Causes that Contribute to the Excess Mortality Risk in Multiple Sclerosis: A Population-Based Study.

BACKGROUND: Lifespan is 6-10 years shorter in multiple sclerosis (MS), but the reasons remain unclear. Using linked clinical- and population-based administrative health databases, we compared cause-specific mortality in an MS cohort to the general population. METHODS: MS patients in British Columbia (BC), Canada, were followed from the later of first MS clinic visit or January 1, 1986, to the earlier of death, emigration, or December 31, 2013. Comprehensive mortality information was obtained by linkage to BC's multiple-cause-of-death mortality data. Causes were grouped using International Classification of Disease codes. Standardized mortality ratios (SMRs) were calculated for underlying cause, and relative mortality ratios (RMRs) for any mention cause, by comparison to mortality rates in the age-, sex-, and calendar year-matched general population. Cause-specific relative mortality was explored by sex and disease course (relapsing onset and primary progressive). RESULTS: Among 6,629 MS patients with 104,236 patient-years of follow-up, 1,416 died. The all-cause mortality risk was increased relative to the general population (SMR 2.71; 95% CI 2.55-2.87). MS was the underlying cause in 50.4%, and a mentioned cause in 77.9%, of deaths. Mortality by underlying cause was higher than expected for genitourinary disorders/infections (SMR 3.55; 95% CI 2.25-5.32), respiratory diseases/infections (SMR 2.69; 95% CI 2.17-3.28), suicide (SMR 2.40; 95% CI 1.61-3.45), cardiovascular disease (SMR 1.57; 95% CI 1.36-1.81), and other infections/septicemia (SMR 1.83; 95% CI 1.15-2.78). Risks of death due to overall cancer, accidents, digestive system disorders, and endocrine/nutritional diseases as underlying causes were similar to the general population. However, mortality with any mention of accidents (RMR 2.71; 95% CI 2.22-3.29) or endocrine/nutritional diseases (RMR 1.75; 95% CI 1.46-2.09) was greater. Bladder cancer mortality was increased in women (SMR 3.87; 95% CI 1.42-8.42) but not men. No notable differences were observed by disease course. CONCLUSIONS: MS itself was the most frequent underlying cause of death. Infections (genitourinary, respiratory, and septicemia), suicides, cardiovascular disease, and accidents contributed significantly to the increased risk of death. Some findings differed by sex, but not disease course. Multiple-cause death data offer advantages over "traditional" use of underlying cause only.

Multiple sclerosis: effect of beta interferon treatment on survival.

Worldwide, the beta interferons remain the most commonly prescribed disease-modifying drugs for multiple sclerosis. However, it is unclear if they alter survival. We investigated the association between beta interferon and mortality in the 'real-world' setting. This was a multi-centre population-based observational study of patients with relapsing-onset multiple sclerosis who were initially registered at a clinic in British Columbia, Canada (1980-2004) or Rennes, France (1976-2013). Data on this cohort were accessed from the clinical multiple sclerosis databases and from individually linked health administrative data; all data were collected prospectively. Participants were followed from the latter of their first multiple sclerosis clinic visit, 18th birthday or 1 January 1996; until death, emigration or 31 December 2013. Only those who were naïve to disease-modifying therapy and immunosuppressant treatment of multiple sclerosis at the start of their follow-up were included in the analysis. A nested case-control approach was used. Up to 20 controls, matched to cases (deaths) by country, sex, age ± 5 years, year and disability level at study entry, were randomly selected from the cohort by incidence density sampling. The associations between all-cause mortality and at least 6 months beta interferon exposure, and also cumulative exposure ('low', 6 months to 3 years; and 'high', >3 years), were estimated by conditional logistic regression adjusting for treatment with other disease-modifying therapies and age in years. Further analyses included separate analyses by sex and country, additional adjustment for comorbidity burden in the Canadian cohort, and estimation of the association between beta interferon and multiple sclerosis-related death in both countries. Among 5989 participants (75% female) with a mean age of 42 (standard deviation, SD 11) years at study entry, there were 742 deaths (70% female) and the mean age at death was 61 (SD 13) years. Of these cases, 649 were matched to between one and 20 controls. Results of the conditional logistic regression analyses are expressed as adjusted odds ratios with 95% confidence intervals. The odds of beta interferon exposure were 32% lower among cases than controls (0.68; 0.53-0.89). Increased survival was associated with >3 years beta interferon exposure (0.44; 0.30-0.66), but not between 6 months and 3 years exposure (1.00; 0.73-1.38). Findings were similar within sex and country, and for multiple sclerosis-related death. Beta interferon treatment was associated with a lower mortality risk among people with relapsing-onset multiple sclerosis. Findings were consistent between two geographically distinct regions in North America and Europe.

