The efficacy of teriflunomide in patients who received prior disease-modifying treatments: Subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies.

Teriflunomide is a once-daily oral immunomodulator approved for relapsing-remitting multiple sclerosis (MS). The objective of this post hoc analysis of the phase 3, pooled TEMSO (NCT00134563) and TOWER (NCT00751881) dataset is to evaluate the effect of teriflunomide treatment on annualised relapse rate and disability worsening across patient subgroups defined according to prior disease-modifying therapy exposure. This analysis provides further supportive evidence for a consistent effect of teriflunomide across a broad range of patients with relapsing MS, including patients who have used and discontinued other disease-modifying therapies.

Established disease-modifying treatments in relapsing-remitting multiple sclerosis.

PURPOSE OF REVIEW: The purpose of this review is to summarize mechanisms of action, efficacy and safety of established disease-modifying treatments (DMTs) that have been widely approved for use in relapsing-remitting multiple sclerosis (RRMS). RECENT FINDINGS: Established and widely used DMTs for the treatment of RRMS include the interferon-ß agents, glatiramer acetate, natalizumab, fingolimod, teriflunomide and dimethyl fumarate. These DMTs have quite different mechanisms of action, efficacy and safety and tolerability profiles, which are summarized concisely in the article below. SUMMARY: The treatment algorithm for RRMS is becoming increasingly complex with the ever-expanding armamentarium of DMTs. The choice of DMT will become an increasingly individual decision, based on a number of factors, including disease activity and severity, safety/tolerability profile and patient preference. Neurologists treating patients with multiple sclerosis (MS) will need a thorough knowledge of efficacy, safety and tolerability of the spectrum of DMTs available for treatment of RRMS to provide comprehensive clinical care.

Novel and imminently emerging treatments in relapsing-remitting multiple sclerosis.

PURPOSE OF REVIEW: To summarize mechanisms of action, efficacy, and safety of novel and imminently emerging disease-modifying treatments (DMTs) intended to be used in relapsing-remitting multiple sclerosis (RRMS). RECENT FINDINGS: Novel and imminently emerging DMTs for the treatment of RRMS include alemtuzumab, daclizumab, ocrelizumab, pegylated interferon-ß-1a, and three times weekly glatiramer acetate. These DMTs have substantially different mechanisms of action, efficacy, and safety and tolerability profiles, which are summarized concisely in this article. SUMMARY: The treatment landscape of RRMS is evolving rapidly as the available treatment options have doubled in recent years, and a number of novel DMTs will likely become available in the near future. Choosing the optimal DMT for patients is becoming an increasingly complex process, and the care of patients with MS will likely require regular input from neurologists subspecializing in the care of patients with MS. As the use of novel DMTs with unknown long-term safety profiles increases, postmarketing surveillance and vigilance with regards to safety monitoring will be essential to confirm the safety and clinical efficacy of these DMTs for patients with RRMS.

Canadian Expert Panel Recommendations for MRI Use in MS Diagnosis and Monitoring.

BACKGROUND: A definitive diagnosis of multiple sclerosis (MS), as distinct from a clinically isolated syndrome, requires one of two conditions: a second clinical attack or particular magnetic resonance imaging (MRI) findings as defined by the McDonald criteria. MRI is also important after a diagnosis is made as a means of monitoring subclinical disease activity. While a standardized protocol for diagnostic and follow-up MRI has been developed by the Consortium of Multiple Sclerosis Centres, acceptance and implementation in Canada have been suboptimal. METHODS: To improve diagnosis, monitoring, and management of a clinically isolated syndrome and MS, a Canadian expert panel created consensus recommendations about the appropriate application of the 2010 McDonald criteria in routine practice, strategies to improve adherence to the standardized Consortium of Multiple Sclerosis Centres MRI protocol, and methods for ensuring effective communication among health care practitioners, in particular referring physicians, neurologists, and radiologists. RESULTS: This article presents eight consensus statements developed by the expert panel, along with the rationale underlying the recommendations and commentaries on how to prioritize resource use within the Canadian healthcare system. CONCLUSIONS: The expert panel calls on neurologists and radiologists in Canada to incorporate the McDonald criteria, the Consortium of Multiple Sclerosis Centres MRI protocol, and other guidance given in this consensus presentation into their practices. By improving communication and general awareness of best practices for MRI use in MS diagnosis and monitoring, we can improve patient care across Canada by providing timely diagnosis, informed management decisions, and better continuity of care.

