Faculty Bibliography
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283
Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study
BACKGROUND:modulator, on disability progression in patients with SPMS. METHODS:This event-driven and exposure-driven, double-blind, phase 3 trial was done at 292 hospital clinics and specialised multiple sclerosis centres in 31 countries. Using interactive response technology to assign numbers linked to treatment arms, patients (age 18-60 years) with SPMS and an Expanded Disability Status Scale score of 3·0-6·5 were randomly assigned (2:1) to once daily oral siponimod 2 mg or placebo for up to 3 years or until the occurrence of a prespecified number of confirmed disability progression (CDP) events. The primary endpoint was time to 3-month CDP. Efficacy was assessed for the full analysis set (ie, all randomly assigned and treated patients); safety was assessed for the safety set. This trial is registered with ClinicalTrials.gov, number NCT01665144. FINDINGS:1651 patients were randomly assigned between Feb 5, 2013, and June 2, 2015 (1105 to the siponimod group, and 546 to the placebo group). One patient did not sign the consent form, and five patients did not receive study drug, all of whom were in the siponimod group. 1645 patients were included in the analyses (1099 in the siponimod group and 546 in the placebo). At baseline, the mean time since first multiple sclerosis symptoms was 16·8 years (SD 8·3), and the mean time since conversion to SPMS was 3·8 years (SD 3·5); 1055 (64%) patients had not relapsed in the previous 2 years, and 918 (56%) of 1651 needed walking assistance. 903 (82%) patients receiving siponimod and 424 (78%) patients receiving placebo completed the study. 288 (26%) of 1096 patients receiving siponimod and 173 (32%) of 545 patients receiving placebo had 3-month CDP (hazard ratio 0·79, 95% CI 0·65-0·95; relative risk reduction 21%; p=0·013). Adverse events occurred in 975 (89%) of 1099 patients receiving siponimod versus 445 (82%) of 546 patients receiving placebo; serious adverse events were reported for 197 (18%) patients in the siponimod group versus 83 (15%) patients in the placebo group. Lymphopenia, increased liver transaminase concentration, bradycardia and bradyarrhythmia at treatment initiation, macular oedema, hypertension, varicella zoster reactivation, and convulsions occurred more frequently with siponimod than with placebo. Initial dose titration mitigated cardiac first-dose effects. Frequencies of infections, malignancies, and fatalities did not differ between groups. INTERPRETATION:Siponimod reduced the risk of disability progression with a safety profile similar to that of other S1P modulators and is likely to be a useful treatment for SPMS. FUNDING:Novartis Pharma AG.
PMID: 29576505
ISSN: 1474-547x
CID: 5348122
Natalizumab Extended Interval Dosing Is Associated with a Reduction in Progressive Multifocal Leukoencephalopathy (PML) Risk in the Touch (R) Registry [Meeting Abstract]
ISI:000429034600272
ISSN: 1352-4585
CID: 3039222
Longitudinal study of multiple sclerosis lesions using ultra-high field (7T) multiparametric MR imaging
Pathophysiology of multiple sclerosis (MS) lesions is dynamic and changes over time. The purpose of this exploratory study was to determine the longitudinal changes in MS lesions over time on ultra-high field MR imaging. Nine patients with MS underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo-T2*-weighted imaging on 7T MRI at baseline and after ~2.4 years of follow-up. Morphologic imaging characteristics, signal intensity patterns and quantitative susceptibility mapping (QSM) values of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on T2*-weighted images and/or SWI as well as hyperintense signal on QSM. Lesions were considered "non-iron-laden" if they were hyperintense on T2*/SWI and isointense or hyperintense on QSM. Total of 162 non-iron-laden and 29 iron-laden lesions were observed at baseline. No change in baseline lesion size during follow up was recorded in 92.7%; no change in lesion-vessel relationship in 86.5%; and no change in signal intensity pattern in 96.9% of lesions. Three lesions which were non-iron-laden at baseline, exhibited iron at follow-up. In two iron-laden lesions, redistribution of iron content was observed at follow-up. Two-thirds of these iron-laden lesions showed an increase in QSM at follow-up relative to baseline, and the remaining one-third exhibited decrease in QSM. Most of the newly formed lesions (11/13, 84.6%) at follow-up were iron-laden. 7T multiparametric MRI is a useful tool for tracking the evolution of MS lesions, especially with regard to changes in iron content.
PMID: 30212476
ISSN: 1932-6203
CID: 3277882
NATALIZUMAB EXTENDED INTERVAL DOSING (EID) IS ASSOCIATED WITH A SIGNIFICANT REDUCTION IN PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) RISK COMPARED WITH STANDARD INTERVAL DOSING (SID) IN THE TOUCH (R) PRESCRIBING PROGRAM [Meeting Abstract]
ISI:000438056200071
ISSN: 0022-3050
CID: 5191992
Short-term disability progression in two multiethnic multiple sclerosis centers in the treatment era
Background/UNASSIGNED:Short-term disease progression is well documented in clinical trials, but there are limited published data on disease course in real-life practice. Methods/UNASSIGNED:Patient-Determined Disease Steps (PDDS). Clinicians recorded disease subtype and relapse status at each visit, but did not rate disability. PMSSS change from the first to the last visit was calculated for the cohort as a whole and for subgroups of interest. Multivariable regression models were constructed for predicting final PMSSS based on readily available predictor variables collected at the initial visit and relapse history during follow up. Results/UNASSIGNED:0.28). The only major predictor of final PMSSS was the initial PMSSS. Demographic variables (age, sex, race) or relapse status did not predict final severity score. Conclusions/UNASSIGNED:Baseline disability in two MS clinics was much lower than in the reference population from which PMSSS was derived. We observed no discernable slowing of disability accumulation during the short-term follow up in our cohort compared with the reference cohort. Overwhelmingly the most important predictor of final disease severity rank score was the initial disease severity rank score.
