Sunday, 25 September 2016

Comparing DMT

Fogarty E, Schmitz S, Tubridy N, Walsh C, Barry M.
Mult Scler Relat Disord. 2016 Sep;9:23-30. doi: 10.1016/j.msard.2016.06.001. Epub 2016 Jun 8.

INTRODUCTION:Randomised studies have demonstrated efficacy of disease-modifying therapies in relapsing remitting multiple sclerosis(RRMS). However it is unclear how the magnitude of treatment efficacy varies across all currently available therapies.
OBJECTIVE:To perform a systematic review and network meta-analysis to evaluate the comparative efficacy of available therapies in reducing relapses and disability progression in RRMS.
METHODS: A systematic review identified 28 randomised, placebo-controlled and direct comparative trials. A network meta-analysis was conducted to estimate comparative annualised relapse rates (ARR) and risks of disability progression (defined by both a 3-month, and 6-month confirmation interval). Potential sources of treatment-effect modification from study-level covariates and baseline risk were evaluated through meta-regression methods. The Surface Under the Cumulative RAnking curve (SUCRA) method was used to provide a ranking of treatments for each outcome.
RESULTS: The magnitude of ARR reduction varied between 15-36% for all interferon-beta products, glatiramer acetate and teriflunomide, and from 50 to 69% for alemtuzumab, dimethyl fumarate, fingolimod and natalizumab. The risk of disability progression (3-month) was reduced by 19-28% with interferon-beta products, glatiramer acetate, fingolimod and teriflunomide, by 38-45% for pegylated interferon-beta, dimethyl fumarate and natalizumab and by 68% with alemtuzumab. Broadly similar estimates for the risk of disability progression (6-month), with the exception of interferon-beta-1b 250mcg which was much more efficacious based on this definition. Alemtuzumab and natalizumab had the highest SUCRA scores (97% and 95% respectively) for ARR, while ranking for disability progression varied depending on the definition of the outcome.
CONCLUSION: Compared with placebo, clear reductions in ARR with disease-modifying therapies were accompanied by more uncertain changes in disability progression. The magnitude of the reduction and the uncertainty associated with treatment effects varied between DMTs. While natalizumab and alemtuzumab demonstrated consistently high ranking across outcomes, with older interferon-beta and glatiramer acetate products ranking lowest, variation in disability progression definitions lead to variation in the relative ranking of treatments. Rigorously conducted comparative studies are required to fully evaluate the comparative treatment effects of disease modifying therapies for RRMS

The CRAB drugs are low efficacy and Alemtuzumab and natalizumab appear to be amongst the most effective, at least in terms of inhibition of relapse. As to disability progression, we still struggle with the most effective outcome measure. The EDSS seems to be a gold standard that is not sensitive to change nor linear and MRI measures all have their issues. 

However, there are so many things that make up best drug, such as efficacy, convenience, cost-effectiveness, CNS activity, safety.

However, will we see head to heads to work out what is the best candidates. Well we know that the CRAB drugs loose out to the newer more effective DMT, but are companies going to do a head to head against an effective drug.?

It could be pharmaceutical suicide if the comparator does better, even percieved better would bad for marketing. Comparing against low hanging fruit is marketing to say "our drug is better".

So it is down to academics to do these studies. However can  thet afford to do it properly, I doubt it because the trials would probably need to be very large to  show superiority of one verses another

Demystifying vitamin D: new study links variants in vitamin D genes to risk of MS

Objective: We sought to estimate the causal effect of low serum 25(OH)D on multiple sclerosis (MS) susceptibility that is not confounded by environmental or lifestyle factors or subject to reverse causality.

Methods: We conducted mendelian randomization (MR) analyses using an instrumental variable (IV) comprising 3 single nucleotide polymorphisms found to be associated with serum 25(OH)D levels at genome-wide significance. We analyzed the effect of the IV on MS risk and both age at onset and disease severity in 2 separate populations using logistic regression models that controlled for sex, year of birth, smoking, education, genetic ancestry, body mass index at age 18–20 years or in 20s, a weighted genetic risk score for 110 known MS-associated variants, and the presence of one or more HLA-DRB1*15:01 alleles.

