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• Seroconversion is important in patients with multiple sclerosis. • The incidence of seroconversion was reported between 6% and 41%. • The incidence of seroreversion was reported between 1% and 11%. • Incidence of seroconversion is higher in European/American countries. Natalizumab is a medication of choice for some patients with relapsing remitting (RR) form of multiple sclerosis (MS). John Cunningham virus (JCV) antibody status is important in cases who are treating with natalizumab. Different studies reported various rates of seroconversion and sero-reversion in patients who had been treated with natalizumab. As there is no systematic review reporting incidence of seroconversion and seroreversion in MS cases who were treated with natalizumab, we aimed to conduct this systematic review and meta-analysis to find pooled incidence of seroconversion and seroreversion in MS cases who were treated with natalizumab. PubMed, Scopus, EMBASE, CINAHL, Web of Science, Ovid, and google scholar were systematically searched. We also searched the gray literature including references from included studies, and conference abstracts which were published up to April 2019. The incidence of seroconversion was reported between 6% and 41% and the incidence of seroreversion was reported between 1% and 11%. The pooled estimate of seroconversion incidence was 19% (95% CI: 13%–25%) (I2 = 96.8%, P < 0.001) and the pooled estimate of seroreversion incidence was 5% (95% CI: 3%–8%) (I2 = 72.2%, P < 0.001). Subgroup analysis by considering the country of the origin showed that the pooled incidence of seroconversion incidence during the studies was 6% in Asian countries and 21% in European/American countries. The incidence difference between subgroups was significant (p < 0.001). Incidence of seroconversion in MS patients who had been treated with natalizumab is higher in European/American countries than Asian countries. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The purpose of this study was to assess the safety and efficacy of mitoxantrone (MX) in pediatric patients with aggressive multiple sclerosis (MS). Methods: A retrospective analysis on pediatric MS patients treated with MX was performed with regards to demographic/clinical parameters and magnetic resonance imaging (MRI) findings. Results: 19 definite pediatric MS cases with mean ± SD age of 15.4 ± 2.8 years underwent 20 mg MX for control of their severe/frequent relapses, high EDSS score or new and active brain MRI lesions. After a median [IQR] follow-up period of 30[12–60] months, 14 cases (73%) were relapse free; the EDSS score decreased by at least 0.5 in 16 cases (84.2%); and gadolinium-enhancing lesion volume fell by 84.2% in 16 cases. Adverse events included nausea and vomiting, fatigue, alopecia, palpitation, cardiomyopathy and mild leukopenia. All adverse events were mild and transient. Conclusion: Our results suggest MX is a good candidate for treatment of children with worsening RRMS and SPMS. Recommendations regarding patient selection, treatment administration, and close follow-up should be considered. Continuing research is needed to establish its efficacy and safety profile in a multinational collaboration with careful follow-up of adverse events. [Copyright &y& Elsevier]

We review the practical application of the tools for studying the genetic epidemiology of complex disease. Whole-genome association studies highlight the need to understand the genetic epidemiology. Elucidating the genetic basis of disease anticipated from these studies has been incomplete, and the importance of the environment and its potential interaction with genes cannot be overlooked. Multiple sclerosis yields several key lessons including how epistatic effects might overshadow the small effects of genes identified from whole-genome association studies. We reinterpret twin studies and demonstrate the use and advantages of adoptee, half-sibling and avuncular-pair studies. These show that the environment acts at a population level, strongly indicating epigenetic modifications to germline susceptibility. There is good reason to think that such interactions will be within the major histocompatibility complex, in which strong epistatic effects have already been demonstrated. Family-based data in multiple sclerosis are applicable to other neurological traits. [Copyright &y& Elsevier]

Summary: Background: Evidence of an association between multiple sclerosis (MS) and other autoimmune diseases would substantiate the hypothesis that MS is an autoimmune disease, and implicate a common mechanism. We aimed to investigate and compare the rate of autoimmune disease in MS patients, in their first-degree relatives, and in their unrelated spouses. Methods: We used data from a national, multicentre, population-based sample to investigate the rate of autoimmune disease in 5031 MS patients, 30 259 of their first-degree relatives, and 2707 spousal controls. We asked patients and controls whether they had any of ten autoimmune diseases: Crohn''s disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, psoriasis, pernicious anaemia, systemic lupus erythematosus, autoimmune thyroid disease, vitiligo, and myasthenia gravis. MS probands were also asked whether their first-degree relatives had Crohn''s disease, ulcerative colitis, rheumatoid arthritis, or type 1 diabetes. Findings: After correction for age and sex, we did not identify any increased risk of autoimmune diseases in MS patients compared with their spousal controls (odds ratio [OR]=1·07, 95% CI 0·86–1·23, χ2=0·47, p=0·49), or in the first-degree relatives of MS probands compared with controls (OR=0·89, 0·63–1·17, χ2=1·11, p=0·29). However, the reported frequency of autoimmune diseases did differ according to the sex of the interviewee (female vs male patients χ2=92·2, p<0·0001; female vs male spousal controls χ2=87·1, p<0·0001). MS patients had slightly higher rates of thyroid disease and pernicious anaemia than did controls, which is consistent with MHC associations for these diseases, but this effect disappeared when results were adjusted for sex. For eight other diseases the rates were similar in MS patients and controls. Families with multiple cases of MS were no more likely to report autoimmune diseases than families with single MS cases. Interpretation: When data were adjusted for sex, no excess of common autoimmune diseases could be identified in MS patients or their families, including multicase pedigrees. Our results suggest that women are more aware of family medical histories than men, which emphasises the potential for ascertainment bias in unstratified data for a sex-limited disease. Family histories should thus be taken from male patients in the presence of a spouse. [Copyright &y& Elsevier]

