Expanded Disability Status Scale Point Research Articles

Validated, Quantitative, Machine Learning-Generated Neurologic Assessment of Multiple Sclerosis Using a Mobile Application.

The BeCare MS Link mobile app collects data as users complete different in-app assessments. It was specifically developed to evaluate the symptomatology and neurologic function of patients with multiple sclerosis (MS) and to become a digital equivalent of the Expanded Disability Status Scale (EDSS) and other standard clinical metrics of MS progression. Our research compared EDSS scores derived from the BeCare MS link app to EDSS scores derived from neurologist assessment for the same cohort of 35 patients diagnosed with MS. App-derived data were supplied to 4 different machine learning algorithms (MLAs) with an independent EDSS score prediction generated from each. These scores were compared with the clinically derived EDSS score to assess the similarity of the scores and to determine an accuracy estimate for each. Of the 4 MLAs employed, the most accurate MLA produced 19 EDSS score predictions that exactly matched the clinically derived scores, 21 score predictions within 0.5 EDSS points, and 32 score predictions within 1 EDSS point. The remaining MLAs also provided a relatively high level of accuracy in predicting EDSS scores when compared with clinically derived EDSS, with over 80% of scores predicted within 1 point and a mean squared error with a range of 1.05 to 1.37. The BeCare MS Link app can replicate the clinically derived EDSS assessment of a patient with MS. The app may also offer a more complete evaluation of disability in patients with MS.

Факторы риска развития психических нарушений у больных рассеянным склерозом

Up to 50% of patients with multiple sclerosis (MS) suffer from mental disorders. The purpose — to study the risk factors for mental disorders development in MS patients. Material and methods. The study group included 315 patients with MS and mental disorders. The control group consisted of 300 MS patients without mental disorders. The diagnosis of MS was established according to the 2017 McDonald criteria. The diagnosis of mental disorders was established in accordance with the ICD-10 criteria. We used Beck Depression Inventory (BDI), Multidimensional Fatigue Inventory (MFI-20), Spielberger State-Trait Anxiety Inventory (STAI), adapted by Khanin, Expanded Disability Status Scale (EDSS), and Holmes and Rahe stress scale. MS progression rate (PR) was calculated using N. A. Malkova (1988) method. Results. The research established a link between mental disorders development and the localization of demyelination foci, with MS PR of at least 0.74 EDSS points per year, and with significant stressful events before MS development. Conclusion. The data obtained can be used to predict the development of mental disorders in MS patients.

Hematopoietic Stem Cell Transplantation in People With Active Secondary Progressive Multiple Sclerosis.

Uncontrolled evidence suggests that autologous hematopoietic stem cell transplantation (AHSCT) can be effective in people with active secondary progressive multiple sclerosis (SPMS). In this study, we compared the effect of AHSCT with that of other anti-inflammatory disease-modifying therapies (DMTs) on long-term disability worsening in active SPMS. We collected data from the Italian Bone Marrow Transplantation Study Group and the Italian Multiple Sclerosis Register. Patients were considered eligible if treatment had been started after the diagnosis of SPMS. Disability worsening was assessed by the cumulative proportion of patients with a 6-month confirmed disability progression (CDP) according to the Expanded Disability Status Scale (EDSS) score. Key secondary endpoints were the EDSS time trend after treatment start and the prevalence of disability improvement over time. Time to first CDP was assessed by means of proportional hazard Cox regression models. A linear mixed model with a time × treatment group interaction was used to assess the longitudinal EDSS time trends. Prevalence of improvement was estimated using a modified Kaplan-Meier estimator and compared between groups by bootstrapping the area under the curve. Seventy-nine AHSCT-treated patients and 1975 patients treated with other DMTs (beta interferons, azathioprine, glatiramer-acetate, mitoxantrone, fingolimod, natalizumab, methotrexate, teriflunomide, cyclophosphamide, dimethyl fumarate, and alemtuzumab) were matched to reduce treatment selection bias using propensity score and overlap weighting approaches. Time to first CDP was significantly longer in transplanted patients (hazard ratio [HR] = 0.50; 95% CI = 0.31-0.81; p = 0.005), with 61.7% of transplanted patients free from CPD at 5 years. Accordingly, EDSS time trend over 10 years was higher in patients treated with other DMTs than in AHSCT-treated patients (+0.157 EDSS points per year compared with -0.013 EDSS points per year; interaction p < 0.001). Patients who underwent AHSCT were more likely to experience a sustained disability improvement: 34.7% of patients maintained an improvement (a lower EDSS than baseline) 3 years after transplant vs 4.6% of patients treated by other DMTs (p < 0.001). The use of AHSCT in people with active SPMS is associated with a slowing of disability progression and a higher likelihood of disability improvement compared with standard immunotherapy. This study provides Class III evidence that autologous hematopoietic stem cell transplants prolonged the time to CDP compared with other DMTs.

