Profiling cognitive-motor interference in a large sample of persons with progressive multiple sclerosis and impaired processing speed: results from the CogEx study.

BACKGROUND: Performing cognitive-motor dual tasks (DTs) may result in reduced walking speed and cognitive performance. The effect in persons with progressive multiple sclerosis (pwPMS) having cognitive dysfunction is unknown. OBJECTIVE: To profile DT-performance during walking in cognitively impaired pwPMS and examine DT-performance by disability level. METHODS: Secondary analyses were conducted on baseline data from the CogEx-study. Participants, enrolled with Symbol Digit Modalities Test 1.282 standard deviations below normative value, performed a cognitive single task ([ST], alternating alphabet), motor ST (walking) and DT (both). Outcomes were number of correct answers on the alternating alphabet task, walking speed, and DT-cost (DTC: decline in performance relative to the ST). Outcomes were compared between EDSS subgroups (≤ 4, 4.5-5.5, ≥ 6). Spearman correlations were conducted between the DTCmotor with clinical measures. Adjusted significance level was 0.01. RESULTS: Overall, participants (n = 307) walked slower and had fewer correct answers on the DT versus ST (both p < 0.001), with a DTCmotor of 15.8% and DTCcognitive of 2.7%. All three subgroups walked slower during the DT versus ST, with DTCmotor different from zero (p's < 0.001). Only the EDSS ≥ 6 group had fewer correct answers on the DT versus ST (p < 0.001), but the DTCcognitive did not differ from zero for any of the groups (p ≥ 0.039). CONCLUSION: Dual tasking substantially affects walking performance in cognitively impaired pwPMS, to a similar degree for EDSS subgroups.

White matter tracts that overlap with the thalamus and the putamen are protected against multiple sclerosis pathology.

BACKGROUND: The thalamus and the putamen are highly connected hubs implicated in multiple sclerosis (MS) pathology. It remains unclear if white matter (WM) tracts, which pass through them, have a different susceptibility to MS pathology, and if so, if their impact on disability predominates over that exerted by disease in other WM tracts. We hypothesized that WM tracts connected to and passing through these hubs (subsequently termed hub+ tracts) would be more susceptible to MS-related pathology than tracts that do not pass through them (hub- tracts) due to retrograde and anterograde distant degeneration. Thus, we compared the lesion load and neurite orientation dispersion and density imaging (NODDI) derived metrics between hub+ and hub- tracts and assessed the relationship between these MRI metrics and those of physical impairment. METHODS: Eighteen patients (mean age of 45.5 years, 12 females) had 3 Tesla MRI consisting of T1-weighted and T2-weighted Fluid Attenuated Inversion Recovery (FLAIR), and NODDI from which the orientation dispersion index (ODI), neurite density index (NDI), and isotropic volume fraction (IVF) were derived. Forty-nine WM tracts, i.e., 12 hub+ and 37 hub- tracts, were segmented out. Exploratory analyses of the differences in lesion burden, whole tract and normal appearing WM (NAWM) NODDI metrics were carried out between the two types of tracts using a Mann-Whitney U test. Correlations with physical impairment, quantified using the expanded disability status scale (EDSS) and timed 25-foot walk (T25FW) test were assessed using Spearman correlation analyses. RESULTS: Hub- tracts had larger T1- (p<0.001) and T2-lesion (p<0.001) volumes; lower ODI (p<0.001), NDI (p<0.001) and higher IVF (p = 0.020) in comparison to hub+ tracts. Measures of tissue injury in hub+ tracts correlated with those of clinical disability, though less strongly than in hub- tracts. CONCLUSIONS: Contrary to our hypothesis, our exploratory pilot study results suggest that WM tracts that overlap with the thalamus and the putamen have a lower degree of lesional and non-lesional tissue injury, suggesting a protective role of the hubs against MS pathology or a higher degree of vulnerability of those not passing through hub stations. We also show a weaker association between disability impairment and hub+ pathology, compared to that in hub- tracts. Our findings point to a potential role of disease location in relation to hubs as guidance for treatment personalization in MS.

Central vein sign: A diagnostic biomarker in multiple sclerosis (CAVS-MS) study protocol for a prospective multicenter trial.