Teriflunomide for the treatment of multiple sclerosis.

Several novel oral agents are emerging for use in multiple sclerosis (MS). Among these oral agents, teriflunomide is showing promise with respect to clinical efficacy and safety in relapsing MS patients. In this review, the authors clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing salient points on the use of teriflunomide in MS, with a discussion of teriflunomide's development, pharmacologic properties, preclinical and clinical trials, and safety and tolerability.

Multiple sclerosis disease-modifying therapy prescribing patterns in Ontario.

BACKGROUND: Differences in Multiple sclerosis (MS) disease-modifying therapy (DMT) prescribing patterns between different groups of neurologists have not been explored. OBJECTIVE: To examine concentrations of prescribing patterns and to assess if MS-specialists use a broader range of DMTs relative to general neurologists. METHODS: We conducted a cross-sectional study using administrative claims databases in Ontario, Canada to link neurologists to 2009 DMT prescription data. MS specialization was defined using both practice location and prescription patterns. Lorenz curves and Gini coefficients were constructed to examine prescribing patterns, separating neurologist characteristics dichotomously and separating Avonex from the other standard DMTs (Betaseron, Rebif and Copaxone). Gini coefficient 95% confidence intervals (CIs) were derived using jack-knife statistical techniques. RESULTS: Prescriptions were highly concentrated with 12% of Ontario neurologists prescribing 80% of DMTs. There was a trend towards Avonex being more commonly prescribed relative to the other DMTs. When MS specialization was defined by DMT prescribing, high-volume prescribing neurologists showed a broader range of DMT prescribing (Gini 0.38-0.44) in comparison to low-volume prescribers (Gini 0.57-0.66). CONCLUSIONS: The majority of DMTs are prescribed by a small subset of neurologists. High-volume prescribing MS-specialists show more variability in DMT use while low-volume prescribers tend to individually focus on a narrower range of DMTs.

Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years.

BACKGROUND: Teriflunomide, an oral disease-modifying therapy in development for patients with relapsing forms of multiple sclerosis (RMS), was well tolerated and effective in reducing magnetic resonance imaging (MRI) lesions in 179 RMS patients in a phase 2 36-week, placebo-controlled study. METHODS: A total of 147 patients who completed the core study entered an open-label extension. Teriflunomide patients continued their assigned dose, and placebo patients were re-allocated to teriflunomide, 7 mg/day or 14 mg/day. An interim analysis was performed at a cut-off on January 8 2010. RESULTS: The mean and median duration of study treatment, including both the core and extension phase, from baseline to the interim cut-off, was 5.6 years (standard deviation: 2.7 years) and 7.1 years (range: 0.05-8.5 years), respectively. Of 147 patients, 62 (42.2%) discontinued (19% due to treatment-emergent adverse events (TEAEs)). The most common TEAEs were mild infections, fatigue, sensory disturbances and diarrhoea. No serious opportunistic infections occurred, with no discontinuations due to infection. Asymptomatic alanine aminotransferase increases (≤3× upper limit of normal (ULN)) were common (7 mg, 64.2%; 14 mg, 62.1%); increases >3×ULN were similar across groups (7 mg, 12.3%; 14 mg, 12.1%). Mild decreases in neutrophil counts occurred; none led to discontinuation. The incidence of malignancies was comparable to that of the general population, and cases were not reminiscent of those observed in immunocompromised patients. Annualised relapse rates remained low, minimal disability progression was observed, with a dose-dependent benefit with teriflunomide 14 mg for several MRI parameters. CONCLUSION: Teriflunomide had a favourable safety profile for up to 8.5 years.

Oral versus intravenous steroids for treatment of relapses in multiple sclerosis.

