologies are currently clinically used to assess energy expenditure in a variety of populations, e.g., persons with multiple sclerosis or frail elderly. To date, ...going beyond physical activity, deriving sensorimotor capacity instead of energy expenditure, is still lacking proof of feasibility.
Methods
In this study, we read out sensors (accelerometer and gyroscope) of smartwatches in a sample of 90 persons with multiple sclerosis over the course of one day of everyday life in an inpatient setting. We derived a variety of different kinematic parameters, in addition to lab-based tests of sensorimotor performance, to examine their interrelation by principal component, cluster, and regression analyses.
Results
These analyses revealed three components of behavior and sensorimotor capacity, namely clinical characteristics with an emphasis on gait, gait-related physical activity, and upper-limb related physical activity. Further, we were able to derive four clusters with different behavioral/capacity patterns in these dimensions. In a last step, regression analyses revealed that three selected smartwatch derived kinematic parameters were able to partially predict sensorimotor capacity, e.g., grip strength and upper-limb tapping.
Conclusions
Our analyses revealed that physical activity can significantly differ between persons with comparable clinical characteristics and that assessments of physical activity solely relying on gait can be misleading. Further, we were able to extract parameters that partially go beyond physical activity, with the potential to be used to monitor the course of disease progression and rehabilitation, or to early identify persons at risk or a sub-clinical threshold of disease severity.
Inpatient rehabilitation has been shown to be an effective intervention for sensorimotor performance in multiple sclerosis (MS) patients. So far, predictions of the rehabilitation outcomes are ...limited. The objective was to predict inpatient rehabilitation outcomes by changes in the Watzmann Severity Scale (WSS), a statistical estimation of the EDSS by sensorimotor capacity. Sensorimotor performance and physical activity during rehabilitation (by actigraphy) were assessed in a sample of 28 MS patients at a facility for neurorehabilitation. Daily changes in the WSS were predicted by a model of multiple linear regression. The resulting model had an R2adjusted of 0.48 (p < 0.01) and revealed five impacting factors (a reduction in the WSS represents an improvement): the number of steps (β-weight = 0.52, p < 0.01), the duration of nocturnal rest time (β-weight = 0.46, p = 0.01), the EDSS at entry (β-weight = 0.38, p = 0.03), a relapsing-remitting MS (β-weight = 0.37, p = 0.03), and the performance in a visuomotor pursuit task with time pressure (β-weight = −0.35, p = 0.04). One standard deviation improvement was predicted when the patient at admission yielded 6600 fewer steps per day, 94 min less rest per night, −2.7 points in the EDSS at entry, a relapsing-remitting MS, and a pursuit task performance that decreased by 2.2 standard deviations. Overall, the patients improved by −0.22 ± 0.51 WSS points during 19.3 ± 4.5 d of inpatient rehabilitation. Different potential explanations of the findings are discussed, one of which proposes that the results reflect an unhealthy lifestyle which, in addition to MS, would explain the higher predicted improvements by rehabilitation tackling both MS and the patients’ lifestyle.
SPARC (secreted protein acidic and rich in cysteine) is a nonstructural, cell-matrix modulating protein involved in angiogenesis and endothelial barrier function, yet its potential role in ...cerebrovascular development, inflammation, and repair in the central nervous system (CNS) remains undetermined.
This study examines SPARC expression in cultured human cerebral microvascular endothelial cells (hCMEC/D3)-an in vitro model of the blood-brain barrier (BBB)-as they transition between proliferative and barrier phenotypes and encounter pro-inflammatory stimuli. SPARC protein levels were quantified by Western blotting and immunocytochemistry and messenger RNA (mRNA) by RT-PCR.
Constitutive SPARC expression by proliferating hCMEC/D3s is reduced as cells mature and establish a confluent monolayer. SPARC expression positively correlated with the proliferation marker Ki-67 suggesting a role for SPARC in cerebrovascular development. The pro-inflammatory molecules tumor necrosis factor-α (TNF-α) and endotoxin lipopolysaccharide (LPS) increased SPARC expression in cerebral endothelia. Interferon gamma (IFN-γ) abrogated SPARC induction observed with TNF-α alone. Barrier function assays show recombinant human (rh)-SPARC increased paracellular permeability and decreased transendothelial electrical resistance (TEER). This was paralleled by reduced zonula occludens-1 (ZO-1) and occludin expression in hCMEC/D3s exposed to rh-SPARC (1-10 μg/ml) compared with cells in media containing a physiological dose of SPARC.
Together, these findings define a role for SPARC in influencing cerebral microvascular properties and function during development and inflammation at the BBB such that it may mediate processes of CNS inflammation and repair.
A debate on shared decision making in multiple sclerosis (MS) was led by a patient advocate and leading neurologists from the MS in the 21st Century Steering Group. Key themes and salient points ...which emerged from the debate and audience discussions are reported in this article. Arguments against shared decision making included the fact that physicians study and practice for years to reach their level of expertise, and that the level of understanding required to make these decisions may not be possible to communicate to patients within time-limited consultations. Furthermore, unreliable online information, information overload or information with marketing bias may also cloud patients’ judgements. Arguments for patient engagement focussed on how ownership of decisions can lead to improved adherence and outcomes, and a strengthening of the physician–patient relationship. Shared decision making requires educating patients to make informed decisions and to understand the risks and consequences of their choices. However, shared decision making may not be the correct option for every patient, and the level of involvement must be driven by the patient. To support patients’ engagement and promote responsible management of their condition, physicians need to (1) foster and maintain a positive, ongoing relationship with their patients, and (2) provide patients with timely, accurate, and understandable information. There was broad agreement that the patient voice should be heard more in discussions around the future of MS care. MS in the 21st Century offers a model for patient involvement in partnership with MS healthcare specialists, and the steering group is currently considering these issues and developing tools and solutions to enhance patient–physician communication and relationships.
Funding
Merck KGaA, Darmstadt, Germany.
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