Natalizumab for the treatment of relapsing multiple sclerosis

Natalizumab is an α4-integrin antagonist approved as monotherapy for patients with relapsing multiple sclerosis (MS), based on demonstrated efficacy in the pivotal AFFIRM study (N = 942). Natalizumab monotherapy reduced risk of disability progression by 42%–54% and annualized relapse rate by 68% during a period of 2 years. Natalizumab was also associated with significant reductions in number of T2-hyperintense, gadolinium-enhancing, and T1-hypointense lesions and in volume of T2-hyperintense lesions (all p < 0.001) on magnetic resonance imaging. Furthermore, natalizumab-treated patients in AFFIRM experienced significant improvements from baseline in the physical and mental components of the Short Form-36 (p ≤ 0.01) and a 35% reduction in risk of clinically significant vision loss (p = 0.008 vs placebo). Natalizumab was well tolerated in phase 3 studies. Common adverse events were generally mild and included headache, fatigue, urinary tract infections, and arthralgia. Serious adverse events were similar between treatment groups. The incidence of serious hypersensitivity reactions associated with natalizumab was <1%. Progressive multifocal leukoencephalopathy was a rare complication of treatment, observed in 2 patients with MS who received natalizumab plus interferon β-1a. The robust clinical benefits of natalizumab, including benefits on patient-reported quality of life, make it an important addition to disease-modifying therapies available to patients with relapsing MS

Quantitative signal properties from standardized MRIs correlate with multiple sclerosis disability

OBJECTIVE: To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS-related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice. METHODS: We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1-weighted and 3D-FLAIR (T2-weighted) images from 5010 participants enrolled in a multinational database of MS patients which collected imaging, neuroperformance and disability measures. RESULTS: Intensity distribution metrics distinguished MS patients from control participants based on normalized non-lesional signal differences. This analysis revealed non-lesional differences between relapsing MS versus progressive MS subtypes. Further, the correlation between our non-lesional measures and disability was approximately three times greater than that between total lesion volume and disability, measured using the patient derived disease steps. Multivariate modeling revealed that measures of extra-lesional tissue integrity and atrophy contribute uniquely, and approximately equally, to the prediction of MS-related disability. INTERPRETATION: These results support the notion that non-lesional abnormalities correlate more strongly with MS-related disability than lesion burden and provide new insight into the basis of abnormalities in NA WM. Non-lesional abnormalities distinguish relapsing from progressive MS but do not distinguish between progressive subtypes suggesting a common progressive pathophysiology. Image intensity parameters and existing biomarkers each independently correlate with MS-related disability

Excessive Biologic Response to IFNβ Is Associated with Poor Treatment Response in Patients with Multiple Sclerosis

Interferon-beta (IFNβ) is used to inhibit disease activity in multiple sclerosis (MS), but its mechanisms of action are incompletely understood, individual treatment response varies, and biological markers predicting response to treatment have yet to be identified.he relationship between the molecular response to IFNβ and treatment response was determined in 85 patients using a longitudinal design in which treatment effect was categorized by brain magnetic resonance imaging as good (n = 70) or poor response (n = 15). Molecular response was quantified using a customized cDNA macroarray assay for 166 IFN-regulated genes (IRGs).The molecular response to IFNβ differed significantly between patients in the pattern and number of regulated genes. The molecular response was strikingly stable for individuals for as long as 24 months, however, suggesting an individual ‘IFN response fingerprint’. Unexpectedly, patients with poor response showed an exaggerated molecular response. IRG induction ratios demonstrated an exaggerated molecular response at both the first and 6-month IFNβ injections.MS patients exhibit individually unique but temporally stable biological responses to IFNβ. Poor treatment response is not explained by the duration of biological effects or the specific genes induced. Rather, individuals with poor treatment response have a generally exaggerated biological response to type 1 IFN injections. We hypothesize that the molecular response to type I IFN identifies a pathogenetically distinct subset of MS patients whose disease is driven in part by innate immunity. The findings suggest a strategy for biologically based, rational use of IFNβ for individual MS patients

Identifying High Metallicity M Giants at Intragroup Distances with SDSS

Tidal stripping and three-body interactions with the central supermassive black hole may eject stars from the Milky Way. These stars would comprise a set of `intragroup' stars that trace the past history of interactions in our galactic neighborhood. Using the Sloan Digital Sky Survey DR7, we identify candidate solar metallicity red giant intragroup stars using color cuts that are designed to exclude nearby M and L dwarfs. We present 677 intragroup candidates that are selected between 300 kpc and 2 Mpc, and are either the reddest intragroup candidates (M7-M10) or are L dwarfs at larger distances than previously detected.Comment: 8 pages, 6 figures, 1 table (for full version, see http://astro.phy.vanderbilt.edu/~palladl2), Accepted for publication in A

Evolving Concepts in the Pathogenesis of Multiple Sclerosis

In recent years, concepts of MS pathogenesis have evolved rapidly. Still considered an immune-initiated inflammatory disease, there has been increasing awareness of several features of the disease. This lecture will review some of these newer aspects

Contemporary and New Immunomodulatory Therapy for Multiple Sclerosis

This presentation will focus on imrnunomodulatory drUgs that have become available for multiple sclerosis over the past seven years. In addition, promising investigational therapies will be reviewed briefly. The presentation will focus on use of these drugs in patients with relapsing remitting MS, with less emphasis on drUgs used in the secondary progressive stage of the disease. In a companion presentation, we will discuss the rationale for early, proactive use of disease monitorjng drugs. The emphasis on early proactive therapy results from increasing evidence that the MS disease process is continuously active in many patients from early in the disease, and that the pathologic process in includes irreversible tissue injury and diffuse axonal pathology