BACKGROUND: This is an updated Cochrane review of the previous version published (Cochrane Database of Systematic Reviews 2009, Issue 3. Art. No.: CD006921. DOI: 10.1002/14651858.CD006921.pub2).Multiple sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), is characterized by recurrent relapses of CNS inflammation ranging from mild to severely disabling.  Relapses have long been treated with steroids to reduce inflammation and hasten recovery.  However, the commonly used intravenous methylprednisolone (IVMP) requires repeated infusions with the added costs of homecare or hospitalization, and may interfere with daily responsibilities. Oral steroids have been used in place of intravenous steroids, with lower direct and indirect costs. OBJECTIVES: The primary objective was to compare efficacy of oral versus intravenous steroids in promoting disability recovery in MS relapses <= six weeks.  Secondary objectives included subsequent relapse rate, disability, ambulation, hospitalization, immunological markers, radiological markers, and quality of life. SEARCH METHODS: A literature search was performed using Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group's Trials Register (January 2012), abstracts from meetings of the American Academy of Neurology (2008-2012), the European Federation of Neurological Sciences (2008-2012), the European Committee for Treatment and Research in Multiple Sclerosis and American Committee for Treatment and Research in Multiple Sclerosis (2008-2012) handsearching. No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized trials comparing oral versus intravenous steroids for acute relapses (<= six weeks) in patients with clinically definite MSover age 16 were eligible. DATA COLLECTION AND ANALYSIS: Three review authors (JB, PO and MH) participated in the independent assessment of all published articles as potentially relevant to the review. Any disagreement was resolved by discussion among review authors.We contacted study authors for additional information.Methodological quality was assessed by the same three review authors. Relevant data were extracted, and effect size was reported as mean difference (MD), mean difference (MD), odds ratio (OR) and absolute risk difference (ARD). MAIN RESULTS: With this current update, a total of five eligible studies (215 patients) were identified. Only one outcome, the proportion of patients with Expanded Disability Status Scale (EDSS) improvement at four weeks, was common to three trials, while two trials examined magnetic resonance imaging (MRI) outcomes. The results of this review shows there is no significant difference in relapse recovery at week four (MD -0.22, 95% confidence interval (95% CI), 0.71 to 0.26, P = 0.20) nor differences in magnetic resonance imaging (MRI) gadolinium enhancement activity based on oral versus intravenous steroid treatment. However, only two of the five studies employed more current and rigorous methodological techniques, so these results must be taken with some caution. The Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) trial and the "Efficacy and Safety of Methylprednisolone Per os Versus IV for the Treatment of Multiple Sclerosis (MS) Relapses" (COPOUSEP) trial, designed to address such limitations, are currently underway. AUTHORS' CONCLUSIONS: The analysis of the five included trials comparing intravenous versus oral steroid therapy for MS relapses do not demonstrate any significant differences in clinical (benefits and adverse events), radiological or pharmacological outcomes. Based on the evidence, oral steroid therapy may be a practical and effective alternative to intravenous steroid therapy in the treatment of MS relapses.

Assessment of JC virus DNA in blood and urine from natalizumab-treated patients.

OBJECTIVE: Analyses were conducted to determine the clinical utility of measuring JC virus (JCV) DNA in blood or urine of natalizumab-treated multiple sclerosis (MS) patients to predict the risk of progressive multifocal leukoencephalopathy (PML). METHODS: A total of 12,850 blood and urine samples from nearly 1,400 patients participating in natalizumab clinical trials were tested for JCV DNA using a commercially available quantitative polymerase chain reaction (qPCR) assay. A subset of these samples was also tested using a more sensitive qPCR assay developed at the National Institutes of Health (NIH). RESULTS: At the time natalizumab dosing was suspended, JCV DNA was detected in plasma by the commercial assay in 4 of 1,397 (0.3%) patients; the NIH assay confirmed these positive samples and detected JCV DNA in an additional 2 of 205 (1%) patients who tested negative with the commercial assay. None of these 6 JCV DNA positive patients developed PML. In a 48-week study testing the safety of natalizumab redosing, JCV DNA was detected in plasma of 6 of 1,094 (0.3%) patients, none of whom developed PML. Urine at baseline and week 48 was assessed in 224 patients; 58 (26%) were positive at baseline, and 55 (25%) were positive after 48 weeks of natalizumab, treatment. JCV DNA was not detected in peripheral blood mononuclear cells from any of these 1,094 patients before or after natalizumab treatment. In 5 patients who developed PML, JCV DNA was not detected in blood at any time point before symptoms first occurred. INTERPRETATION: Measuring JCV DNA in blood or urine with currently available methods is unlikely to be useful for predicting PML risk in natalizumab-treated MS patients.