High-dose immunosuppressive therapy with autologous hematopoietic stem cell transplantation in multiple sclerosis: preliminary clinical results of approbation of the method

Introduction. In 2018–2020, a study was conducted in the Russian Federation on the efficacy and safety of highdose immunosuppressive therapy with autologous hematopoietic stem cell transplantation (HDIT-AHSCT) in multiple sclerosis (MS).The aim of the study was to analyze preliminary data on the effectiveness and safety of the HDIT-AHSCT in patients with MS who participated in the clinical approbation of the method.Material and methods. 21 patients were included in a single-center Pavlov University (Saint Petersburg) observational study. In 10 patients (47.6%) the Expanded Disability Status Scale (EDSS) ranged from 1.0 to 4.0, in 10 — from 4.5 to 6.0 points, 1 patient with primary-progressive MS (PPMS) had 6.5 EDSS points. Cyclophosphamide conditioning regimen (200 mg/kg) in combination with rituximab (1000 mg/m2) was used. Neurological assessment (EDSS, SNRS, T25-FW, 9-HPT, PASAT, MoCA, HADS) and brain MRI were performed before and after 12 months. The early and long-term complications of HDIT-AHSCT were also analyzed.Results. One year after HDIT-AHSCT improvement and significant improvement were noted in 10 patients (47.6%), stabilization — in 8 (38.1%), relapse/progression — in 3 (14.3%). A lower effect was observed in patients with spasticity of more than 3 points by the MAS. According to MRI data 18 patients (85.7%) had stabilization of MS with no disease activity after 1 year, that met the No Evidence of Disease Activity (NEDA) criteria. Long-term complications included autoimmune thyroiditis (n = 1) and amenorrhea in two patients older than 38 years. No TRM were registered during the observation period.Conclusion. HDIT-AHSCT is an effective method of treating patients with multiple sclerosis. The results of the research demonstrate the safety and effectiveness of HDIT-AHSCT and it can be used to expanse the opportunities for providing treatment of patients with MS in the Russian Federation.

Should frequent MRI monitoring be performed in natalizumab-treated MS patients? A contribution to a recent debate

Background: Brain magnetic resonance imaging (MRI) is the most effective surveillance tool for the detection of asymptomatic progressive multifocal leukoencephalopathy (PML). However, the optimal frequency for routine MRI surveillance is under-investigated. Objective: To understand whether, upon their first MRI appearance, PML lesions present a difference in volume when comparing patients who frequently underwent MRI surveillance (3/4 months) with those who were assessed at longer intervals (6/12 months) and to understand the impact of the volume of lesions on clinical outcome. Methods: The data of patients included in the Italian PML cohort were retrospectively analysed. Patients who had all the pre-diagnostic MRI scans available (n = 37) were included. The volume of PML lesion was calculated by manually outlining the PML lesion. Results: Compared with patients who underwent MRI examination at least every 4 months, patients who were assessed less frequently had a lesion of significantly higher volume (median: 2567 (883–3583) vs. 664 mm3 (392–963) p = 0.006) and suffered a higher rate of disability (median: 2.25 expanded disability status scale points (–2.5 to 8) vs. 0.5 (–1 to 2.5) p = 0.004). Conclusion: The positive clinical outcome of patients undergoing frequent MRI surveillance and the small volume of the PML lesion upon first appearance justify a frequent surveillance using MRI in patients at high risk of PML.