Results: Findings from MR analyses using the IV showed increasing levels of 25(OH)D are associated with a decreased risk of MS in both populations. In white, non-Hispanic members of Kaiser Permanente Northern California (1,056 MS cases and 9,015 controls), the odds ratio (OR) was 0.79 (p 5 0.04, 95% confidence interval (CI): 0.64–0.99). In members of a Swedish population from the Epidemiological Investigation of Multiple Sclerosis and Genes and Environment in Multiple Sclerosis MS case-control studies (6,335 cases and 5,762 controls), the OR was 0.86 (p 5 0.03, 95% CI: 0.76–0.98). A meta-analysis of the 2 populations gave a combined OR of 0.85 (p 5 0.003, 95% CI: 0.76–0.94). No association was observed for age at onset or disease severity.

Conclusions: These results provide strong evidence that low serum 25(OH)D concentration is a cause of MS, independent of established risk factors.

The interpretation
The association between low levels of vitamin D and the risk of multiple sclerosis (MS) has been demonstrated in several big studies. There is clearly a correlation between vitamin D status and MS risk, but this does not imply causation. It is difficult to tell from big observational studies whether vitamin D deficiency causes MS or whether there is something else going on. This graphic depicts three possible explanations for the observed association:

Potential explanations for the observed association between vitamin D status and MS risk

This question is important because if we had unequivocal evidence that low vitamin D increased peoples’ risk of developing MS, we would have a stronger case for prescribing vitamin D as a preventative measure for selected patients.

Why is it so tricky to prove a causal relationship between vitamin D status and MS risk? In big population studies of MS, investigators do their best to measure all kinds of variables – factors that could influence risk - and they try to control for these when they analyse the data to look for causal relationships.
However, these studies cannot ever fully overcome the problem of reverse causation - the possibility that MS causes low vitamin D levels - and the problem of confounding – the possibility that other factors, such as ethnicity, sunshine exposure, or obesity predispose to MS independently of their effect on vitamin D status.

So, how can we ever work out if low vitamin D causes MS in big population studies?

Lisa Barcellos and friends have come up with a clever answer to this problem. They used a technique called Mendelian Randomisation to get around the problems of reverse causation and confounding. The approach is called Mendelian Randomisation because it relies on one of Mendel’s laws of inheritance – this states that which alleles (versions) of a gene are inherited is independent of the inheritance of other genes. Everyone in the population will therefore have a random selection of alleles affecting vitamin D status. So if you know how these alleles relate to vitamin D status, you can use the genotype (i.e. the set of alleles someone has) as a surrogate marker of vitamin D status. This obviates the problems of reverse causation and confounding.

Barcellos et al found 3 single nucleotide polymorphisms (SNPs) from published work that are closely associated with vitamin D levels. They then tried to see if these SNP alleles were associated with MS risk, age of onset, and disease severity.

This approach is neat because SNPs are encoded in the genome for life - they are not affected by lifestyle factors, environmental factors, or by MS itself. So if these SNPs provide an accurate surrogate marker of vitamin D status, they provide a simple way of determining whether low vitamin D levels actually cause MS, rather than just being correlated with it. This approach to studying associations can be thought of as a natural randomised controlled trial, whereby MS risk can be compared in people with SNPs predisposing to low vitamin D vs. those with SNPs predisposing to normal vitamin D.

This study collected data from 2 separate massive cohorts, totalling a whopping >7000 people with MS and >14000 healthy controls. The pooled odds ratio for developing MS was 0.85, meaning that the odds of developing MS are significantly reduced by having genes that predispose to normal vitamin D. There was no association between these SNPs and either age of onset or severity.

