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Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity. Our understanding of the pathophysiology of MS has deepened considerably in recent years, resulting in different therapies to modify the disease course. Furthermore, several drugs have lately shown efficacy in phase III studies and their approval is expected in the near future. As treatment options expand, a future challenge will be to find the optimal treatment for the individual patient. Summary: This mini-review gives an overview of the current knowledge of MS with emphasis on the latest diagnostic criteria and both current and upcoming treatment options. Key Messages: Treatment of MS changes rapidly as the knowledge and therapeutic options in MS expand. Clinical Impact: Diagnosis of MS is based on McDonald criteria. MS therapy can be divided into relapse, disease-modifying and symptomatic treatment. Relapses are commonly treated with intravenous methylprednisolone. First-line therapy consists of either interferon-β, glatiramer acetate or teriflunomide. In general, agents used as escalation therapies (natalizumab, fingolimod and mitoxantrone) are more potent than the agents used for first-line therapy; however, these have potentially serious side effects and should be used with care.

Many of the available disability outcome measures used in clinical trials of multiple sclerosis are insensitive to change over time, inadequately validated, or insensitive to patient-perceived health status or quality of life. Increasing focus on therapies that slow or reverse disability progression makes it essential to refine existing measures or to develop new tools. Major changes to the expanded disability status scale should be avoided to prevent the loss of acceptance by regulators as a measure for primary outcomes in trials that provide substantial evidence of effectiveness. Rather, we recommend practical refinements. Conversely, although substantial data support the multiple sclerosis functional composite as an alternative measure, changes to its component tests and scoring method are needed. Novel approaches, including the use of composite endpoints, patient-reported outcomes, and measurement of biomarkers, show promise as adjuncts to the current disability measures, but are insufficiently validated to serve as substitutes. A collaborative approach that involves academic experts, regulators, industry representitives, and funding agencies is needed to most effectively develop disability outcome measures.

Optical coherence tomography (OCT) is a new method that could aid analysis of neurodegeneration in multiple sclerosis (MS) by capturing thinning of the retinal nerve fibre layer (RNFL). Meta-analyses of data for time domain OCT show RNFL thinning of 20·38 μm (95% CI 17·91–22·86, n=2063, p<0·0001) after optic neuritis in MS, and of 7·08 μm (5·52–8·65, n=3154, p<0·0001) in MS without optic neuritis. The estimated RNFL thinning in patients with MS is greater than the extent expected in normal ageing, probably because of retrograde trans-synaptic degeneration and progressive loss of retinal ganglion cells, in addition to the more pronounced thinning caused by optic neuritis if present. RNFL thickness correlates with visual and neurological functioning as well as with paraclinical data. Developments that could improve understanding of the relation between structure and function in MS pathophysiology include spectral or Fourier domain OCT technology, polarisation-sensitive OCT, fluorescence labelling, structural assessment of action-potential propagation, and segmentation algorithms allowing quantitative assessment of retinal layers.

In this 24-month, randomized trial involving patients with relapsing–remitting multiple sclerosis, oral fingolimod reduced the rates of relapse and disability progression, as compared with placebo. Adverse events reported in patients treated with fingolimod included bradycardia, atrioventricular conduction block, macular edema, elevations in liver-enzyme levels, and mild hypertension. In patients with relapsing–remitting multiple sclerosis, oral fingolimod reduced the rates of relapse and disability progression, as compared with placebo. Adverse events included bradycardia, atrioventricular conduction block, macular edema, elevations in liver-enzyme levels, and mild hypertension. Fingolimod (FTY720) is an oral sphingosine-1-phosphate–receptor modulator 1 that is currently being evaluated for the treatment of multiple sclerosis. There is evidence that fingolimod acts by preventing lymphocyte egress from lymph nodes. 2 , 3 This leads to a reduced infiltration of potentially autoaggressive lymphocytes into the central nervous system. 4 , 5 Preclinical findings also suggest that fingolimod may promote neuroprotective and reparative processes within the central nervous system through modulation of sphingosine-1-phosphate receptors expressed on neural cells. 6 – 12 A 6-month, phase 2, placebo-controlled study 13 and its open-label extension study 14 showed sustained suppression, for up to 5 years, of both relapse and inflammatory activity . . .

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. 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. 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. Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies. Biogen Idec.

Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS. In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 μg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211. Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0·59, 95% CI 0·44–0·80; p=0·0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0·60, 0·39–0·92; p=0·022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0·31). Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

The armamentarium for the treatment of relapsing-remitting multiple sclerosis (RRMS) is increasing rapidly. Several oral treatments have shown benefit and will generate much interest because of the convenience of such administration. However, availability of convenient oral drugs will not necessarily translate into clinical effectiveness and safety. Here, we provide an interim report about the mechanisms of action, and efficacy and safety results that have been reported since January, 2010, for five new oral drugs. Additionally, we draw attention to issues that neurologists and patients will encounter when considering the use of new oral drugs. Positive results have been reported for five new oral drugs for RRMS—fingolimod, cladribine, teriflunomide, laquinimod, and dimethyl fumarate—in phase 3 studies; a few new oral drugs are likely to be approved for RRMS soon. Emerging oral treatments are ushering in a new era in the treatment of MS, providing not only new treatment options but also new challenges. Since data for some of the new drugs have not been reported in peer-reviewed journals yet and safety profiles are not yet fully developed, opinions about the use of these new oral drugs in practice are preliminary and tentative. Practice will evolve with time as information and experience accumulates. Of importance will be results from comparator trials, information about management of patients with breakthrough disease, results from long-term safety studies, and results of studies to assess the potential for neuroprotective effects of the new drugs.

The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression. Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 μg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211. 235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0·63, 95% CI 0·48–0·83; p=0·003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0·76, 0·52–1·11; p=0·177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b. Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes. Bayer Schering Pharma.

This placebo-controlled, randomized trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab (an α 4 integrin antagonist) in all the primary and secondary outcome measures. After two years, the probability of sustained progression of disability was 17 percent with natalizumab and 29 percent with placebo. Fatigue and allergic reaction were more common among patients receiving natalizumab. This trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab in all the primary and secondary outcome measures. In this trial, natalizumab in combination with interferon was more effective than interferon alone. Progressive multifocal leukoencephalopathy developed in two patients. In this systematic evaluation for PML in patients who received natalizumab in clinical trials, no additional cases were identified. Relapsing multiple sclerosis is characterized by the intermittent development of inflammatory lesions in the brain and spinal cord, resulting in plaques of demyelination and axonal loss. Lymphocyte migration across the blood–brain barrier is thought to be an important early step in the formation of lesions. 1 The interaction of α 4 β 1 integrin, a protein on the surface of lymphocytes, with vascular-cell adhesion molecule 1 (VCAM-1), which is expressed on the surface of vascular endothelial cells in brain and spinal cord blood vessels, mediates the adhesion and migration of lymphocytes in areas of inflammation. 2 – 6 Furthermore, the interaction of α . . .

Oral fumarate (BG00012) might have dual anti-inflammatory and neuroprotective effects. Our aim was to assess the efficacy and safety of BG00012 in patients with relapsing-remitting multiple sclerosis. 257 patients, aged 18–55 years, with relapsing-remitting multiple sclerosis were randomly assigned to receive 120 mg once daily (n=64), 120 mg three times daily (n=64), or 240 mg three times daily (n=64) BG00012, or placebo (n=65) for 24 weeks. During an extension period of 24 weeks for safety assessment, patients treated with placebo received BG00012 240 mg three times daily. The primary endpoint was total number of new gadolinium enhancing (GdE) lesions on brain MRI scans at weeks 12, 16, 20, and 24. Additional endpoints included cumulative number of new GdE lesions (weeks 4–24), new or enlarging T2-hyperintense lesions, new T1-hypointense lesions at week 24, and annualised relapse rate. Analysis was done on the efficacy-evaluable population. Safety and tolerability were also assessed. This study is registered with ClinicalTrials.gov, number NCT00168701. Treatment with BG00012 240 mg three times daily reduced by 69% the mean total number of new GdE lesions from week 12 to 24 compared with placebo (1·4 vs 4·5, p<0·0001). It also reduced number of new or enlarging T2-hyperintense (p=0·0006) and new T1-hypointense (p=0·014) lesions compared with placebo. BG00012 reduced annualised relapse rate by 32% (0·44 vs 0·65 for placebo; p=0·272). Adverse events more common in patients given BG00012 than in those given placebo included abdominal pain, flushing, and hot flush. Dose-related adverse events in patients on BG00012 were headache, fatigue, and feeling hot. The anti-inflammatory effects and favourable safety profile of BG00012 warrant further long-term phase III studies in large patient groups. Biogen Idec, Inc.