Randomized Trial of Thymectomy in Myasthenia Gravis.

BACKGROUND: Thymectomy has been a mainstay in the treatment of myasthenia gravis, but there is no conclusive evidence of its benefit. We conducted a multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone. METHODS: We compared extended transsternal thymectomy plus alternate-day prednisone with alternate-day prednisone alone. Patients 18 to 65 years of age who had generalized nonthymomatous myasthenia gravis with a disease duration of less than 5 years were included if they had Myasthenia Gravis Foundation of America clinical class II to IV disease (on a scale from I to V, with higher classes indicating more severe disease) and elevated circulating concentrations of acetylcholine-receptor antibody. The primary outcomes were the time-weighted average Quantitative Myasthenia Gravis score (on a scale from 0 to 39, with higher scores indicating more severe disease) over a 3-year period, as assessed by means of blinded rating, and the time-weighted average required dose of prednisone over a 3-year period. RESULTS: A total of 126 patients underwent randomization between 2006 and 2012 at 36 sites. Patients who underwent thymectomy had a lower time-weighted average Quantitative Myasthenia Gravis score over a 3-year period than those who received prednisone alone (6.15 vs. 8.99, P<0.001); patients in the thymectomy group also had a lower average requirement for alternate-day prednisone (44 mg vs. 60 mg, P<0.001). Fewer patients in the thymectomy group than in the prednisone-only group required immunosuppression with azathioprine (17% vs. 48%, P<0.001) or were hospitalized for exacerbations (9% vs. 37%, P<0.001). The number of patients with treatment-associated complications did not differ significantly between groups (P=0.73), but patients in the thymectomy group had fewer treatment-associated symptoms related to immunosuppressive medications (P<0.001) and lower distress levels related to symptoms (P=0.003). CONCLUSIONS: Thymectomy improved clinical outcomes over a 3-year period in patients with nonthymomatous myasthenia gravis. (Funded by the National Institute of Neurological Disorders and Stroke and others; MGTX ClinicalTrials.gov number, NCT00294658.).

Assessing the long-term effectiveness of interferon-beta and glatiramer acetate in multiple sclerosis: final 10-year results from the UK multiple sclerosis risk-sharing scheme.

BACKGROUND: Because multiple sclerosis (MS) is a chronic disease causing disability over decades, it is crucial to know if the short-term effects of disease-modifying therapies reported in randomised controlled trials reduce long-term disability. This 10-year prospective observational study of disability outcomes (Expanded Disability Status Scale (EDSS) and utility) was set up, in conjunction with a risk-sharing agreement between payers and producers, to investigate this issue. METHODS: The outcomes of the UK treated patients were compared with a modelled untreated control based on the British Columbia MS data set to assess the long-term effectiveness of these treatments. Two complementary analysis models were used: a multilevel model (MLM) and a continuous Markov model. RESULTS: 4862 patients with MS were eligible for the primary analysis (mean and median follow-up times 8.7 and 10 years). EDSS worsening was reduced by 28% (MLM), 7% (Markov) and 24% time-adjusted Markov in the total cohort, and by 31% (MLM) and 14% (Markov) for relapsing remitting patients. The utility worsening was reduced by 23%-24% in the total cohort and by 24%-31% in the RR patients depending on the model used. All sensitivity analyses showed a treatment effect. There was a 4-year (CI 2.7 to 5.3) delay to EDSS 6.0. An apparent waning of treatment effect with time was seen. Subgroup analyses suggested better treatment effects in those treated earlier and with lower EDSS scores. CONCLUSIONS: This study supports a beneficial effect on long-term disability with first-line MS disease-modifying treatments, which is clinically meaningful. However the waning effect noted requires further study.

Predictive validity of NEDA in the 16- and 21-year follow-up from the pivotal trial of interferon beta-1b.