Sustained improvement in Expanded Disability Status Scale as a new efficacy measure of neurological change in multiple sclerosis: treatment effects with natalizumab in patients with relapsing multiple sclerosis.

BACKGROUND: Validated measures of sustained improvements in neurological function have not been established for multiple sclerosis (MS) clinical studies. OBJECTIVE: To evaluate sustained Expanded Disability Status Scale (EDSS) change as a potential indicator of neurological improvement and as an outcome measure in MS clinical studies. METHODS: Analyses were performed on patients (n = 620) from the pivotal natalizumab study AFFIRM with baseline EDSS scores ≥2.0. Cumulative probabilities of neurological improvement, defined as a 1.0-point decrease in EDSS score sustained for ≥12 weeks, were estimated by Kaplan-Meier analysis. A Cox proportional hazards model identified associated baseline factors and examined treatment effects. RESULTS: Sustained improvement (as well as sustained worsening) in neurological disability was seen in AFFIRM patients. Sustained EDSS changes correlated well with quality of life measurements (SF36 and VAS). Natalizumab increased the cumulative probability of improvement over 2 years by 69% versus placebo (HR = 1.69; 95% CI 1.16-2.45; p = 0.006). Sensitivity analyses showed consistent benefits of natalizumab with variations in improvement magnitude and duration, and baseline disease activity. CONCLUSION: These analyses demonstrate that sustained EDSS improvement is an additional measure that is sensitive to treatment effects over 2 years and correlates with quality of life. Further research is warranted to validate its use as an MS study clinical outcome.

The toronto observational study of natalizumab in multiple sclerosis.

BACKGROUND: Natalizumab is indicated for the treatment of relapsing multiple sclerosis (MS) with insufficient response to first-line disease-modifying therapy (DMT). We studied the efficacy of natalizumab for treatment of MS in a single centre observational design. METHODS: A retrospective observational study of 146 patients [66% female; mean age 37.4; 72% relapsing remitting MS (RRMS), 28% secondary progressive MS (SPMS)] referred for natalizumab treatment at St. Michael's Hospital MS Clinic between 2007 and August 2009. Data included demographic, clinical (Expanded Disability Status Scale (EDSS) and annualized relapse rate (ARR)) and patient self-report measures. RESULTS: The mean duration of treatment was 20 months in those treated with natalizumab and 97% had received prior DMTs. Eighty-three patients (57%) received at least 12 months of natalizumab treatment. In those who received at least 12 months of treatment, baseline ARR and EDSS were 1.6 and 2.7 in RRMS patients versus 1.0 and 5.4 in SPMS with relapses. The ARR decreased with natalizumab treatment to 0.38 (76% reduction, p<0.001) in RRMS versus 0.32 in SPMS patients (68% reduction, p=0.01). There was a treatment associated 11% reduction in EDSS to 2.4 (p=0.04) in RRMS, but no significant change in SPMS. Eighty-five percent of patients reported improved overall quality of life (QOL) and 62% indicated improved energy. CONCLUSIONS: There was a major reduction in relapse rate, stabilization in EDSS and improvement in QOL and energy in some patients on natalizumab, all similar to treatment effects in the pivotal trial.

Adherence to multiple sclerosis disease-modifying therapies in Ontario is low.

