Tuesday, 27 September 2016

EBV and smoking in MS: Two peas in a pod?

Negative interaction between smoking and EBV in the risk of multiple sclerosis: The EnvIMS study

Published online before print September 23, 2016, doi: 10.1177/1352458516671028

Kjetil Bjørnevik, Trond Riise,Inger Bostrom, llaria Casetta,Marianna Cortese,Enrico Granieri,Trygve Holmøy,Margitta T Kampman,Anne-Marie Landtblom,Sandra Magalhaes,Maura Pugliatti,Christina Wolfson,Kjell-Morten Myhr.


Background: Results from previous studies on a possible interaction between smoking and Epstein–Barr virus (EBV) in the risk of multiple sclerosis (MS) are conflicting.

Objectives: To examine the interaction between smoking and infectious mononucleosis (IM) in the risk of MS.

Methods: Within the case–control study on Environmental Factors In Multiple Sclerosis (EnvIMS), 1904 MS patients and 3694 population-based frequency-matched healthy controls from Norway, Italy, and Sweden reported on prior exposure to smoking and history of IM. We examined the interaction between the two exposures on the additive and multiplicative scale.

Results: Smoking and IM were each found to be associated with an increased MS risk in all three countries, and there was a negative multiplicative interaction between the two exposures in each country separately as well as in the pooled analysis (p  = 0.001). Among those who reported IM, there was no increased risk associated with smoking (odds ratio (OR): 0.95, 95% confidence interval (CI): 0.66–1.37). The direction of the estimated interactions on the additive scale was consistent with a negative interaction in all three countries (relative excess risk due to interaction (RERI): −0.98, 95% CI: −2.05–0.15, p = 0.09).

Conclusion: Our findings indicate competing antagonism, where the two exposures compete to affect the outcome.

Smoking and EBV (the virus that leads to glandular fever) are reported risk factors for developing MS. What happens if you had both smoked and had glandular fever, is your cumulative risk higher? You would have thought so, but apparently not according to work by Bjornevik et al.

This work matches PwMS with healthy people (case-control study) in Europe (Norway, Italy, Siberia, Sweden) and Canada and whether they smoked or had glandular fever (exposures) in their early life. The problem with this is that it is susceptible to recall bias as people are asked to recall historical information. 
Nonetheless,  it is a large study and may filter out these errors.

They report that both risk factors affect the likelihood of developing MS in the absence of the other, but may compete with each other when both are present. For example, the effect estimated for EBV was lower when smoking was also present. This hints at the two exposures having a shared biological pathway in the way they operate in the development of MS. But , it is important to note that one isn't protective for the others effect, but simply that they may compete with each other (two peas...).

Monday, 26 September 2016

ResearchSpeak: ECTRIMS highlight ocrelizumab NEDA data

How important is rebaseling when assessing NEDA rates? Essential - just look at the stunning ocrelizumab NEDA data. #ECTRIMS2016 #ResearchSpeak #MSBlog

"The poster below is another one of my ECTRIMS highlights. There is little doubt that ocrelizumab is a highly effective DMT. However, how does it perform if you treat-2-target of NEDA (T2T-NEDA)? I have been saying for sometime that to implement T2T-NEDA in clinical practice you have to rebaseline your metrics after the DMT in question has had time to work. For most maintenance DMTs this is 6 months."

"The analysis below shows that if you do this with ocrelizumab, then over 80% of subjects are NEDA from 6-24 months (figure 3). To the best of my knowledge this is the best NEDA data out there after rebaselining. I have yet to see the HSCT rebaseling NEDA rates, but I suspect they will be in the same ballpark. What is also important to highlight is the remarkable observation that 57% of the IFN-beta (Rebif) treated participants were also NEDA in this epoch. Based on earlier interferon data this is much better than one would expect. It looks as if from contemporary trials that the efficacy of Rebif has improved. Why? One reason could be that the population of trial participants have included subjects with more benign MS or Rebif has gotten better. I suspect both are correct. Most subjects in the Opera studies received RNF (Rebif new formulation). We know that RNF is associated with fewer NABs (neutralizing anti-bodies), which affect its efficacy; hence there are reasons to expect that Rebif's efficacy has improved. I am sure a lot of people will jump on the Rebif NEDA data to support its continued use as an effective DMT in the 'majority' of MSers."

"It will be interesting to see how the regulators, payers and/or healthcare commissioners respond to this data. I sincerely hope the regulators give ocrelizumab a liberal label that will allow first-line use in MSers with active disease. This will then allow HCPs and their patients to decide on which DMTs they want to use. However, as always in price-sensitive markets the payers and commissioner may have a different take on things particularly if ocrelizumab is priced at a premium."

CoI: multiple

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.