BACKGROUND: Long-term follow-up from the randomized trial of interferon beta-1b (IFNB-1b) permitted the assessment of different definitions of no evidence of disease activity (NEDA) for predicting long-term outcome in multiple sclerosis (MS). OBJECTIVE: To examine the predictive validity of different NEDA definitions. METHODS: Predictive validity for negative disability outcomes (NDOs) at 16 years and survival at 21 years post-randomization were assessed. NEDA in the first 2 years was defined as follows: clinical NEDA: no relapses or Expanded Disability Status Scale (EDSS) progression from baseline to Year 2; NEDA-3a: no relapses, no confirmed ⩾1-point EDSS progression, and no new T2-active lesions; NEDA-3b: no relapses, no EDSS progression, and no increase in T2 burden of disease (T2-BOD); and NEDA-4: no relapses, no EDSS progression, and no increase in T2-BOD or atrophy. NDOs were defined as death, need for wheelchair, EDSS ⩾6, or progressive MS. RESULTS: A total of 245 and 371 patients were evaluated at 16 and 21 years, respectively. Clinical NEDA predicted NDOs ( p = 0.0029), as did baseline EDSS ( p < 0.0001), baseline T2-BOD ( p < 0.0001), and change in T2-BOD ( p = 0.0033). IFNB-1b treatment ( p = 0.0251), relapse rate in the 2 years before study start ( p = 0.0260), T2-BOD at baseline ( p = 0.0014), and change in T2-BOD ( p = 0.0129) predicted survival at 21 years. CONCLUSION: Clinical NEDA predicted long-term disability outcome. By contrast, definitions of NEDA that included on-therapy changes in magnetic resonance imaging variables did not increase the predictive validity.

Disability progression in aggressive multiple sclerosis.

OBJECTIVE: To examine disease progression in 'aggressive' multiple sclerosis (MS), British Columbia, Canada (1980-2009). METHODS: Aggressive (or 'malignant') MS was defined as Expanded Disability Status Scale (EDSS) ⩾6 within 5 years from onset. The first EDSS ⩾6 was termed 'baseline'. Within 2, 3 and 5 years post-baseline, patients were categorized as follows: 'worsened' or 'improved', relative to baseline EDSS (the remainder exhibited no change or had no new scores). The associations between patient characteristics (sex, relapsing onset/primary progressive, onset age, onset symptoms, disease duration, cumulative prior relapses and baseline EDSS) and worsening in disability were examined longitudinally using logistic regression. RESULTS: Of the 225/4341 (5.2%) aggressive/malignant MS patients, 134 (59.6%) were female, 167 (74.2%) were relapsing onset, 94 (41.8%) had received disease-modifying drugs at some point and the mean follow-up was 8.7 years. The proportion of patients who 'worsened' increased from 40.4% to 57.8%, while those who 'improved' varied little (range, 8.9%-10.2%). The odds of worsening increased with disease duration (adjusted odds ratio (AOR) = 1.36; 95% confidence interval (CI) = 1.22-1.52) and the presence of primary progressive (vs relapsing-onset) MS (AOR = 1.85; 95% CI = 1.01-3.38). CONCLUSION: Apart from disease duration and a primary progressive course, no clinically useful associations of subsequent disease worsening in patients with aggressive/malignant MS were identified.

Association between the use of selective serotonin reuptake inhibitors and multiple sclerosis disability progression.

BACKGROUND: Benefits of selective serotonin reuptake inhibitors (SSRIs) in modifying the multiple sclerosis (MS) disease course have been suggested, but their ability to delay disability progression remains unknown. We examined the association between SSRI exposure and MS disability progression. METHODS: A nested case-control study was conducted using the British Columbia (Canada) Multiple Sclerosis clinical data linked to health administrative data. The primary outcome was a sustained score of 6 (requires a cane to walk) on the Expanded Disability Status Scale (EDSS), and the secondary outcome was the onset of secondary progressive MS (SPMS, an advanced stage of MS). The cases were those who reached a study outcome and were matched with up to four randomly selected controls by sex, age, EDSS and calendar year at study entry using incidence density sampling. The associations between disability worsening and SSRI exposure were assessed with conditional logistic regression models, adjusted for confounders. RESULTS: A total of 3920 patients were included in the main analyses, of which 272 reached sustained EDSS 6 and 187 reached SPMS. SSRI exposure was significantly different between patients who reached sustained EDSS 6 and controls [adjusted odds ratio (adjOR):1.44; 95% confidence interval (CI):1.03-2.01]. However, SSRI exposure was not significantly different between those who reached SPMS and their controls (adjOR:1.35; 95%CI:0.89-2.04). CONCLUSION: We found no evidence to suggest that SSRI exposure was associated with a delay in MS disability accumulation or progression. Copyright © 2016 John Wiley & Sons, Ltd.