The specificity and implementation of current MRI-based diagnostic criteria for multiple sclerosis (MS) are imperfect. Approximately 1 in 5 of individuals diagnosed with MS are eventually determined not to have the disease, with overreliance on MRI findings a major cause of MS misdiagnosis. The central vein sign (CVS), a proposed MRI biomarker for MS lesions, has been extensively studied in numerous cross sectional studies and may increase diagnostic specificity for MS. CVS has desirable analytical, measurement, and scalability properties. "Central Vein Sign: A Diagnostic Biomarker in Multiple Sclerosis (CAVS-MS)" is an NIH-supported, 2-year, prospective, international, multicenter study conducted by the North American Imaging in MS Cooperative (NAIMS) to evaluate CVS as a diagnostic biomarker for immediate translation into clinical care. Study objectives include determining the concordance of CVS and McDonald Criteria to diagnose MS, the sensitivity of CVS to detect MS in those with typical presentations, and the specificity of CVS among those with atypical presentations. The study will recruit a total of 400 participants (200 with typical and 200 with atypical presentations) across 11 sites. T2*-weighted, high-isotropic-resolution, segmented echo-planar MRI will be acquired at baseline and 24 months on 3-tesla scanners, and FLAIR* images (combination of FLAIR and T2*) will be generated for evaluating CVS. Data will be processed on a cloud-based platform that contains clinical and CVS rating modules. Imaging quality control will be conducted by automated methods and neuroradiologist review. CVS will be determined by Select6* and Select3* lesion methods following published criteria at each site and by central readers, including neurologists and neuroradiologists. Automated CVS detection and algorithms for incorporation of CVS into McDonald Criteria will be tested. Diagnosis will be adjudicated by three neurologists who served on the 2017 International Panel on the Diagnosis of MS. The CAVS-MS study aims to definitively establish CVS as a diagnostic biomarker that can be applied broadly to individuals presenting for evaluation of the diagnosis of MS.

CSF plasmablasts differentiate MS from other neurologic disorders.

Multiparametric flow cytometry (FC) of CSF allows one to easily estimate the percentage of lymphocyte subpopulations in CSF. We hypothesized that an increased ratio of B-lineage cells in CSF of MS patients, as assessed with FC, could be useful for diagnostics. We analyzed CSF of 137 patients (70 MS, 24 infectious/autoimmune neurologic disorders (INDs), and 43 non-infectious/autoimmune neurologic disorders (NINDs)), and showed that CSF plasmablasts of >0.1% had a sensitivity of 40% for MS and specificity of 92% when comparing MS and IND, while plasmablasts of >0.25% had sensitivity of 36%, and 100% specificity.

Divergent effects of AKI to CKD models on inflammation and fibrosis.

Chronic kidney disease (CKD) is a condition with significant morbidity and mortality that affects 15% of adults in the United States. One cause of CKD is acute kidney injury (AKI), which commonly occurs secondary to sepsis, ischemic events, and drug-induced nephrotoxicity. Unilateral ischemia-reperfusion injury (UIRI) without contralateral nephrectomy (CLN) and repeated low-dose cisplatin (RLDC) models of AKI to CKD demonstrate responses characteristic of the transition; however, previous studies have not effectively compared the pathogenesis. We demonstrate both models instigate renal dysfunction, inflammatory cytokine responses, and fibrosis. However, the models exhibit differences in urinary excretory function, inflammatory cell infiltration, and degree of fibrotic response. UIRI without CLN demonstrated worsening perfusion and function, measured with 99mTc-mercaptoacetyltriglycine-3 imaging, and physiologic compensation in the contralateral kidney. Furthermore, UIRI without CLN elicited a robust inflammatory response that was characterized by a prolonged polymorphonuclear cell and natural killer cell infiltrate and an early expansion of kidney resident macrophages, followed by T-cell infiltration. Symmetrical diminished function occurred in RLDC kidneys and progressively worsened until day 17 of the study. Surprisingly, RLDC mice demonstrated a decrease in inflammatory cell numbers relative to controls. However, RLDC kidneys expressed increased levels of kidney injury molecule-1 (KIM-1), high mobility group box-1 ( HMGB1), and colony stimulating factor-1 ( CSF-1), which likely recruits inflammatory cells in response to injury. These data emphasize how the divergent etiologies of AKI to CKD models affect the kidney microenvironment and outcomes. This study provides support for subtyping AKI by etiology in human studies, aiding in the elucidation of injury-specific pathophysiologic mechanisms of the AKI to CKD transition.