BACKGROUND/OBJECTIVE: Differences in patient adherence to various disease-modifying drugs (DMDs) in the treatment of multiple sclerosis (MS) are not well understood. The goal of this study was to evaluate adherence of adult MS patients in Ontario with public drug plan coverage to various DMDs: intramuscular interferon beta-1a (i.m. IFNß-1a, Avonex), subcutaneous interferon beta-1a (s.c. IFNß-1a, Rebif), subcutaneous interferon beta-1b (IFNß-1b, Betaseron) or glatiramer acetate (Copaxone). METHODS: In this retrospective cohort study, Ontario Public Drug Plan beneficiaries aged 15 or older who were newly treated with i.m. IFNß-1a, s.c. IFNß-1a, IFNß-1b or glatiramer acetate between April 2006 and March 2008 were followed forward until treatment discontinuation, switch to another DMD or a maximum two year follow-up period. Cumulative persistence rates were analyzed by the Kaplan-Meier method. The proportion of patients reaching the study endpoints after the two year follow-up period was also calculated. RESULTS: Cumulative persistence rates for all four DMDs were similar over time (p=0.80), ranging from 73.6-79.1% at six months, 59.1-63.1% at one year and 41.5-47.4% at two years. After two years, the proportion of patients who had discontinued treatment, switched to another DMD or died was similar among DMDs (p=0.79, Fisher's exact test). Switching between DMD types was low and occurred in 3.4-6.5% of new DMD users. CONCLUSIONS: Adherence to DMDs in adult MS patients in Ontario is poor, which is consistent with previously reported adherence rates to MS DMDs in other regions. No significant differences in adherence exist between the DMDs evaluated in this study.

Increasing use of disease modifying drugs for MS in Canada.

BACKGROUND/OBJECTIVES: The course of multiple sclerosis may be slowed by use of the disease modifying drugs (DMDs): subcutaneous or intramuscular interferon beta-1a, interferon beta-1b, glatiramer acetate, and natalizumab. We set out to compare utilization of these drugs in the Canadian provinces from 2002-2007. METHODS: Using a retrospective cohort analysis, we reviewed population data from International Medical Statistics (IMS) Health between November 2001 and October 2007. RESULTS: The total annual number of DMD prescriptions increased from 3.9, in 2002, to 5.1, in 2007, per 1,000 Canadians. The total annual cost of prescriptions rose from $187 million to $287 million. Of the four provinces responsible for the majority of prescriptions--Alberta, BC, Ontario, and Quebec--Quebec had the highest average annual prescription rate (7 per 1,000 population) and BC had the lowest rate (3.3 per 1,000 population). Subcutaneous interferon beta-1a was the most commonly used drug whereas glatiramer acetate showed the greatest growth in use from 2002 to 2007. CONCLUSIONS: Disease modifying drugs prescription rates and costs increased by more than 30% between 2002 and 2007. There was wide variation in DMD prescription rates and relative drug preferences across the provinces.

Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis: a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study.

BACKGROUND: The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. METHODS: Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. FINDINGS: 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. INTERPRETATION: Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).

Oral versus intravenous steroids for treatment of relapses in multiple sclerosis.

BACKGROUND: Multiple Sclerosis (MS), a chronic inflammatory and neurodegenerative disease of the central nervous system (CNS), is characterized by recurrent relapses of CNS inflammation ranging from mild to severely disabling. Relapses have long been treated with steroids to reduce inflammation and hasten recovery. However, the commonly used intravenous methylprednisolone requires repeated infusions with the added costs of homecare or hospitalization, and may interfere with daily responsibilities. Oral steroids have been used in place of intravenous steroids, with lower direct and indirect costs. OBJECTIVES: The primary objective was to compare efficacy of oral versus intravenous steroids for MS relapses <= 6 weeks. Secondary comparisons included subsequent relapse rate, disability, ambulation, hospitalization, immunological markers, radiological markers, and quality of life. SEARCH STRATEGY: A literature search was performed using Cochrane MS Group Trials Register (July 2008), Cochrane Central Register of Controlled Trials (CENTRAL) "The Cochrane Library 2008, issue 3, MEDLINE (PubMed) (1966-July 2008), EMBASE (1980-July 2008), abstracts from meetings of the American Academy of Neurology (2002-2008), the European Federation of Neurological Sciences (2002-2008), the European Committee for Treatment and Research in Multiple Sclerosis and American Committee for Treatment and Research in Multiple Sclerosis (2002-2008) handsearching. No language restrictions were applied. SELECTION CRITERIA: Randomized or quasi-randomized trials comparing oral and intravenous steroids for acute relapses (<=30 days) in clinically definite MS patients over age 16 were eligible. DATA COLLECTION AND ANALYSIS: Methodological was assessed using trial publications and personal communication. Elevant data was extracted, and effect size was reported as mean difference (MD),weighted mean difference (WMD), odds ratio (OR) and absolute risk difference (ARD). MAIN RESULTS: Eligible studies (167 patients) were identified. Only one outcome, the proportion of patients with EDSS improvement at 4 weeks, was common to three trials. Otherwise outcomes were too heterogeneous to pool. Only one trial employed an equivalence design, but all reported no statistically significant difference in outcomes between groups. Namely, there was no significant difference in the degree of recovery 4 weeks following treatment. No difference was found in subsequent relapse rate, disability, hospitalization, ambulation, bioavailability, or in magnetic resonance imaging (MRI). Due to methodological limitations, heterogeneous treatment regimens and limited data, formal conclusions about equivalence of oral and intravenous steroidscannot be made. Oral Megadose Corticosteroid Therapy of Acute Exacerbations of Multiple Sclerosis (OMEGA) trial, designed to address such limitations, is currently underway. AUTHORS' CONCLUSIONS: The trials reviewed support the hypothesis that no significant differences in clinical, radiological or pharmacological outcomes oral and intravenous steroids for MS relapses exist. However, with the small number of patients and methodological limitations, conclusions of equivalence are premature.

