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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.

Background Classically, randomised controlled trials (RCTs) are considered the gold standard for demonstrating product efficacy for the regulatory approval of medicines. However, as personalised medicine becomes increasingly common, patient recruitment into RCTs is affected and – sometimes – it is not possible to include a control arm [1]. Real-world data (RWD) are data that are collected outside of RCTs [2]. They are gaining increasing attention for their use in regulatory decision-making. The United States twenty-first Century Cures Act mandated that the US Food and Drug Administration (FDA) should provide guidance about the circumstances under which manufacturers can use RWD to support the approval of a medicine. More recently, investigators from the European Medicines Agency (EMA) detailed their views on this topic [3]. RWD for regulatory approval: opportunities and challenges Eichler et al., from the EMA, state that, “the RCT will, in our view, remain the best available standard and be required in many circumstances, but will need to be complemented by other methodologies to address research questions where a traditional RCT may be unfeasible or unethical.” Thus, the gauntlet has been laid down for RWD to be used to support European regulatory approval. Indeed, RWD has been used by the EMA to approve several medicines for rare/orphan indications [4]. Eichler and colleagues, however, highlight that RWD methods must be critically appraised before they can be more widely accepted. They suggest that this appraisal can be undertaken via prospective validation of any proposed method with a pre-defined protocol. Why the need for validation? Studies of the concordance between the results of RCTs and RWD studies investigating the same research question have given mixed results [5, 6]. It has been suggested that this discordance can be attributed to differences in the populations being investigated, or bias in RWD studies as a result of lack of randomisation. Using an example of cancer risk in statin users, Dickerman and co-workers attempted to understand why RWD studies have shown a protective effect and RCTs showed no effect on neoplasm incidence [7]. One of the key principles of an RCT is to assess patient characteristics at baseline to check study eligibility based on inclusion/exclusion criteria. If eligibility is met, the next task is to randomise subjects into groups and, subsequently, to provide treatment as assigned for each group. Dickerman et al. operationalised a similar ‘target trial’ approach using RWD and followed up trial-eligible new and non-users of statins to compare rates of cancer between these groups. Performing the analysis in this way enabled the researchers to illustrate that results from RWD were in acquiescence with those from RCTs. Furthermore, previously reported differences were largely a result of two avoidable issues: immortal time and selection bias caused by the inclusion of prevalent statin users (prevalent users had to have survived without cancer up to baseline, leading to artificially lower rates of cancer in the statin group), rather than being attributed to the lack of randomisation per se. As Dickerman et al. acknowledge, a limitation of the outcome they studied is that confounding by indication (whereby the reason for prescribing a patient medication is also associated with the outcome of interest) is unlikely to have a major role. Where the outcome is more likely to be affected by confounding by indication, then – to mimic the randomisation element of an RCT and appropriately compare treatment groups – RWD studies must carefully adjust for all baseline confounders. In this regard, Carrigan et al. recently report results exploring a research question more likely to be affected by confounding by indication [8]: whether control groups generated from RWD could approximate the control arms used in published RCTs in non-small cell lung cancer. In 10 of the 11 analyses conducted, hazard ratio estimates for overall survival derived from comparing RWD control arms with the intervention arm from the RCT were similar to those seen in the original RCT comparison. However, the analyses showed that a simple ‘target trial’ alignment of the RWD arm with the trial inclusion/exclusion criteria could not fully replicate the RCT effect estimate; additional adjustment to control for confounding using propensity scores was required. The single non-concordant analysis was thought to be associated with a biomarker that was likely enriched in the RCT but was not present in RWD and therefore could not be adjusted for. This exception to the overall consistency between RWD and RCT findings highlights the importance of needing RWD with information available on all possible confounders to avoid generating inaccurate results. These two recent studies show that analytical methods and approaches are in place to enable consistency between RCT and RWD results. Further evidence will arise from the FDA-funded RCT DUPLICATE project, which will investigate RCT–RWD concordance on a larger scale [9]. In light of this, the question arises: how many examples are required before regulators can begin to accept RWD for regulatory decision-making? Eichler et al. state that the answer is unlikely to be simple: decision-makers should perhaps first accept RWD analyses for situations in which there is a relatively small impact (e.g. label expansion) and then gradually expand acceptability as confidence in the method grows.

