Multiple Sclerosis and Related Disorders (2014) 3, 139–140

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Editors’ Welcome Welcome to the first issue of the New Year; it is our second birthday. We would like to take this opportunity to welcome the appointment of Alison Thomson as Lay Editor to the journal; her role is to junk the jargon and produce lay summaries of all original articles published in the journal. The aim of the lay summaries is to make the contents of articles accessible to MSers, their families and friends, and other lay readers. Alison also brings a youthful face to the journal; she is the youngest member of our editorial board by some way. In this issue Mark Freedman and colleagues review, and compare, 5 phase III trials of disease-modifying therapies in clinically-isolated syndromes (CIS). The proportion of placebotreated CIS patients who developed clinically-definite MS within 2 years was 38–45% across the studies, and this rate was significantly reduced by disease-modifying therapies (DMT). The authors conclude that these studies support early use of DMT for patients with CIS at high risk of conversion to multiple sclerosis. Several MRI-related studies are included in this issue. Abdel-Fahim and colleagues demonstrate how the detection of focal cortical lesions can be improved using 7T magnetization transfer imaging (MTR) in patients with multiple sclerosis. In the 18 patients studied with MTR, 26%, more lesions were detected when compared to 7T MPRAGE and 58% compared to 7T T2*. High-field scanners are clearly an advance and will certainly lead to better ascertainment of the MS disease burden when they become more widely available. Using current 3T technology, Nelson and colleagues compare 3D magnetization prepared rapid acquisition with gradient echo (MPRAGE) sequences with double inversion recovery (DIR) combined with phase sensitive inversion recovery (PSIR) (DIR/PSIR) to assess which method was better at detecting intracortical MS lesions. DIR/PSIR images were clearly superior, revealing 58% more intracortical lesions than MPRAGE. Contrast-to-noise ratio of cortical lesions was inferior on the MPRAGE images. Another study (Altmann et al.) employed magnetization transfer ratio (MTR) as a putative in vivo biomarker of remyelination. They analyzed data from a natural history study of relapsing remitting MS and calculated that a therapeutic effect that resulted in 30% remyelination of T2 lesions could be detected with 80% power in 38 patients per arm based on in vivo data, and in 66 subjects per arm based on ex vivo 2211-0348/$ - see front matter & 2014 Published by Elsevier B.V.

data. It is clear that these sample sizes make MTR a feasible outcome measure for proof-of-concept remyelination trials in MS. This is an important step in the testing of emerging drugs that target remyelination in MS. This study has been selected as the Editor0 s Choice article from this issue of the journal as it represents a milestone in the development of clinical trials to test strategies that target remyelination as a primary outcome. The role of abnormal iron accumulation in MS has been debated for decades. Quinn and colleagues using R2* as an MRI metric for iron concentration clearly show that patients with MS have significantly increased iron in basal ganglia structures and cortical areas. Thalamic iron correlated positively with the Expanded Disability Status Scale (EDSS). Importantly, no correlations were found between any changes in iron content and the internal jugular vein cross-sectional area, a finding that argues strongly against venous abnormalities as a cause of iron accumulation in the MS brain. Alex Rae-Grant and colleagues diligently review the pathologic literature from 1839 to 2012 on MS venous pathology; specifically, observations concerning the perivenular distribution of lesions and large vein pathology. In their analysis of 102 papers, the first specific mention of central venules characterizing MS plaques dates back to Rindfleisch in 1863. Subsequently, Putnam and others in the 1930s hypothesized that venous pathology caused MS. While the controversy over venous disease in MS appears to be new, the observation of perivenular MS plaques and venous theories about MS pathogenesis are not. In an interesting statistical paper, Eric Chamot and colleagues discuss the application of bifactor confirmatory factor analysis to a study of disability outcomes from the North American interferon beta-1a clinical trial (Avonex); the final bifactor model explained 59% of total variance. They propose such modeling to understand the structure of disability in MS and to refine composite measures of global disability in MS. Hopefully, this approach will be applied to other data sets to confirm their findings. Pediatric onset multiple sclerosis (POMS) features regularly in our journal. Benson and colleagues show that the annualized relapse rate is 2.3 times higher in POMS, compared to the adult onset variety. Despite this, it is not associated with greater disability. These findings and other insights from their work will be invaluable when designing clinical trials for POMS. The commentary on a rare leukoencephalopathy associated