National estimates of self-reported sitting time in adults with multiple sclerosis.

BACKGROUND: Limited data exist on the prevalence and distribution of sedentary behavior (SB) in multiple sclerosis (MS). OBJECTIVE: The objective of this paper is to describe sitting time as a metric of SB in a large national sample of people with MS. METHODS: A total of 8004 individuals from the North American Research Committee on MS (NARCOMS) Registry completed the sitting time question from the International Physical Activity Questionnaire in spring 2015. We present descriptive data on sitting time for the total sample and across sociodemographic, clinical, and behavioral characteristics. RESULTS: The final sample included 6483 individuals. Of these, 36.7% were classified with mild disability, 24.7% with moderate disability, and 38.6% with severe disability. Median sitting time for the total sample was 480 min/day (P25 = 310 min/day, P75 = 720 min/day). Sitting time was highest for individuals with MS who were male (540 min/day), not married (540 min/day), had a disease duration >30 years (540 min/day), were underweight (540.5 min/day), had an annual income of < $15,000 (585 min/day), presented with a progressive form of MS (600 min/day), were classified as insufficiently active (600 min/day), or presented with severe disability (661 min/day). CONCLUSION: Sitting time is twice as high in individuals with MS compared to the general population (240 min/day).

Assessing the feasibility of the Effectiveness of Discontinuing Bisphosphonates trial: a pilot study.

The Effectiveness of Discontinuing Bisphosphonates (EDGE) study is a planned pragmatic clinical trial to guide "drug holiday" clinical decision making. This pilot study assessed work flow and feasibility of such a study. While participant recruitment and treatment adherence were suboptimal, administrative procedures were generally feasible and minimally disrupted clinic flow. INTRODUCTION: The comparative effectiveness of continuing or discontinuing long-term alendronate (ALN) on fractures is unknown. A large pragmatic ALN discontinuation study has potential to answer this question. METHODS: We conducted a 6-month pilot study of the planned the EDGE study among current long-term ALN users (women aged ≥65 with ≥3 years of ALN use) to determine study work flow and feasibility including evaluating the administrative aspects of trial conduct (e.g., time to contract, institutional review board (IRB) approval), assessing rates of site and participant recruitment, and evaluating post-randomization outcomes, including adherence, bisphosphonate-associated adverse events, and participant and site satisfaction. We assessed outcomes 1 and 6 months after randomization. RESULTS: Nine sites participated, including seven community-based medical practices and two academic medical centers. On average (SD), contract execution took 3.4 (2.3) months and IRB approval took 13.9 (4.1) days. Sites recruited 27 participants (13 to continue ALN and 14 to discontinue ALN). Over follow-up, 22% of participants did not adhere to their randomization assignment: 30.8% in the continuation arm and 14.3% in the discontinuation arm. No fractures or adverse events were reported. Sites reported no issues regarding work flow, and participants were highly satisfied with the study. CONCLUSIONS: Administrative procedures of the EDGE study were generally feasible, with minimal disruption to clinic flow. In this convenience sample, participant recruitment was suboptimal across most practice sites. Accounting for low treatment arm adherence, a comprehensive recruitment approach will be needed to effectively achieve the scientific goals of the EDGE study.