Multiple sclerosis (MS) appears to develop in genetically susceptible individuals as a result of environmental exposures. Epstein-Barr virus (EBV) infection is an almost universal finding among individuals with MS. Symptomatic EBV infection as manifested by infectious mononucleosis (IM) has been shown in a previous meta-analysis to be associated with the risk of MS, however a number of much larger studies have since been published. We performed a Medline search to identify articles published since the original meta-analysis investigating MS risk following IM. A total of 18 articles were included in this study, including 19390 MS patients and 16007 controls. We calculated the relative risk of MS following IM using a generic inverse variance with random effects model. This showed that the risk of MS was strongly associated with IM (relative risk (RR) 2.17; 95% confidence interval 1.97-2.39; p<10(-54)). Our results establish firmly that a history of infectious mononucleosis significantly increases the risk of multiple sclerosis. Future work should focus on the mechanism of this association and interaction with other risk factors.

As advanced non-small cell lung cancer (aNSCLC) is being increasingly divided into rare oncogene-driven subsets, conducting randomised trials becomes challenging. Using real-world data (RWD) to construct control arms for single-arm trials provides an option for comparative data. However, non-randomised treatment comparisons have the potential to be biased and cause concern for decision-makers. Using the example of pralsetinib from a RET fusion-positive aNSCLC single-arm trial (NCT03037385), we demonstrate a relative survival benefit when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. Quantitative bias analyses show that results for the RWD-trial comparisons are robust to data missingness, potential poorer outcomes in RWD and residual confounding. Overall, the study provides evidence in favour of pralsetinib as a first-line treatment for RET fusion-positive aNSCLC. The quantification of potential bias performed in this study can be used as a template for future studies of this nature. Real-world data (RWD) based control arms provide an option to compare the effectiveness of single-arm trials. By performing multiple quantitative bias analyses to alleviate concerns about trial-RWD comparability, here the authors show that the RET inhibitor pralsetinib provides survival benefit in patients with RET fusion-positive non-small cell lung cancer from the ARROW single-arm trial, (NCT03037385) when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts.

Multiple sclerosis (MS) is a leading cause of disability in young adults. Susceptibility to MS is determined by environmental exposure on the background of genetic risk factors. A previous meta-analysis suggested that smoking was an important risk factor for MS but many other studies have been published since then. We performed a Medline search to identify articles published that investigated MS risk following cigarette smoking. A total of 14 articles were included in this study. This represented data on 3,052 cases and 457,619 controls. We analysed these studies in both a conservative (limiting our analysis to only those where smoking behaviour was described prior to disease onset) and non-conservative manner. Our results show that smoking is associated with MS susceptibility (conservative: risk ratio (RR) 1.48, 95% confidence interval (CI) 1.35-1.63, p < 10⁻¹⁵; non-conservative: RR 1.52, 95% CI 1.39-1.66, p < 10⁻¹⁹). We also analysed 4 studies reporting risk of secondary progression in MS and found that this fell just short of statistical significance with considerable heterogeneity (RR 1.88, 95% CI 0.98-3.61, p = 0.06). Our results demonstrate that cigarette smoking is important in determining MS susceptibility but the effect on the progression of disease is less certain. Further work is needed to understand the mechanism behind this association and how smoking integrates with other established risk factors.

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non-MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous \"VDRE\" sequence found in non-MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention.