140 with chloride channel mutations will be of particular interest to pediatric neurologists Theoretically, similar novel channelopathies may await discovery by adult neurologists. Mitsikostas and colleagues report the clinical and laboratory features concerning 9/13 cases of natalizumab-related PML cases in Greece. Their experience appears typical of other series. Unfortunately there were three deaths in their cohort, a timely reminder of the requirement to switch PML high-risk patients to another therapy. Their observations emphasize the need for close surveillance to help promote early identification of PML and natalizumab withdrawal. Hitherto, it was accepted that neutralizing antibodies (NAb) to interferon-beta (IFNβ) reduce its therapeutic efficacy. Hegen et al. report a small negative study, using the repeated administration of high-dose IFNβ-1b intravenously in NAb positive patients with MS. Their protocol failed to reinduce self-tolerance to IFNβ, nor did it re-establish bioavailability to exogenously administered IFNβ. This is an interesting study as it implies NAbs directed toward a selfprotein represent an iatrogenic autoimmune disease that can be induced by the therapeutic administration of a recombinant protein. Immunologists concerned with the induction of autoimmune disease may find NAbs an interesting model of autoimmunity and use it to test immune tolerance strategies in humans. Nobody doubts that MS is an economic burden on society. The scale of the problem is seldom appreciated. Campbell and colleagues evaluate the burden of disease in the United States using nationally representative data from the Medical Expenditure Panel Survey. Their study estimates the total population prevalence of MS to be 572,312 (95% CI: 397,004–747,619) with annual direct costs $24,327 higher for the MS population compared to the non-MS residents. People with MS were 3.3 times more likely to be unemployed, had 4.4 times greater number of days in bed and lost 10 quality-adjusted life years (QALYs) compared to the non-MS cohort. Their study confirms that MS is associated with higher healthcare costs, reduced productivity due to unemployment, days spent in bed, and lower health-related quality of life. Ramasamy and colleagues explore CYP24A1 (24-hydroxylase) function, the cytochrome that initiates breakdown of 1,25-dihydroxyvitamin D3, in human brain. Network analysis shows a significant enrichment of functional terms related to immune response in eight out of the ten brain regions

B. Banwell et al. studied, implying that a known MS risk allele (rs2248359-C) increases CYP24A1 expression in human brain. This provides a genetic link between MS and vitamin D metabolism and predicts that the physiologically active form of vitamin D3 is protective against demyelination. Whether or not the immunomodulatory functions of vitamin D3 in human brain are involved in MS pathogenesis will require additional work. In a related review on epigenetic mechanisms, Peter van den Elson and colleagues discuss a role for MS-specific epigenetic changes that control gene expression. They discuss the application of small molecule inhibitors that target epigenetic machinery as a treatment in experimental animal models of demyelination and imply that such approaches may be applicable to treating MS. Rituximab (anti-CD20) is a B-cell depleting monoclonal antibody that is licensed for treating rheumatoid arthritis and has been shown to be effective in a phase 2 trial of relapsing- remitting MS. Whether rituximab works via depleting B cells or has additional effects on T cells is a moot point. Graves and colleagues address this question in their study of patients with MS or NMO who received at least one rituximab infusion. Initial treatment with rituximab transiently reduced CD4+ and CD8+ T-cells by 26% and 22%, respectively. However, subsequent infusions of rituximab did not result in a significant drop in either class of T cell. Whether the initial changes in T cells are linked to the mode of action of rituximab, or whether they increase the risk of infection in susceptible individuals, will require further study. Our review by the Literature Selection Technical Review Committee of the U.S. National Library of Medicine was just below their recently elevated threshold to allow articles published in MSARD to be indexed in PubMed. We remain positive that when they assess our journal in 2015 it will be listed in the index. Meanwhile all open-access articles will be indexed, which is why some of articles appear on PubMed. We remain heartened by the interest you have shown in the content of our journal and your continuing support.

Brenda Banwell, Gavin Giovannoni, Chris Hawkes, Fred Lublin

Editors' welcome.

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