The Mendelian Randomisation method for studying the relationship between vitamin D status and MS risk

While population data is never going to be as convincing as a randomised controlled trial, this study provides quite strong evidence that vitamin D status has a causal role in determining risk of MS. These findings only apply to Caucasian people, as non-Caucasian people were excluded from the study. A key assumption of this study is that the SNPs assessed only influence MS risk via their effects on vitamin D status – while we have no evidence that this assumption is wrong, we do not know what the exact function of these SNPs is, and so it is possible that they have as yet unknown effects which influence MS risk.

We now have another important piece of evidence that low vitamin D causes a slight increase in MS risk. But it is a separate question whether supplementing vitamin D reduces the risk of developing MS. Unfortunately this can only be answered through a well-designed randomised controlled trial.

Saturday, 24 September 2016

ClinicSpeak & NeuroSpeak: MS Ireland & Brain Health

Brain Health and wellness in MS is all the rage. Good! #BrainHealth #MSBlog #ClinicSpeak

"I am in Cork at MS Ireland's annual meeting. The good news is that this year's meeting for HCPs and MSers is focusing on Brain Health and Wellness. It is very reassuring how quickly awareness on the Brain Health issue had spread across the field. I sincerely hope the 'Brain Health' policy document has something to do with it (please see our new website). The good news is that the policy document has now been published in full and can be cited via PubMed (see below). If you haven't read it yet give it a go; it is written in plain English for a wide audience."

Giovannoni et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016 Sep;9 Suppl 1:S5-S48. 

INTRODUCTION: We present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used widely among those committed to creating a better future for people with MS and their families.

METHODS: Structured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs).

RESULTS: Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services. We recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and disability progression should be included in the definition of disease activity and monitored regularly when practical. On suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A shared decision-making process that embodies dialogue and considers all appropriate DMTs should be implemented. Monitoring data should be recorded formally in registries to generate real-world evidence. In many jurisdictions, access to DMTs is limited. To improve treatment access the relevant bodies should consider all costs to all parties when conducting economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models.

CONCLUSIONS: The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.

Friday, 23 September 2016

NeuroSpeak: calling all MSologists and trainees

Why haven't you registered for the MS Trust Conference with your team from 6-7 November? #MSTrust #NeuroSpeak #MSBlog

"In a pioneering spirit the MS Trust decided to launch a new initiative. They wanted to bring MS teams together at their annual MS Trust conference. The management of MS in the modern era is about multidisciplinary teams that work together to improve the outcome of people with MS. The MS Trust then approached the ABN to help design a programme that would be of interest to neurologists, neurology trainees and MSologists. The ABN MS Specialist Interest Group and the MS Trust then designed a masterclass session for neurologists. The uptake so far has been so abysmal that the MS Trust is now considering cancelling it. This saddens me; in the modern era any opportunity to bring together doctors and other HCPs should be welcomed. The days of them and us are surely over? More importantly, the meeting is also a good opportunity for team building. If you don't go yourself can you please make a plan to send one of your juniors?"

"Another trend, which is unstoppable, is the move away from face-to-face meetings toward webinars. The following is an international webinar series that I have agreed to participate in; PRIME. The good news is that it is for all HCPs, both physicians and clinical nurse specialists. The bad news is that it is not for people with MS. I dream about a day when people with the disease and their healthcare professionals will be able to attend the same teaching sessions online and/or in person."

"We tried to get MSers in wheelchairs to man our #ThinkHand stand at ECTRIMS and were told by the organisers that this was not allowed under ABPI guidelines. It is a great pity MSers are not allowed to attend ECTRIMS unless they register and keep it a secret. Do you think MSers would be shocked at the extravagance of the marketing fest?"

Thursday, 22 September 2016

NeuroSpeak: HSCT in the UK

Is HSCT as a treatment for MS becoming mainstream in the UK? #NeuroSpeak #ClinicSpeak #MSBlog

"The following meeting may be of interest to UK MSologists and pwMS. At least the UK MS community is taking HSCT seriously. With the plummeting mortality related to HSCT maybe it will become routine in many centres? It is looking safer; is it as safe as alemtuzumab treatment? We know already that it is cheaper. I can't see why the NHS won't fund a study to answer the question once and all; what is more effective and cost-effective HSCT or alemtuzumab?"