Antibody dissociation rates are predictive of neutralizing antibody (NAb) course: a comparison of interferon beta-1b-treated Multiple Sclerosis (MS) patients with transient versus sustained NAbs.

A proportion of multiple sclerosis (MS) patients treated with interferon-ß (IFNß) develop neutralizing antibodies (NAbs), which can reduce therapeutic efficacy. In the Betaseron/Betaferon in Newly Emerging MS for Initial Treatment (BENEFIT) study, 88/277 patients developed NAbs, 48 having transient positivity and 29 having sustained positivity. This study aimed to investigate the antibody binding characteristics of serial sera in a subset of these two patient groups. Using Biacore™, a surface plasmon resonance-based technology that monitors biomolecular interactions in real time, we immobilized pure IFNß-1b and analyzed antibody binding responses and dissociation rates of these sera. NAb titers correlated directly with binding responses and inversely with dissociation rates, and sera from sustained NAb patients demonstrated significantly higher binding responses and slower dissociation rates than sera from transient NAb patients. Thus, transient and sustained NAbs are quantitatively and qualitatively different, and interestingly, binding responses and dissociation rates at month 12 could predict the NAb course.

Marginal structural Cox models for estimating the association between ß-interferon exposure and disease progression in a multiple sclerosis cohort.

Longitudinal observational data are required to assess the association between exposure to ß-interferon medications and disease progression among relapsing-remitting multiple sclerosis (MS) patients in the "real-world" clinical practice setting. Marginal structural Cox models (MSCMs) can provide distinct advantages over traditional approaches by allowing adjustment for time-varying confounders such as MS relapses, as well as baseline characteristics, through the use of inverse probability weighting. We assessed the suitability of MSCMs to analyze data from a large cohort of 1,697 relapsing-remitting MS patients in British Columbia, Canada (1995-2008). In the context of this observational study, which spanned more than a decade and involved patients with a chronic yet fluctuating disease, the recently proposed "normalized stabilized" weights were found to be the most appropriate choice of weights. Using this model, no association between ß-interferon exposure and the hazard of disability progression was found (hazard ratio = 1.36, 95% confidence interval: 0.95, 1.94). For sensitivity analyses, truncated normalized unstabilized weights were used in additional MSCMs and to construct inverse probability weight-adjusted survival curves; the findings did not change. Additionally, qualitatively similar conclusions from approximation approaches to the weighted Cox model (i.e., MSCM) extend confidence in the findings.

Assessment of cancer risk with ß-interferon treatment for multiple sclerosis.

OBJECTIVE: The risk of cancer after exposure to the ß-interferons (IFNßs) for multiple sclerosis (MS) has not been established. We assessed whether IFNß treatment for MS is associated with cancer risk or the risk of specific cancers in a population-based observational study. METHODS: The British Columbia MS database was linked to the provincial Cancer Registry, Vital Statistics death files and Health Registration files. Using a nested case-control design, MS cancer cases were matched with up to 20 randomly selected MS controls at the date of cancer diagnosis by sex, age (± 5 years) and study entry year using incidence density sampling. Associations between treatment exposure and overall or specific (breast, colorectal, lung and prostate) cancers were estimated by conditional logistic regression, adjusted for MS disease duration and age. Tumour size at cancer diagnosis was compared between treated and untreated patients using the stratified Wilcoxon test to explore potential lead time bias. RESULTS: The cohort included 5146 relapsing-onset MS patients and 48,705 person-years of follow-up, during which 227 cancers were diagnosed. Exposure to IFNß was not significantly different for cases and controls (OR 1.28; 95% CI 0.87 to 1.88). There was a non-significant trend towards an increased risk of IFNß exposure in the breast cancer cases (OR 1.77; 95% CI 0.92 to 3.42), but no evidence of a dose-response effect. Tumour size was similar between IFNß treated and untreated cases. CONCLUSIONS: There was no evidence of an increased cancer risk with exposure to IFNß over a 12-year observation period. However, the trend towards an association between IFNß and breast cancer should be investigated further.

Association between beta-interferon exposure and hospital events in multiple sclerosis.