Background Contemporary debates about drug pricing feature several widely held misconceptions, including the relationship between incentives and innovation, the proportion of total healthcare spending on pharmaceuticals, and whether the economic evaluation of a medicine can be influenced by things other than clinical efficacy. Main body All citizens should have access to timely, equitable, and cost-effective care covered by public funds, private insurance, or a combination of both. Better managing the collective burden of diseases borne by today’s and future generations depends in part on developing better technologies, including better medicines. As in any innovative industry, the expectation of adequate financial returns incentivizes innovators and their investors to develop new medicines. Estimating expected returns requires that they forecast revenues, based on the future price trajectory and volume of use over time. How market participants decide what price to set or accept can be complicated, and some observers and stakeholders want to confirm whether the net prices society pays for novel medicines, whether as a reward for past innovation or an incentive for future innovation, are commensurate with those medicines’ incremental value. But we must also ask “value to whom?”; medicines not only bring immediate clinical benefits to patients treated today, but also can provide a broad spectrum of short- and long-term benefits to patients, their families, and society. Spending across all facets of healthcare has grown over the last 25 years, but both inpatient and outpatient spending has outpaced drug spending growth even as our drug armamentarium is constantly improving with safer and more effective medicines. In large part, this is because, unlike hospitals, drugs typically go generic, thus making room in our budgets for new and better ones, even as they often keep patients out of hospitals, driving further savings. Conclusion A thorough evaluation of drug spending and value can help to promote a better allocation of healthcare resources for both the healthy and the sick, both of whom must pay for healthcare. Taking a holistic approach to assessing drug value makes it clear that a branded drug’s value to a patient is often only a small fraction of the drug’s total value to society. Societal value merits consideration when determining whether and how to make a medicine affordable and accessible to patients: a drug that is worth its price to society should not be rendered inaccessible to ill patients by imposing high out-of-pocket costs or restricting coverage based on narrow health technology assessments (HTAs). Furthermore, recognizing the total societal cost of un- or undertreated conditions is crucial to gaining a thorough understanding of what guides the biomedical innovation ecosystem to create value for society. It would be unwise to discourage the development of new solutions without first appreciating the cost of leaving the problems unsolved.

Background Venous thromboembolism (VTE) is a common complication during and after a hospital admission. Although it is mainly considered a complication of surgery, it often occurs in people who have not undergone surgery, with recent evidence suggesting that immune-mediated diseases may play a role in VTE risk. We, therefore, decided to study the risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in people admitted to hospital with a range of immune-mediated diseases. Methods We analysed databases of linked statistical records of hospital admissions and death certificates for the Oxford Record Linkage Study area (ORLS1:1968 to 1998 and ORLS2:1999 to 2008) and the whole of England (1999 to 2008). Rate ratios for VTE were determined, comparing immune-mediated disease cohorts with comparison cohorts. Results Significantly elevated risks of VTE were found, in all three populations studied, in people with a hospital record of admission for autoimmune haemolytic anaemia, chronic active hepatitis, dermatomyositis/polymyositis, type 1 diabetes mellitus, multiple sclerosis, myasthenia gravis, myxoedema, pemphigus/pemphigoid, polyarteritis nodosa, psoriasis, rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. Rate ratios were considerably higher for some of these diseases than others: for example, for systemic lupus erythematosus the rate ratios were 3.61 (2.36 to 5.31) in the ORLS1 population, 4.60 (3.19 to 6.43) in ORLS2 and 3.71 (3.43 to 4.02) in the England dataset. Conclusions People admitted to hospital with immune-mediated diseases may be at an increased risk of subsequent VTE. Our findings need independent confirmation or refutation; but, if confirmed, there may be a role for thromboprophylaxis in some patients with these diseases.

Background A season of birth effect in immune-mediated diseases (ID) such as multiple sclerosis and type 1 diabetes has been consistently reported. We aimed to investigate whether season of birth influences the risk of rheumatoid arthritis, Crohn's disease, ulcerative colitis and systemic lupus erythematosus in addition to multiple sclerosis, and to explore the correlation between the risk of ID and predicted ultraviolet B (UVB) light exposure and vitamin D status during gestation. Methods The monthly distribution of births of patients with ID from the UK (n = 115,172) was compared to that of the general population using the Cosinor test. Predicted UVB radiation and vitamin D status in different time windows during pregnancy were calculated for each month of birth and correlated with risk of ID using the Spearman's correlation coefficient. Results The distributions of ID births significantly differed from that of the general population ( P = 5e -12 ) with a peak in April (odds ratio = 1.045, 95% confidence interval = 1.024, 1.067, P < 0.0001) and a trough in October (odds ratio = 0.945, 95% confidence interval = 0.925, 0.966, P < 0.0001). Stratification by disease subtype showed seasonality in all ID but Crohn's disease. The risk of ID was inversely correlated with predicted second trimester UVB exposure (Spearman's rho = -0.49, P = 0.00005) and third trimester vitamin D status (Spearman's rho = -0.44, P = 0.0003). Conclusions The risk of different ID in the UK is significantly influenced by the season of birth, suggesting the presence of a shared seasonal risk factor or factors predisposing to ID. Gestational UVB and vitamin D exposure may be implicated in the aetiology of ID.

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. 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. 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, χ 2=124·4; rank correlation r=0·84). 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.