Lipid-related genetic polymorphisms significantly modulate the association between lipids and disability progression in multiple sclerosis

ObjectiveTo investigate whether lipid-related or body mass index (BMI)–related common genetic polymorphisms modulate the associations between serum lipid levels, BMI and disability progression in multiple sclerosis (MS).MethodsThe association between disability...

A cross-sectional study on the relationship between cardiorespiratory fitness, disease severity and walking speed in persons with Multiple Sclerosis

BackgroundIn persons with Multiple Sclerosis (PwMS) cardiorespiratory fitness has been associated with disease severity, walking capacity and comorbidities. However, current evidence is of moderate quality and a large-scale single-center study is needed to further elucidate these relationships ObjectiveThe purpose of the study was 1) to examine the relationship between cardiorespiratory fitness and disease severity in PwMS; 2) to investigate the relationship between cardiorespiratory fitness and walking speed and comorbidities; and 3) to examine the potential impact of Multiple Sclerosis (MS) disease type on these relationships MethodsData was collected from a database consisting of data from 700 inpatients at Valens Rehabilitation Center, Switzerland. VO2peak (cardiorespiratory fitness), information on disease course and MS type, walking performance, comorbidities and anthropometric was eligible from 242 PwMS. ResultsCardiorespiratory fitness and Expanded Disability Status Scale (EDSS) was inversely related (r = −0.465, p < .01). A multiple linear regression analysis showed that an increase of 1 point on the EDSS score was associated with a decrease of 1.88 mL kg−1 min−1 and explained 36% of the variance, when adjusted for time since diagnosis, gender, age, and MS type.Walking speed and cardiorespiratory fitness was significantly correlated (r = 0.584, p < .01) and the relapse remitting MS (RRMS) group (1.12 ± 0.42 m/s) walked significantly faster than the secondary progressive MS (SPMS) group (0.91 ± 0.37 m/s) p < .05, but the difference was non-significant when adjusted for age, p = .429. ConclusionThe present study shows that 1) an increase of 1 EDSS point is associated with a decrease of 1.88 mL kg−1 min−1 when adjusted for time since diagnosis, gender, age and MS type, 2) cardiorespiratory fitness and walking speed was significantly related but only minimally affected by MS type, and 3) hypertension is associated with a lower cardiorespiratory fitness level.

Residual disability after severe relapse in people with multiple sclerosis treated with disease-modifying therapy

Background: The rate of post-relapse residual disability in patients with relapsing–remitting multiple sclerosis (RRMS) treated with disease-modifying drugs (DMD) has not been studied. Objective: To assess relapse residual disability in DMD-treated RRMS patients. Methods: We followed DMD-treated RRMS patients presenting with acute relapse who received high-dose steroids. Increases in Expanded Disability Status Scale (EDSS) of at least 2.0, 1.0–1.5 or 0.5 were defined as severe, moderate or mild relapses, respectively. The proportions of patients with post-relapse residual disability defined as the failure to regain pre-relapse neurological status at 1, 4 and 12 months were evaluated. Results: Out of 1672 relapses in DMD-treated RRMS patients, 17% were severe. In patients who presented with a severe relapse, we observed post-relapse residual disability of at least 1.0 EDSS point in 60.1%, 55.9% and 48.2% of patients at 1, 2 and 12 months of follow-up, respectively. Post-relapse residual disability of at least 2.0 EDSS points was observed in 37.4%, 30.7% and 20.7% of patients after 1, 2 and 12 months, respectively. Conclusion: A high rate of incomplete recovery was seen 12 months following severe relapse among RRMS patients and may contribute to the accumulation of long-term disability.

Therapeutic Effect of Plasma Exchange in Steroid Refractory Inflammatory Demyelination of Central Nervous System: Outcome from a Tertiary Centre in Malaysia