Background: Prediction of susceptibility to multiple sclerosis (MS) might have important clinical applications, either as part of a diagnostic algorithm or as a means to identify high-risk individuals for prospective studies. We investigated the usefulness of an aggregate measure of risk of MS that is based on genetic susceptibility loci. We also assessed the added effect of environmental risk factors that are associated with susceptibility for MS.Methods: We created a weighted genetic risk score (wGRS) that includes 16 MS susceptibility loci. We tested our model with data from 2215 individuals with MS and 2189 controls (derivation samples), a validation set of 1340 individuals with MS and 1109 controls taken from several MS therapeutic trials (TT cohort), and a second validation set of 143 individuals with MS and 281 controls from the US Nurses' Health Studies I and II (NHS/NHS II), for whom we also have data on smoking and immune response to Epstein-Barr virus (EBV).Findings: Individuals with a wGRS that was more than 1.25 SD from the mean had a significantly higher odds of MS in all datasets. In the derivation sample, the mean (SD) wGRS was 3.5 (0.7) for individuals with MS and 3.0 (0.6) for controls (p<0.0001); in the TT validation sample, the mean wGRS was 3.4 (0.7) for individuals with MS versus 3.1 (0.7) for controls (p<0.0001); and in the NHS/NHS II dataset, the mean wGRS was 3.4 (0.8) for individuals with MS versus 3.0 (0.7) for controls (p<0.0001). In the derivation cohort, the area under the receiver operating characteristic curve (C statistic; a measure of the ability of a model to discriminate between individuals with MS and controls) for the genetic-only model was 0.70 and for the genetics plus sex model was 0.74 (p<0.0001). In the TT and NHS cohorts, the C statistics for the genetic-only model were both 0.64; adding sex to the TT model increased the C statistic to 0.72 (p<0.0001), whereas adding smoking and immune response to EBV to the NHS model increased the C statistic to 0.68 (p=0.02). However, the wGRS does not seem to be correlated with the conversion of clinically isolated syndrome to MS.Interpretation: The inclusion of 16 susceptibility alleles into a wGRS can modestly predict MS risk, shows consistent discriminatory ability in independent samples, and is enhanced by the inclusion of non-genetic risk factors into the algorithm. Future iterations of the wGRS might therefore make a contribution to algorithms that can predict a diagnosis of MS in a clinical or research setting. [ABSTRACT FROM AUTHOR]

Evidence about the comparative effects of new treatments is typically collected in randomized controlled trials (RCTs). In some instances, RCTs are not possible, or their value is limited by an inability to capture treatment effects over the longer term or in all relevant population subgroups. In these cases, nonrandomized studies (NRS) using real-world data (RWD) are increasingly used to complement trial evidence on treatment effects for health technology assessment (HTA). However, there have been concerns over a lack of acceptability of this evidence by HTA agencies. This article aims to identify the barriers to the acceptance of NRS and steps that may facilitate increases in the acceptability of NRS in the future. Opinions of the authorship team based on their experience in real-world evidence research in academic, HTA, and industry settings, supported by a critical assessment of existing studies. Barriers were identified that are applicable to key stakeholder groups, including HTA agencies (eg, the lack of comprehensive methodological guidelines for using RWD), evidence generators (eg, avoidable deviations from best practices), and external stakeholders (eg, data controllers providing timely access to high-quality RWD). Future steps that may facilitate future acceptability of NRS include improvements in the quality, integration, and accessibility of RWD, wider use of demonstration projects to highlight the value and applicability of nonrandomized designs, living, and more detailed HTA guidelines, and improvements in HTA infrastructure relating to RWD. NRS can represent a crucial source of evidence on treatment effects for use in HTA when RCT evidence is limited. • Multiple studies have elicited the views of health technology assessment (HTA) agencies and other key stakeholders on barriers to the acceptance of real-world data (RWD) studies more generally, including concerns relating to methodology (eg, residual biases), data availability, governance and quality, and limited trust in RWD studies, as well as barriers relating to HTA policy and partnerships. • We focus specifically on the barriers to the acceptance of nonrandomized studies (NRS) estimating comparative effectiveness. We outline a pathway determining the acceptance and assign the responsibility for specific barriers to key stakeholders, including (1) evidence-appraisers (HTA agencies), such as providing comprehensive methodological guidelines for conducting NRS, (2) evidence generators (manufacturers), such as whether latest best practices are adhered too, and (3) external stakeholders (eg, data controllers), such as whether there is timely access to high-quality RWD. • We discuss future steps requiring a joint effort between all stakeholders that could facilitate increased acceptability of NRS, including improvements in the quality and accessibility of RWD, use of demonstration projects to benchmark NRS results against RCT evidence and highlight the value and applicability best-practice methods, and ensuring up-to-date and detailed HTA real-world evidence guidelines. [ABSTRACT FROM AUTHOR]