Health-related quality of life in multiple sclerosis: effects of natalizumab.

OBJECTIVE: To report the relationship between disease activity and health-related quality of life (HRQoL) in relapsing multiple sclerosis, and the impact of natalizumab. METHODS: HRQoL data were available from 2,113 multiple sclerosis patients in natalizumab clinical studies. In the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM) study, patients received natalizumab 300 mg (n = 627) or placebo (n = 315); in the Safety and Efficacy of Natalizumab in Combination with Interferon Beta-1a in Patients with Relapsing Remitting Multiple Sclerosis (SENTINEL) study, patients received interferon beta-1a (IFN-beta-1a) plus natalizumab 300 mg (n = 589), or IFN-beta-1a plus placebo (n = 582). The Short Form-36 (SF-36) and a subject global assessment visual analog scale were administered at baseline and weeks 24, 52, and 104. Prespecified analyses included changes from baseline to week 104 in SF-36 and visual analog scale scores. Odds ratios for clinically meaningful improvement or worsening on the SF-36 Physical Component Summary (PCS) and Mental Component Summary were calculated. RESULTS: Mean baseline SF-36 scores were significantly less than the general US population and correlated with Expanded Disability Status Scale scores, sustained disability progression, relapse number, and increased volume of brain magnetic resonance imaging lesions. Natalizumab significantly improved SF-36 PCS and Mental Component Summary scores at week 104 in AFFIRM. PCS changes were significantly improved by week 24 and at all subsequent time points. Natalizumab-treated patients in both studies were more likely to experience clinically important improvement and less likely to experience clinically important deterioration on the SF-36 PCS. The visual analog scale also showed significantly improved HRQoL with natalizumab. INTERPRETATION: HRQoL was impaired in relapsing multiple sclerosis patients, correlated with severity of disease as measured by neurological ratings or magnetic resonance imaging, and improved significantly with natalizumab.

Natalizumab treatment for multiple sclerosis: recommendations for patient selection and monitoring.

Natalizumab is a new treatment option for patients with active relapsing-remitting multiple sclerosis. In phase III studies, natalizumab was highly effective and well tolerated; however, three cases of progressive multifocal leucoencephalopathy (PML) were identified (estimated incidence of one per 1000; 95% CI 0.2-2.8; mean treatment period 17.9 months). In this Review we summarise the current information on PML, the three confirmed cases of PML, and the results of an extensive safety assessment of all patients treated with natalizumab. On the basis of these reviews, we make recommendations for appropriate selection of candidates for natalizumab and pretreatment assessments. In addition, a three-step diagnostic and management algorithm was developed to monitor natalizumab-treated patients with multiple sclerosis for PML and other opportunistic infections. The algorithm includes strategies for clinical, MRI, and laboratory assessments. Maintaining clinical vigilance allows for early suspension of natalizumab in potential cases of PML, thereby increasing the opportunity for immune reconstitution, which may improve prognosis if PML is confirmed.

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.