Objective: To evaluate the efficacy of plasma exchange (PLEX) in steroid refractory inflammatory demyelination diseases (IDD) of Central nervous system (CNS). Methods: Retrospective review of patients presented with steroid refractory IDD from 2006 to 2016 that underwent PLEX. Clinical data on neurological assessment, time to treatment initiation, visual acuity (VA) and Expanded Disability Status Scale (EDSS) were gathered from the medical records. The primary outcome was improvement at 3 months after PLEX. Statistical analysis was done using the SPSS version 21. Results: Forty-three plasma exchanges were performed involving 27 patients (NMOSD= 22, RRMS= 4, ITM= 1). The mean age of patient was 43.60 ± 15.18, and the mean EDSS was 7.98 ± 1.07 at presentation. The anti-AQP4 antibody was detected in 81.5%. Treatment success was observed in 21/43 (48.8%) of patients with a significant improvement of 2.13 EDSS point post PLEX. A lower baseline EDSS score ≤ 6 showed a trend toward good outcome (p= 0.07). AQP4 status had no influence on treatment outcome. Male gender, preserved reflexes, use of DMT and shorter time to PLEX initiation, were not associated with treatment outcome. Conclusion: PLEX is an effective treatment for steroid refractory IDD, regardless of the AQP4 antibody status. A lower baseline EDSS might be associated with a better treatment outcome. PLEX should be considered irrespective of the symptom duration.

The burden of multiple sclerosis 2015: Methods of data collection, assessment and analysis of costs, quality of life and symptoms

Introduction: This article describes the methods used to perform this large European-wide burden-of-illness study on multiple sclerosis (MS) using individual patient data. Methods: The study collected all MS-related resource consumption, workforce participation, prevalent disease symptoms and health-related quality of life (HRQoL). Patients were recruited by national patient associations and, after informed consent, completed a specific questionnaire either on-line or on paper. Analyses were performed by country as well as for the study overall. Costs were estimated from the societal perspective, using publicly available unit costs and reported in national currencies and in EUR 2015 adjusted for purchasing power parity. The results are reported by disease severity groups according to self-assessed Expanded Disability Status Scale (EDSS) (mild, moderate, severe) and by EDSS point to highlight the development of costs as disability progresses. Results: A total of 16,808 patients in 16 countries participated in the study: Austria, Belgium, Denmark, Czech Republic, France, Germany, Hungary, Italy, the Netherlands, Poland, Portugal, Russia, Spain, Sweden, Switzerland and the United Kingdom. Conclusion: This study, endorsed by the European Platform of MS Societies, provides up-to-date information on costs and expands the previously available information on HRQoL and symptoms.

Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis.

Glucocorticoids are the standard of care for multiple sclerosis (MS) relapses, but the most desirable route of administration is still matter of debate. The aim of the study was to compare the efficacy and safety of oral versus intravenous steroids for treatment of acute relapses in patients with MS. Randomized or quasi-randomized, parallel group trials with direct comparison between oral and intravenous steroid treatment in MS patients with acute relapse were identified through a systematic literature search. Six trials were included involving 419 participants, 210 for oral, and 209 for intravenous groups, respectively. The weighted mean differences (WMDs) in the Kurtzke's Expanded Disability Status Scale (EDSS) score reduction between the oral and intravenous groups were 0.32 [(-0.09 to 0.73); p=0.129] and 0.11 [(-0.12 to 0.33); p=0.355] at 1 and 4 weeks after treatment, respectively. The risk ratios (RRs) for improvement by at least one EDSS point were 0.79 [(0.37-1.68); p=0.539] at week 1 and 0.92 (0.76-1.12); p=0.400] at week 4. There were no differences in the relapse rate and relapse freedom at 6 months between groups. The WMDs in the mean percentage reduction of Gadolinium-enhancing lesions between oral and intravenous arms were 0.14 (-0.02, 0.29); p=0.083] and 0.04 (-0.19, 0.28); p=0.705] at 1 and 4 weeks from treatment. Among the adverse events, insomnia was significantly associated with the oral route of steroid administration [RR 1.25 (1.07-1.46); p=0.005]. In adult patients with acute MS relapse, there were no clear-cut differences in the efficacy and overall tolerability between oral and intravenous steroids.