• Although real-world evidence is increasingly being accepted by health technology assessment agencies, concerns remain with regards to residual confounding. • Quantitative bias analysis and negative controls are 2 methods that have been recommended as best practice by health technology assessment agencies such as the National Institute for Health and Care Excellence, which can evaluate and correct for this potential bias. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a common, complex neurological disease. The precise aetiology of MS is not yet known, although epidemiological data indicate that both genetic and environmental factors are important. The evidence that the environment acts long before MS becomes clinically evident is well established and suggests the existence of a prodromal phase for the disease. The increasing incidence of MS emphasises the need for strategies to prevent this chronic disorder, and the possibility of a prodrome indicates a window of opportunity to potentially reverse early disease processes before clinical disease becomes evident. Studying a prodrome requires techniques other than clinical observation such as monitoring endophenotypes that result from associated risk factors. However, our current knowledge of causal pathways and endophenotypes in MS is limited. Identifying and studying individuals with a high risk of developing the disease provides a powerful opportunity to understand the MS causal cascade and is highly relevant to strategies that are aimed at preventing this debilitating disease. [ABSTRACT FROM AUTHOR]

Governments and health technology assessment agencies are putting greater focus on and efforts in understanding and addressing health inequities. Cost-effectiveness analyses are used to evaluate the costs and health gains of different interventions to inform the decision-making process on funding of new treatments. Distributional cost-effectiveness analysis (DCEA) is an extension of cost-effectiveness analysis that quantifies the equity impact of funding new treatments. Key challenges for the routine and consistent implementation of DCEA are the lack of clearly defined equity concerns from decision makers and endorsed measures to define equity subgroups and the availability of evidence that allows analysis of differences in data inputs associated with the equity characteristics of interest. In this article, we detail the data gaps and challenges to build robust DCEA analysis routinely in health technology assessment and suggest actions to overcome these hurdles. • Governments are putting greater focus on tackling health inequities, and health technology assessment bodies are responding by working to formally incorporate equity considerations into the decision-making process on funding of interventions. • Distributional cost-effectiveness analysis (DCEA) is a method to assess how health effects and costs are distributed between subpopulations and any ensuing trade-offs between maximizing overall population health and equity. DCEA provides a quantitative method for incorporating equity impact assessment into decision making. • Data gaps may limit the implementation of robust DCEA routinely for products undergoing health technology assessment. Therefore, data collection, analysis, and reporting need to be improved and aligned with the equity concepts of interest to decision makers. [ABSTRACT FROM AUTHOR]

Epigenetics is rising to prominence in biology as a mechanism by which environmental factors have intermediate-term effects on gene expression without changing the underlying genetic sequence. This can occur through the selective methylation of DNA bases and modification of histones. There are wide-ranging implications for the gene–environment debate and epigenetic mechanisms are causing a reevaluation of many traditional concepts such as heritability. The reversible nature of epigenetics also provides plausible treatment or prevention prospects for diseases previously thought hard-coded into the genome. Here, we consider how growing knowledge of epigenetics is altering our understanding of biology and medicine, and its implications for future research. [Copyright &y& Elsevier]

• Venous thromboembolism (VTE) is a major cause of mortality and morbidity worldwide. • Data on VTE patients was extracted from the Norwegian Patient Registry. • Recently the incidence and prevalence of VTE in Norway has been relatively stable. • The incidence of PE has increased, whereas DVT incidence has decreased slightly. [ABSTRACT FROM AUTHOR]

Summary: Background: Incidence of multiple sclerosis is thought to be increasing, but this notion has been difficult to substantiate. In a longitudinal population-based dataset of patients with multiple sclerosis obtained over more than three decades, we did not show a difference in time to diagnosis by sex. We reasoned that if a sex-specific change in incidence was occurring, the female to male sex ratio would serve as a surrogate of incidence change. Methods: Since environmental risk factors seem to act early in life, we calculated sex ratios by birth year in 27 074 Canadian patients with multiple sclerosis identified as part of a longitudinal population-based dataset. Findings: The female to male sex ratio by year of birth has been increasing for at least 50 years and now exceeds 3·2:1 in Canada. Year of birth was a significant predictor for sex ratio (p<0·0001, χ2=124·4; rank correlation r=0·84). Interpretation: The substantial increase in the female to male sex ratio in Canada seems to result from a disproportional increase in incidence of multiple sclerosis in women. This rapid change must have environmental origins even if it is associated with a gene–environment interaction, and implies that a large proportion of multiple sclerosis cases may be preventable in situ. Although the reasons why incidence of the disease is increasing are unknown, there are major implications for health-care provision because lifetime costs of multiple sclerosis exceed £1 million per case in the UK. [Copyright &y& Elsevier]