PURPOSE: A systematic evaluation of hospital events can be an important surrogate measure for drug effectiveness or adverse effects. The purpose of this study was to examine the association between beta-interferon use and hospital events in a large cohort of patients with multiple sclerosis (MS). METHODS: Retrospective cohort study comparing beta-interferon exposed and unexposed patients using clinical data from the British Columbia MS (BCMS) database linked with health administrative databases, 1996-2008. For each patient, the primary outcome was the number of hospital events in each month, analyzed by quasi Poisson regression. Beta-interferon exposure was examined two ways: current and cumulative exposure. Secondary outcomes included whether a hospital event occurred in each month for each specific primary diagnoses, grouped by International Classification of Diseases categories. RESULTS: Current exposure to beta-interferon was not associated with an altered rate of hospital events (adjusted incident rate ratio 1.018; 95% CI 0.803-1.290). Similarly, there was no association with cumulative exposure. Cumulative beta-interferon exposure was associated with a lower odds of respiratory disease-related hospital events compared to those never exposed to beta-interferon. CONCLUSIONS: Exposure to beta-interferon for MS was not associated with a change in overall hospital event rates. Preliminary evidence suggests that the beta-interferons may have a protective effect against respiratory diseases requiring hospitalization in MS patients.

Characterising aggressive multiple sclerosis.

OBJECTIVE: To explore the occurrence and characteristics of aggressive multiple sclerosis (AMS) in adult-onset multiple sclerosis (MS) patients. METHODS: Prospectively collected data (1980-2009) from British Columbia, Canada, were retrospectively analysed. AMS was defined in three different ways (AMS1, 2 and 3): 'AMS1'--confirmed Expanded Disability Status Scale (EDSS) ≥ 6 within 5 years of MS onset; 'AMS2'--confirmed EDSS ≥ 6 by age 40; and 'AMS3'--secondary progressive MS within 3 years of a relapsing-onset course. Three respective 'non-aggressive' MS comparison cohorts were selected. Patients' characteristics were compared between aggressive and non-aggressive cohorts using multivariable logistic regression, with findings expressed as adjusted OR (AOR) and 95% CI. RESULTS: Application of the three definitions to the source population of 5891 patients resulted in 235/4285 (5.5%) patients fulfilling criteria for AMS1 (59.6% were female; 74.5% had relapsing-onset MS), 388/2762 (14.0%) for AMS2 (65.2% were female; 92.8% had relapsing-onset MS) and 195/4918 (4.0%) patients for AMS3 (61.0% were female). Compared to the respective control cohorts, those with AMS were more likely to be male (AOR=1.5, 95% CI 1.1 to 2.0 (AMS1); 1.6, 95% CI 1.3 to 2.1 (AMS2); 1.8, 95% CI 1.3 to 2.4 (AMS3)), older at MS symptom onset (AOR=1.1; 95% CI 1.1 to 1.1 (AMS1 and AMS3)) and have primary progressive MS (AOR=2.3, 95% CI 1.6 to 3.3 (AMS1); 2.7, 95% CI 1.7 to 4.4 (AMS2)). CONCLUSIONS: AMS was identified in 4-14% of patients, depending on the definition used. Although there was a relative preponderance of men and primary progressive MS presenting with AMS, the majority of patients were still women and those with relapsing-onset MS.

Oligoclonal bands and cerebrospinal fluid markers in multiple sclerosis: associations with disease course and progression.

BACKGROUND: The use of oligoclonal bands (OCBs) and cerebrospinal fluid (CSF) parameters are established in the diagnosis of MS, but poorly as markers of disease. OBJECTIVE: To investigate the role of OCBs in disease course and progression. METHODS: CSF data for 1120 patients with MS were analyzed for associations between OCBs and CSF parameters and clinical data (disease course [relapsing-onset MS (ROMS) vs primary-progressive MS (PPMS)]), disability progression (proportion reaching Expanded Disability Status Scale 6 within 10 years of onset and progression index) and ethnicity. RESULTS: Of patients with MS, 72.5% had detectable OCBs. For patients with detectable OCBs, 84.6% had ROMS and 15.4% PPMS versus 89.7% and 10.3%, respectively for those without detectable OCBs (p=0.04). Total CSF IgG and protein levels were higher in PPMS compared with ROMS (p<0.001). Disease progression appeared independent of OCB status. Patients with CSF (vs without) data were more likely to be male, older at onset, have PPMS and lack optic neuropathy at onset (p<0.001). CONCLUSIONS: OCB positivity and elevated total CSF IgG and protein were moderately associated with a PPMS disease course, but not disease progression. Patients with atypical clinical presentations were more likely to have had CSF work-up, suggesting a testing bias.