Hospitalization is associated with subsequent disability in multiple sclerosis

BackgroundAlthough an increasing amount of research has evaluated interactions between MS and comorbid chronic disease, few data exist regarding the interactions between MS and acute illness. As compared to age and sex-matched persons without MS, persons with MS experience higher rates of hospitalization and critical illness, and higher mortality rates and health care utilization following critical illness. We aimed to determine whether acute illness requiring hospitalization is associated with progression of multiple sclerosis (MS). MethodsWe conducted this population-based, retrospective cohort study by linking data from the regional MS Clinic in Calgary, Canada with the Canadian Discharge Abstract Database to identify non-obstetric hospitalizations. We included individuals with a confirmed diagnosis of MS, at least one recorded Expanded Disability Status Scale (EDSS) measurement, and known age of symptom onset of age 10 years or older. Using data from 2009 to 2014, we used generalized linear models with generalized estimating equations to establish the association within individuals between hospitalization and the time course of MS-related disability (as measured by the EDSS), adjusting for sex, age, disease course at onset, and use of disease-modifying therapies. ResultsWe included 2104 individuals with MS in the analysis, who had a median of 4 EDSS measurements each. Of these 491 (23.3%) had at least one hospitalization. Most subjects were female, with a relapsing disease course at onset, and a mean (SD) age at symptom onset of 33.0 (10.0) years. The underlying rate of disability progression averaged 0.9 EDSS points per decade. Following hospitalization, there was a step increase in EDSS, averaging 0.23 points, equivalent to 2.5 years of time-related disease progression. Hospitalization did not alter the subsequent temporal rate of disability progression. The findings did not differ in those hospitalized for MS versus other reasons. ConclusionsAcute illness requiring hospitalization is associated with a worsening of MS-related disability.

Natalizumab discontinuation in patients with multiple sclerosis: Profiling risk and benefits at therapeutic crossroads

Objective: The objective of this paper is to estimate the risk of reaching well-established disability milestones after withdrawal of natalizumab (NTZ) due to concern about the risk of progressive multifocal leukoencephalopathy in patients with multiple sclerosis (MS). Methods: Data from 415 patients with MS followed-up for six years after starting NTZ were collected from seven tertiary MS centers. The risk of disability worsening, i.e. reaching Expanded Disability Status Scale (EDSS) scores of 4.0 or 6.0, and the likelihood of experiencing a disability reduction of one EDSS point (or more), were assessed by propensity score-adjusted analyses in patients who discontinued and in those still on treatment at the end of follow-up. Results: A total of 318 patients who received standard NTZ treatment without experiencing evidence of disability worsening in the first two years were included in the six-year follow-up analysis, with 196 (61.6%) still on treatment and 122 (38.4%) discontinuing after a median time of 3.5 years. Patients in the discontinuing group had a more than two-fold increased risk of disability worsening (p = 0.007), and a 68% decreased likelihood of experiencing disability reduction (p = 0.009) compared with the continuing group. Conclusion: While discussing the overall risk/benefit profile of NTZ, patients should be advised that, in case of treatment discontinuation, the risk of disability worsening is one in three, and increases to one in two if the EDSS score at NTZ start is above 3.0.

Natalizumab reduces relapse clinical severity and improves relapse recovery in MS

ObjectivesCompare relapse clinical severity, post-relapse residual disability, and the probability of confirmed complete recovery from relapse between patients who relapsed during natalizumab (n=183/627 [29%]) and placebo (n=176/315 [56%]) treatments in the AFFIRM trial. MethodsIn this post-hoc analysis, relapse clinical severity and residual disability were defined by change in Expanded Disability Status Scale (EDSS) score occurring between pre-relapse and at-relapse assessment and between pre-relapse and post-relapse assessment, respectively. Patients were considered completely recovered from relapse when their post-relapse EDSS score was less than or equal to their pre-relapse EDSS score, and this was maintained for 12 or 24 weeks. ResultsAt relapse, an increase in EDSS score of ≥0.5 points occurred in 71% of natalizumab and 84% of placebo patients (P=0.0088); an increase of ≥1.0 point occurred in 49% of natalizumab and 61% of placebo patients (P=0.0349) (mean increase in EDSS at relapse: natalizumab=0.77; placebo=1.09; P=0.0044). After relapse, residual disability of ≥0.5 EDSS points remained in 31% of natalizumab and 45% of placebo patients (P=0.0136) (mean post-relapse residual EDSS increase: natalizumab=0.06; placebo=0.28; P=0.0170). In patients with an increase in EDSS of ≥0.5 or ≥1.0 during relapse, natalizumab increased the probability of 12-week confirmed complete recovery from relapse by 55% (hazard ratio [HR]=1.554; P=0.0161) and 67% (HR=1.673; P=0.0319) compared to placebo, respectively. ConclusionsIn AFFIRM, natalizumab treatment decreased the clinical severity of relapses and improved recovery from disability induced by relapses. These beneficial effects would limit the step-wise accumulation of disability.

Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo-controlled, phase 3 trial

Teriflunomide is an oral disease-modifying therapy approved for treatment of relapsing or relapsing-remitting multiple sclerosis. We aimed to provide further evidence for the safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis. This international, randomised, double-blind, placebo-controlled, phase 3 study enrolled adults aged 18-55 years with relapsing multiple sclerosis, one or more relapse in the previous 12 months or two or more in the previous 24 months but no relapse in the previous 30 days, and an Expanded Disability Status Scale (EDSS) score of 5.5 points or less. Patients were recruited from 189 sites in 26 countries and randomly assigned (1:1:1) to once-daily placebo, teriflunomide 7 mg, or teriflunomide 14 mg via an interactive voice recognition system. Treatment duration was variable, ending 48 weeks after the last patient was included. The primary endpoint was annualised relapse rate (number of relapses per patient-year) and the key secondary endpoint was time to sustained accumulation of disability (an EDSS score increase of at least 1 EDSS point sustained for a minimum of 12 weeks), both analysed in the modified intention-to-treat population (all patients who received at least one dose of assigned study medication). This study is registered with ClinicalTrials.gov, number NCT00751881. Between Sept 17, 2008, and Feb 17, 2011, 1169 patients were randomly assigned to a treatment group, of whom 388, 407, and 370 patients received at least one dose of placebo, teriflunomide 7 mg, or teriflunomide 14 mg, respectively. By the end of the study, the annualised relapse rate was higher in patients assigned to placebo (0.50 [95% CI 0.43-0.58]) than in those assigned to teriflunomide 14 mg (0.32 [0.27-0.38]; p=0.0001) or teriflunomide 7 mg (0.39 [0.33-0.46]; p=0.0183). Compared with placebo, teriflunomide 14 mg reduced the risk of sustained accumulation of disability (hazard ratio [HR] 0.68 [95% CI 0.47-1.00]; log-rank p=0.0442); however, teriflunomide 7 mg had no effect on sustained accumulation of disability (HR 0.95 [0.68-1.35]; log-rank p=0.7620). The most common adverse events were alanine aminotransferase increases (32 [8%] of 385 patients in the placebo group vs 46 [11%] of 409 patients in the teriflunomide 7 mg group vs 52 [14%] of 371 patients in the teriflunomide 14 mg group), hair thinning (17 [4%] vs 42 [10%] vs 50 [13%]), and headache (42 [11%] vs 60 [15%] vs 46 [12%]). Incidence of serious adverse events was similar in all treatment groups (47 [12%] vs 52 [13%] vs 44 [12%]). Four deaths occurred, none of which was considered to be related to study drug (respiratory infection in the placebo group, traffic accident in the teriflunomide 7 mg group, and suicide and septicaemia due to Gram-negative infection complicated by disseminated intravascular coagulopathy in the teriflunomide 14 mg group). Teriflunomide 14 mg was associated with a lower relapse rate and less disability accumulation compared with placebo, with a similar safety and tolerability profile to that reported in previous studies. These results confirm the dose effect reported in previous trials and support the use of teriflunomide 14 mg in patients with relapsing multiple sclerosis. Genzyme, a Sanofi company.

Predictors of long‐term outcome in multiple sclerosis patients treated with interferon beta