PMCID:6134488
PMID: 30214486
ISSN: 1756-2856
CID: 3277922
Clinical Reasoning: A patient with a history of encephalomyelitis and recurrent optic neuritis
PMCID:5679419
PMID: 29109139
ISSN: 1526-632x
CID: 2772062
Predictors of relapses and disability progression after stopping disease-modifying therapies for multiple sclerosis [Meeting Abstract]
Background: MS patients often stop disease-modifying therapy (DMT). MSBase, a 50,000-patient, global observational MS registry, provides a unique opportunity to identify predictors of relapses and disease progression after DMTs are stopped. Objectives: To identify predictors of relapse and confirmed disability progression after stopping DMTs. Methods: We included MS patients who, at the time of stopping DMT, were >=18 years and were on a DMT continuously for >=1 year. We also required that, after stopping DMT, each patient be followed for >2 years; did not restart DMT for > 6 months (to exclude therapy 'switchers'); and did not become pregnant for >1 year. Predictors of time to first relapse and 3-month confirmed progression (1.5 EDSS steps for baseline EDSS 0; 0.5-for baseline EDSS 6-6.5; 1-for all others) were analyzed using Cox proportional hazards regression. Hazard proportionality was assessed with scaled Schoenfeld residuals; p< 0.05 was considered significant. Results: We identified 4,842 patients in the MSBase who met our inclusion criteria (74% female; mean (SD) age 40.7 years (10.4); mean (SD) disease duration 11.6 years (7.7)). Median (IQR) EDSS at baseline was 3 (1.5, 5.5). The discontinued DMTs were: IFNb-1a sc in 28%; IFNb-1b-26%; IFNb-1a im-20%; glatiramer acetate 18%; natalizumab-6%; fingolimod 3%. Most common reasons for discontinuation, recorded for 48% patients, were adverse events (9%), inconvenience (7%) and intolerance (7%). Post-DMT follow up was 31,691 patient-years. Post-DMT annualized relapse rate (ARR) was 0.22 and was lowest post-IFNb-1b (ARR=0.19) and highest post-Natalizumab (ARR=0.32). Disability data was available for 2,678 patients. The incidence of post-DMT confirmed disability progression was 8.23 per 100 person-years (95% CI: 7.72, 8.76); it was lowest post-IFNb-1a (6.40 (5.45, 7.51)) and highest post-Natalizumab (12.55 (10.04, 15.69). DMT was restarted by 2,984 (61.6%) patients after a median (IQR) of 18.22 months (IQR 10.97, 36.60). For each DMT, we will present predictors of time to relapse and confirmed disability progression, and DMT restart based on Cox regression model. Conclusions: Understanding risk factors for post-DMT relapses and disability accumulation after cessation of DMTs may allow clinicians to identify patients at low risk of disease worsening, who may choose to safely discontinue a particular DMT, and those at high risk, who would be well advised to continue on therapy
EMBASE:619357797
ISSN: 1477-0970
CID: 2871672
Hispanic Americans and African Americans with multiple sclerosis have more severe disease course than Caucasian Americans
Whether disease course in Hispanic Americans (HA) with multiple sclerosis (MS) is different from Caucasian Americans (CA) or African Americans (AA) is unknown. We compared MS severity in the three main ethnic populations in our tertiary MS clinics using disease duration-adjusted rank score of disability: Patient-Derived Multiple Sclerosis Severity Score (P-MSSS). The age- and gender-adjusted P-MSSS was significantly higher in HA (3.9 +/- 2.6) and AA (4.5 +/- 3.0) compared to CA (3.4 +/- 2.6; p < 0.0001 for both). Adjusting for insurance did not change these results. These findings suggest that HA, as AA, have more rapid disability accumulation than CA.
PMID: 27899551
ISSN: 1477-0970
CID: 2329282
Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting
PMID: 28673111
ISSN: 1477-0970
CID: 2617192
Multiple sclerosis journal : experimental, translational & clinical. 2017:3(3).DOI: 10.1177/2055217317728301
Which symptoms contribute the most to patients' perception of health in multiple sclerosis?
BACKGROUND: Multiple sclerosis is a polysymptomatic disease. Little is known about relative contributions of the different multiple sclerosis symptoms to self-perception of health. OBJECTIVES: To investigate the relationship between symptom severity in 11 domains affected by multiple sclerosis and self-rated health. METHODS: Multiple sclerosis patients in two multiple sclerosis centers assessed self-rated health with a validated instrument and symptom burden with symptoMScreen, a validated battery of Likert scales for 11 domains commonly affected by multiple sclerosis. Pearson correlations and multivariate linear regressions were used to investigate the relationship between symptoMScreen scores and self-rated health. RESULTS: Among 1865 multiple sclerosis outpatients (68% women, 78% with relapsing-remitting multiple sclerosis, mean age 46.38 +/- 12.47 years, disease duration 13.43 +/- 10.04 years), average self-rated health score was 2.30 ('moderate to good'). Symptom burden (composite symptoMScreen score) highly correlated with self-rated health (r = 0.68, P < 0.0001) as did each of the symptoMScreen domain subscores. In regression analysis, pain (t = 7.00), ambulation (t = 6.91), and fatigue (t = 5.85) contributed the highest amount of variance in self-rated health (P < 0.001). CONCLUSIONS: Pain contributed the most to multiple sclerosis outpatients' perception of health, followed by gait dysfunction and fatigue. These findings suggest that 'invisible disability' may be more important to patients' sense of wellbeing than physical disability, and challenge the notion that physical disability should be the primary outcome measure in multiple sclerosis.
PMCID:5588807
PMID: 28904811
ISSN: 2055-2173
CID: 2701412