Multiple sclerosis and inflammatory bowel diseases: what we know and what we would need to know!

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) but the causes have not been defined. The disease process appears to involve interplay between environmental factors and certain susceptibility genes. It is likely that the identification of the exact etiological mechanisms will permit the development of preventive and curative treatments. Evaluation of several diseases found to be more often associated than by chance alone may reveal clues to the etiology of those disorders. An association between MS and inflammatory bowel diseases (IBD) was suggested by the observation of an increased incidence of IBD among MS patients. A problem in the interpretation of the data rests, in part, with the observation that abnormal findings in brain magnetic resonance imaging (MRI) may be reported as MS in IBD patients. Defining the limits between incidental MRI findings and findings compatible with MS has resulted in further exploration of this possible association.

Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing.

We define late-onset myasthenia gravis (LOMG) when symptoms appear at ≥65 years of age. There has been a continuous increase in the incidence of LOMG with a clear male predominance. Commonly, patients present with focal (ocular or bulbar) weakness. A high index of suspicion required to achieve early diagnosis and to improve prognosis. Management options include acetylcholinesterase inhibitors, steroids, and immunosuppressants. The most controversial issue in treatment is thymectomy, because not enough data are available. Successful treatment is associated with improved survival, and death is often secondary to comorbidities.

Cancer risk in multiple sclerosis: findings from British Columbia, Canada.

Findings regarding cancer risk in people with multiple sclerosis have been inconsistent and few studies have explored the possibility of diagnostic neglect. The influence of a relapsing-onset versus primary progressive course on cancer risk is unknown. We examined cancer risk and tumour size at diagnosis in a cohort of patients with multiple sclerosis compared to the general population and we explored the influence of disease course. Clinical data of patients with multiple sclerosis residing in British Columbia, Canada who visited a British Columbia multiple sclerosis clinic from 1980 to 2004 were linked to provincial cancer registry, vital statistics and health registration data. Patients were followed for incident cancers between onset of multiple sclerosis, and the earlier of emigration, death or study end (31 December 2007). Cancer incidence was compared with that in the age-, sex- and calendar year-matched population of British Columbia. Tumour size at diagnosis of breast, prostate, colorectal and lung cancers were compared with population controls, matched for cancer site, sex, age and calendar year at cancer diagnosis, using the stratified Wilcoxon test. There were 6820 patients included, with 110 666 person-years of follow-up. The standardized incidence ratio for all cancers was 0.86 (95% confidence interval: 0.78-0.94). Colorectal cancer risk was also significantly reduced (standardized incidence ratio: 0.56; 95% confidence interval: 0.37-0.81). Risk reductions were similar by sex and for relapsing-onset and primary progressive multiple sclerosis. Tumour size was larger than expected in the cohort (P = 0.04). Overall cancer risk was lower in patients with multiple sclerosis than in the age-, sex- and calendar year matched general population. The larger tumour sizes at cancer diagnosis suggested diagnostic neglect; this could have major implications for the health, well-being and longevity of people with multiple sclerosis.

Natural, innate improvements in multiple sclerosis disability.

BACKGROUND: Improvements in multiple sclerosis (MS) disability have recently been reported in immunomodulatory drug (IMD) clinical trials and observational studies. However, improvements have rarely been examined in natural history or IMD naive patients. We investigated annual and biennial improvements in Expanded Disability Status Scale (EDSS) scores in British Columbia, Canada. METHODS: The British Columbian MS database was accessed for definite MS patients (1980-2009). Consecutive IMD-free EDSS scores one and two years apart (± 3 months) were examined; improvements (≥0.5,≥1,≥2 EDSS points) and sustained improvements (confirmed at one year) were described. The influence of patient characteristics on improvements was examined using logistic regression. RESULTS: From 16,132 EDSS scores, 7653 yearly and 5845 biennial EDSS intervals were available for 2961 and 2382 patients respectively. Of the yearly intervals, 14.9% showed an improvement (≥0.5 points), 8.3% ≥1 point and 2.2% ≥2 point improvement, with nearly half being sustained. Corresponding worsenings were observed in 32.9%, 20.5% and 7.9% respectively, with stability in just over half (53%). Biennial findings were similar. Characteristics generally associated with improvements included: female sex, younger age, shorter disease duration, relapsing-onset and presence of moderate disability (compared with mild or advanced) and a previous episode of worsening (disassociated from a relapse). However, improvements were also observed after periods of stability and in primary-progressive MS. CONCLUSION: Improvements in MS disability over one or two years are not unusual. We suggest the term 'innate improvements'. Our findings have implication for the design of clinical trials and observational studies in MS targeting improvements on the EDSS.

Association between use of interferon beta and progression of disability in patients with relapsing-remitting multiple sclerosis.

CONTEXT: Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. OBJECTIVE: To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. DESIGN, SETTING, AND PATIENTS: Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. MAIN OUTCOME MEASURES: The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. RESULTS: The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. CONCLUSION: Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Pathological basis of diffusely abnormal white matter: insights from magnetic resonance imaging and histology.

BACKGROUND: The pathological basis of diffusely abnormal white matter (DAWM) in multiple sclerosis (MS) has not been elucidated in detail, but may be an important element in disability and clinical progression. METHODS: Fifty-three subjects with MS were examined with T1, multi-echo T2 and magnetization transfer (MT). Twenty-three samples of formalin-fixed MS brain tissue were examined with multi-echo T2 and subsequently stained for myelin phospholipids using luxol fast blue, for axons using Bielschowsky, immunohistochemically for the myelin proteins myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3' phosphohydrolase (CNP) and for astrocytes using glial fibrillary acidic protein (GFAP). Regions of interest in DAWM were compared with normal appearing white matter. RESULTS: Fourteen of 53 subjects with MS in the in vivo study showed the presence of DAWM. Subjects with DAWM were found to have a significantly lower Expanded Disability Status Scale (EDSS) and shorter disease duration (DD) when compared with subjects without DAWM (EDSS: 1.5 versus 3.0, p = 0.031; DD: 5.4 versus 10.3 years, p = 0.045). DAWM in vivo had reduced myelin water and MT ratio, and increased T2 and water content. Histological analysis suggests DAWM, which shows a reduction of the myelin water fraction, is characterized by selective reduction of myelin phospholipids, but with a relative preservation of myelin proteins and axons. CONCLUSIONS: These findings suggest that the primary abnormality in DAWM is a reduction or perturbation of myelin phospholipids that correlates with a reduction of the myelin water fraction.

Evidence for a two-stage disability progression in multiple sclerosis.

It is well documented that disability accumulation in multiple sclerosis is correlated with axonal injury and that the extent of axonal injury is correlated with the degree of inflammation. However, the interdependence between focal inflammation, diffuse inflammation and neurodegeneration, and their relative contribution to clinical deficits, remains ambiguous. A hypothesis might be that early focal inflammation could be the pivotal event from which all else follows, suggesting the consideration of multiple sclerosis as a two-stage disease. This prompted us to define two phases in the disease course of multiple sclerosis by using two scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: an early phase, 'Phase 1', from multiple sclerosis clinical onset to irreversible Disability Status Scale 3 and a late phase, 'Phase 2', from irreversible Disability Status Scale 3 to irreversible Disability Status Scale 6. Outcome was assessed through five parameters: Phase 1 duration, age at Disability Status Scale 3, time to Disability Status Scale 6 from multiple sclerosis onset, Phase 2 duration and age at Disability Status Scale 6. The first three were calculated among all patients, while the last two were computed only among patients who had reached Disability Status Scale 3. The possible influence of early clinical markers on these outcomes was studied using Kaplan-Meier estimates and Cox models. The analysis was performed in the Rennes multiple sclerosis database (2054 patients, accounting for 26,273 patient-years) as a whole, and according to phenotype at onset (1609 relapsing/445 progressive onset). Our results indicated that the disability progression during Phase 2 was independent of that during Phase 1. Indeed, the median Phase 2 duration was nearly identical (from 6 to 9 years) irrespective of Phase 1 duration (<3, 3 to <6, 6 to <10, 10 to <15, >or=15 years) in the whole population, and in both phenotypes. In relapsing onset multiple sclerosis, gender, age at onset, residual deficit after the first relapse and relapses during the first 2 years of multiple sclerosis were found to be independent predictive factors of disability progression, but only during Phase 1. Our findings demonstrate that multiple sclerosis disability progression follows a two-stage process, with a first stage probably dependent on focal inflammation and a second stage probably independent of current focal inflammation. This concept has obvious implications for the future therapeutic strategy in multiple sclerosis.