Extended interval dosing of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab (NTZ), a monoclonal antibody to human α4ß1/ß7 integrin, is an effective therapy for multiple sclerosis (MS), albeit associated with progressive multifocal leukoencephalopathy (PML). Clinicians have been extending the dose of infusions with a hypothesis of reducing PML risk. The aim of the study is to evaluate the clinical consequences of reducing NTZ frequency of infusion up to 8 weeks 5 days. METHODS: A retrospective chart review in 9 MS centres was performed in order to identify patients treated with extended interval dosing (EID) regimens of NTZ. Patients were stratified into 3 groups based on EID NTZ treatment schedule in individual centres: early extended dosing (EED; n=249) every 4 weeks 3 days to 6 weeks 6 days; late extended dosing (LED; n=274) every 7 weeks to 8 weeks 5 days; variable extended dosing (n=382) alternating between EED and LED. These groups were compared with patients on standard interval dosing (SID; n=1093) every 4 weeks. RESULTS: 17% of patients on SID had new T2 lesions compared with 14% in EID (p=0.02); 7% of patients had enhancing T1 lesions in SID compared with 9% in EID (p=0.08); annualised relapse rate was 0.14 in the SID group, and 0.09 in the EID group. No evidence of clinical or radiographic disease activity was observed in 62% of SID and 61% of EID patients (p=0.83). No cases of PML were observed in EID group compared with 4 cases in SID cohort. CONCLUSIONS: Dosing intervals up to 8 weeks 5 days did not diminish effectiveness of NTZ therapy. Further monitoring is ongoing to evaluate if the risk of PML is reduced in patients on EID.

Rigorous control conditions diminish treatment effects in weight loss-randomized controlled trials.

BACKGROUND: It has not been established whether control conditions with large weight losses (WLs) diminish expected treatment effects in WL or prevention of weight gain (PWG)-randomized controlled trials (RCTs). SUBJECTS/METHODS: We performed a meta-analysis of 239 WL/PWG RCTs that include a control group and at least one treatment group. A maximum likelihood meta-analysis framework was used to model and understand the relationship between treatment effects and control group outcomes. RESULTS: Under the informed model, an increase in control group WL of 1 kg corresponds with an expected shrinkage of the treatment effect by 0.309 kg (95% confidence interval (-0.480, -0.138), P=0.00081); this result is robust against violations of the model assumptions. CONCLUSIONS: We find that control conditions with large WLs diminish expected treatment effects. Our investigation may be helpful to clinicians as they design future WL/PWG studies.

Translation of a Ski School Sun Safety Program to North American Ski and Snowboard Schools.

Health promotion programs that develop and implement strategies to promote sun safety practices to children have the potential to reduce skin cancer occurrence later in life. Go Sun Smart (GSS), a sun safety program for employees and guests of ski areas, was distributed to determine if an enhanced dissemination strategy was more effective than a basic dissemination strategy at reaching parents at ski and snowboard schools. On-site observations of GSS use and surveys of 909 parents/caregivers with children enrolled in ski and snowboard schools at 63 ski areas were conducted and analyzed using techniques for clustered designs. No differences were identified by dissemination strategy. Greater implementation of GSS (>5 messages posted) was associated with greater parental recall, 36.6% versus 16.7%, of materials, but not greater sun protection practices. Greater recall of messages, regardless of level of implementation, resulted in greater sun protection practices including applying sunscreen (p < .05), providing sunglasses and goggles (p < .01), and more use of all sun protection practices (p < .01). Ski areas with more program materials appeared to reach parents with sun safety advice and thus convinced them to take more precautions for their children. Sun safety need not be at odds with children's outdoor recreation activities.

A full-brain, bootstrapped analysis of diffusion tensor imaging robustly differentiates Parkinson disease from healthy controls.

There is a compelling need for early, accurate diagnosis of Parkinson's disease (PD). Various magnetic resonance imaging modalities are being explored as an adjunct to diagnosis. A significant challenge in using MR imaging for diagnosis is developing appropriate algorithms for extracting diagnostically relevant information from brain images. In previous work, we have demonstrated that individual subject variability can have a substantial effect on identifying and determining the borders of regions of analysis, and that this variability may impact on prediction accuracy. In this paper we evaluate a new statistical algorithm to determine if we can improve accuracy of prediction using a subjects left-out validation of a DTI analysis. Twenty subjects with PD and 22 healthy controls were imaged to evaluate if a full brain diffusion tensor imaging-fractional anisotropy (DTI-FA) map might be capable of segregating PD from controls. In this paper, we present a new statistical algorithm based on bootstrapping. We compare the capacity of this algorithm to classify the identity of subjects left out of the analysis with the accuracy of other statistical techniques, including standard cluster-thresholding. The bootstrapped analysis approach was able to correctly discriminate the 20 subjects with PD from the 22 healthy controls (area under the receiver operator curve or AUROC 0.90); however the sensitivity and specificity of standard cluster-thresholding techniques at various voxel-specific thresholds were less effective (AUROC 0.72-0.75). Based on these results sufficient information to generate diagnostically relevant statistical maps may already be collected by current MRI scanners. We present one statistical technique that might be used to extract diagnostically relevant information from a full brain analysis.