To identify early predictors of long-term outcomes in patients with relapsing-remitting multiple sclerosis (RRMS) treated with intramuscular (IM) interferon beta-1a (IFNβ-1a). A multicenter, observational, 15-year follow-up study of patients who completed ≥2 years in the pivotal trial of IM IFNβ-1a for RRMS was conducted. One hundred thirty-six patients participated in the 15-year follow-up (69 originally randomized to IM IFNβ-1a and 67 to placebo). After the 2-year clinical trial, treatment was not regulated by study protocol. Disease activity during the 2-year trial was defined as: ≥2 gadolinium-enhancing lesions (cumulative) on year 1 and/or year 2 magnetic resonance imaging (MRI); ≥3 new T2 lesions on year 2 MRI compared to baseline; and ≥2 relapses over 2 years. Odds ratios were calculated for early disease activity predicting severe Expanded Disability Status Scale (EDSS) worsening (worst quartile of change, ≥4.5 EDSS points) during the 15-year interval. The proportion of patients experiencing early disease activity was lower in patients on IM IFNβ-1a than placebo for all disease activity markers (range, 23.5-29.0% vs 41.0-45.5%). In the IM IFNβ-1a group, persistent disease activity predicted severe EDSS worsening: gadolinium-enhancing lesions (odds ratio [OR], 8.96; p < 0.001); relapses (OR, 4.44; p = 0.010); and new T2 lesions (OR, 2.90; p = 0.080). In placebo patients, early disease activity was not as strongly associated with long-term outcomes (OR range, 1.53-2.62; p = 0.069-0.408). Disease activity despite treatment with IFNβ is associated with unfavorable long-term outcomes. Particular attention should be paid to gadolinium-enhancing lesions on IFNβ therapy, as their presence strongly correlates with severe disability 15 years later. The results provide rationale for monitoring IFNβ-treated patients with MRI, and for changing therapy in patients with active disease.

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.

Treatment of Severe Relapsing-Remitting Multiple Sclerosis with High-Dose Immunosuppressive Therapy and Autologous Hematopoietic Cell Transplantation: Early Results of the HALT MS Clinical Trial (Immune Tolerance Network: ITN033AI)

Abstract 3075Multiple sclerosis (MS) is an autoimmune disease which in most patients presents as defined relapses followed by remissions (relapsing-remitting (RR)). Over time the clinical course evolves to a gradual but irreversible loss of neurological function to which a neurodegenerative process likely contributes. Previous studies of high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were done in patients with advanced progressive MS and many patients continued to lose neurological function. To investigate the potential benefit of HDIT/HCT to halt the evolution of MS and prevent the development of the neurodegenerative processes, HDIT/HCT was studied in RRMS.A phase II clinical trial of HDIT (BCNU, etoposide, ara-C and melphalan (BEAM) and antithymocyte globulin (ATG)) and autologous HCT was conducted in patients with highly active RRMS who had failed conventional therapy to determine if sustained remissions could be induced. Eligibility criteria required Expanded Disability Status Scale (EDSS) 3.0 (moderate disability, fully ambulatory) -5.5 (severe disability, ambulatory only 100 meters without aids) and ≥2 relapses on MS treatment with EDSS worsening over the previous 18 months. Hematopoietic progenitor cells were mobilized with G-CSF and a 10-day course of prednisone. The graft was CD34-selected (Baxter, Isolex). The primary endpoint was treatment-failure defined as a composite endpoint of 1) mortality 2) relapse 3) new lesions on MRI or 4) progression in disability ≥1.0 EDSS point. Adverse events (AE) were recorded according to NCI-CTCAE v3.0. Twenty-five patients at a median age of 38(27–53) years had autologous hematopoietic stem cells collected. There were 7 Grade 3 non-hematopoietic AEs during mobilization; mostly line-associated thromboses and infections. There was 1 Grade 4 AE with pretransplant withdrawal from study; a pulmonary embolus associated with heparin-induced thrombocytopenia and pre-existing arteriovenous malformation in the brain. During mobilization, a MS flare occurred in one patient who was non-compliant with the prednisone prophylaxis. Twenty-four patients proceeded to transplant. Median follow-up is 80(52–232) weeks. Patients were infused with a median of 4.58(2.95–9.73) × 106 CD34+ cells/kg. Neutrophil recovery occurred at a median of +11(9–15) days. In the 1st year after transplant, there were 17 Grade 3 and 4 Grade 4 non-hematopoietic, non-GI AEs. The Grade 4 AEs were suicide attempt (recorded as 2 separate events), hypokalemia and increase in ALT. At baseline (n=24), one (n=23) and two (n=8) years after HDIT/HCT, the mean EDSS (SD) was 4.42(+/−0.637), 3.78(+/−0.951) and 4.13(+/−0.916) respectively. There was only one case with gadolinium-enhancing lesions after 6 months (at Year 3) (Table 1). T2 lesion volume decreased and T1 lesion volume increased from baseline to Month 12. Despite the decrease in T2 lesion volume, there was early posttransplant loss in brain volume. Four patients failed by the composite endpoint (relapses at +22 and +96 weeks; new MRI brain lesions at +197 weeks and progression of disability/death at +82/138 weeks). Event-free survival at 1 and 2 years was 95.8(90% CI :73.9, 99.4)% and 76.7(90% CI :41.1, 92.4)% respectively. 22/24 patients were without progression of disability at last follow-up.Table 1:Brain MRI: Changes in first year after transplant.Baseline n=24Month 2 n=24Month 6 n=24Month 12 n=23Total Gd+ lesions [n (%)]014 (58%)19 (90%)22 (96%)22 (100%)14 (17%)0 (0%)1 (4%)0 (0%)2+6 (25%)2 (10%)0 (0%)0 (0%)T2 lesion volume change (cc)*n202320Median(min, max)-0.13 (-6.51,1.26)-0.60 (-6.46,1.73)-0.58 (-5.14,0.97)1T1 lesion volume change (cc)*n202320Median (min, max)-0.002 (-1.10, 0.87)0.02 (-0.87, 0.99)0.11 (-0.40,1.74)2Brain volume change (%)*n202419Mean (SD)-0.91 (0.73)3-1.19 (0.86)-1.28 (1.01)Wilcoxon signed rank test: 1) p=0.0014; 2) p=0.0186 3) t-test: p<0.0001Conducted by the Immune Tolerance Network, sponsored by NIAID, National Institutes of Health, Bethesda, MD.*Change from baselineHigh-dose immunochemotherapy was well-tolerated with few serious early complications. Early control of highly active RRMS was obtained post transplant but has not been complete in all patients. Patient follow-up is planned for 5 years to determine durability of responses. Disclosures:Stuve:Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Consultancy, Honoraria; Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Honoraria; Teva Neruoscience: Research Funding. Arnold:NeuroRx Research: Equity Ownership. Wundes:Biogen Idec: Consultancy, Research Funding, Speakers Bureau; Teva pharmaceutics: Consultancy.

Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results

The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). Total body irradiation, cyclophosphamide, and antithymocyte globulin were followed by transplantation of autologous, CD34-selected peripheral blood stem cells (PBSC). Neurological examinations, brain MRIs and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean EDSS=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥ 1.0 EDSS point was 0.52 (95% CI, 0.30 to 0.75). Five patients had an EDSS at baseline of ≤ 6.0; four of these had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.

A phase III study evaluating the efficacy and safety of MBP8298 in secondary progressive MS

To evaluate the efficacy and safety of MBP8298 in subjects with secondary progressive multiple sclerosis (SPMS) who express human leukocyte antigen (HLA) haplotype DR2 or DR4 (DR2(+) or DR4(+)). This multicenter randomized 2-year, double-blind, placebo-controlled study included 612 subjects with a diagnosis of SPMS and an Expanded Disability Status Scale (EDSS) score of 3.5-6.5, stratified according to baseline EDSS score (3.5-5.0, or 5.5-6.5) and HLA haplotype (DR2(+) or DR4(+), or DR2(-)/DR4(-)). Upon entry of 100 DR2(-)/DR4(-) subjects, further study enrollment was limited to DR2(+) or DR4(+) subjects. Subjects were randomly assigned to either 500 mg MBP8298 or placebo, given by IV injection once every 6 months for 2 years. The primary outcome measure was time to progression by ≥1.0 EDSS point (or 0.5 point if baseline EDSS was 5.5 or higher), confirmed 6 months later. Secondary outcomes included mean change in EDSS, mean change in Multiple Sclerosis Functional Composite, MRI changes, annualized relapse rate, and quality of life. There were no significant differences between treatment groups in either the primary or secondary endpoints. MBP8298 was well tolerated in all treated subjects with no safety issues identified. In the population studied, treatment with MBP8298 did not provide a clinical benefit compared to placebo. This study provides Class 1 evidence that MBP8298 is not effective in patients with SPMS who are HLA DR2(+) or DR4(+).