Composite end points to assess delay of disability progression by MS treatments.

BACKGROUND: The Expanded Disability Status Scale (EDSS) has low sensitivity and reliability for detecting sustained disability progression (SDP) in multiple sclerosis (MS) trials. OBJECTIVE: This study evaluated composite disability end points as alternatives to EDSS alone. METHODS: SDP rates were determined using 96-week data from the Olympus trial (rituximab in patients with primary progressive MS). SDP was analyzed using composite disability end points: SDP in EDSS, timed 25-foot walk test (T25FWT), or 9-hole peg test (9HPT) (composite A); SDP in T25FWT or 9HPT (composite B); SDP in EDSS and (T25FWT or 9HPT) (composite C); and SDP in any two (EDSS, T25FWT, and 9HPT) (composite D). RESULTS: Overall agreements between EDSS and other disability measures in defining SDP were 66%-73%. Composite A showed similar treatment effect estimate versus EDSS alone with much higher SDP rates. Composite B, C, and D all showed larger treatment effect estimate with different or similar SDP rates versus EDSS alone. Using composite A (24-week confirmation only), B, C, or D could reduce sample sizes needed for MS trials. CONCLUSION: Composite end points including multiple accepted disability measures could be superior to EDSS alone in analyzing disability progression and should be considered in future MS trials.

Survival in commercially insured multiple sclerosis patients and comparator subjects in the U.S.

OBJECTIVE: Compare survival in patients with multiple sclerosis (MS) from a U.S. commercial health insurance database with a matched cohort of non-MS subjects. METHODS: 30,402 MS patients and 89,818 non-MS subjects (comparators) in the OptumInsight Research (OIR) database from 1996 to 2009 were included. An MS diagnosis required at least 3 consecutive months of database reporting, with two or more ICD-9 codes of 340 at least 30 days apart, or the combination of 1 ICD-9-340 code and at least 1 MS disease-modifying treatment (DMT) code. Comparators required the absence of ICD-9-340 and DMT codes throughout database reporting. Up to three comparators were matched to each patient for: age in the year of the first relevant code (index year - at least 3 months of reporting in that year were required); sex; region of residence in the index year. Deaths were ascertained from the National Death Index and the Social Security Administration Death Master File. Subjects not identified as deceased were assumed to be alive through the end of 2009. RESULTS: Annual mortality rates were 899/100,000 among MS patients and 446/100,000 among comparators. Standardized mortality ratios compared to the U.S. population were 1.70 and 0.80, respectively. Kaplan-Meier analysis yielded a median survival from birth that was 6 years lower among MS patients than among comparators. CONCLUSIONS: The results show, for the first time in a U.S. population, a survival disadvantage for contemporary MS patients compared to non-MS subjects from the same healthcare system. The 6-year decrement in lifespan parallels a recent report from British Columbia.

Indoor carbon monoxide: a case study in England for detection and interventions to reduce population exposure.

BACKGROUND: Potential exposure to carbon monoxide (CO) in private homes is largely unquantified. AIM: To estimate prevalence of potential exposure to CO in residential dwellings and describe associated interventions in an inner-city community. METHODS: A housing association in London, Hackney Homes, began fitting CO alarms in the 22,831 local authority homes it is responsible for in January 2010. A gas engineer investigated each alarm activation and recorded the information on a standard form. We undertook a cross-sectional study of all 22,831 homes, using data from these forms. Descriptive analysis was performed, including incidence, monthly variation, cause of alarm activation, and actions taken. RESULTS: Between November 2011 and April 2012, 106 incidents were reported. Of these, 34.6% identified an issue with a gas appliance, and 10.6% identified misuse of cooking methods as the cause of activation. Relevant interventions were put in place, including disconnection of the gas appliance and education around cooking methods. DISCUSSION: Little is known about the burden of CO poisoning in residential dwellings. This study provides important information on the path to quantifying population exposure to CO as well as establishing a possible approach to access this key information and realistic interventions to reduce potential exposure.

Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. METHODS: In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18 months of therapy were enrolled. GA was initiated 4 weeks after the last dose of natalizumab. RESULTS: 62.5% of patients were relapse-free 12 months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12 months of post-natalizumab-GA therapy is not associated with clinical deterioration. CONCLUSIONS: Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.

No association between conventional brain MR imaging and chronic cerebrospinal venous insufficiency in multiple sclerosis.

BACKGROUND AND PURPOSE: CCSVI has been reported to occur at high frequency in MS. Its significance in relation to MR imaging parameters also needs to be determined, both in patients with MS and HCs. Therefore, this study determined the associations of CCSVI and conventional MR imaging outcomes in patients with MS and in HCs. MATERIALS AND METHODS: T2, T1, and gadolinium lesion number, LV, and brain atrophy were assessed on 3T MR imaging in 301 subjects, of whom 162 had RRMS, 66 had secondary-progressive MS subtype, and 73 were HCs. CCSVI was assessed using extracranial and transcranial Doppler evaluation. The MR imaging measure differences were explored with 27 borderline cases for CCSVI, added to both the negative and positive CCSVI groups to assess sensitivity of the results of these cases. RESULTS: No significant differences between subjects with and without CCSVI were found in any of the individual diagnostic subgroups or MS disease subtypes for lesion burden and atrophy measures, independently of the CCSVI classification criteria used, except for a trend for higher T2 lesion number (irrespective of how borderline cases were classified) and lower brain volume (when borderline cases were included in the positive group) in patients with RRMS with CCSVI. No CCSVI or MR imaging differences were found between 26 HCs with, or 47 without, a familial relationship. CONCLUSIONS: CCSVI is not associated with more severe lesion burden or brain atrophy in patients with MS or in HCs.

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNß-1b trial.

OBJECTIVE: To examine the effects of interferon beta (IFNß)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. METHODS: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNß-1b 250 µg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. RESULTS: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNß-1b 250 µg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNß-1b 250 µg-treated patients (46.0% among IFNß-1b 50 µg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. CONCLUSIONS: There was a significant survival advantage in this cohort of patients receiving early IFNß-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNß-1b benefit on all-cause mortality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that early treatment with IFNß-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Cumulative impact of comorbidity on quality of life in MS.

BACKGROUND: Little is known about the impact of comorbidity on health-related quality of life (HRQOL) in multiple sclerosis (MS). We investigated the association of comorbidity and health-related HRQOL among participants in the North American Research Committee on Multiple Sclerosis (NARCOMS). MATERIALS AND METHODS: In 2006, we queried NARCOMS participants regarding physical and mental comorbidities and HRQOL, using the Short-Form 12. We summarized physical HRQOL using the aggregate Physical Component Scale (PCS-12) score and mental HRQOL using the aggregate Mental Component Scale (MCS-12) score. We assessed multivariable associations between comorbidity and HRQOL using a general linear model, adjusting for potential confounders. RESULTS: Among 8983 respondents, the mean (SD) PCS-12 was 36.9 (11.8) and MCS-12 was 45.6 (11.6). After adjustment for sociodemographic and clinical factors, participants with any physical comorbidity had a lower PCS-12 (37.2; 95% CI: 36.4-38.1) than those without any physical comorbidity (40.1; 95% CI: 39.0-41.1). As the number of physical comorbidities increased, PCS-12 scores decreased (r = -0.25; 95% CI: -0.23 to -0.27) indicating lower reported HRQOL. Participants with any mental comorbidity had a lower MCS-12 (40.7; 95% CI: 39.8-41.6) than those without any mental comorbidity (48.5; 95% CI: 47.7-49.4). CONCLUSIONS: Comorbidity is associated with reduced HRQOL in MS. Further research should evaluate whether more aggressive treatment of comorbidities improves the HRQOL of MS patients.

The CombiRx trial of combined therapy with interferon and glatiramer acetate in relapsing remitting MS: Design and baseline characteristics.

BACKGROUND: Interferon-ß1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective. OBJECTIVE: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA. METHODS: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio. RESULTS: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions. CONCLUSION: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy.