Sunday, 19 February 2017

The SPMS trial that never was.

Double-Blind Controlled Randomized Trial of Cyclophosphamide versus Methylprednisolone in Secondary Progressive Multiple Sclerosis.Brochet B, Deloire MS, Perez P, Loock T, Baschet L, Debouverie M, Pittion S, Ouallet JC, Clavelou P, de Sèze J, Collongues N, Vermersch P, Zéphir H, Castelnovo G, Labauge P, Lebrun C, Cohen M, Ruet A; PROMESS study investigators..
PLoS One. 2017 Jan 3;12(1):e0168834. doi: 10.1371/journal.pone.0168834.

BACKGROUND:Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying progression but no randomized trial was conducted so far.
OBJECTIVE:To compare CPM to methylprednisolone (MP) in SPMS.
METHODS:Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model.
RESULTS:Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 [95% CI: 0·31-1·22](p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely ([1·14-4.29]; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected.
CONCLUSION:Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability.
TRIAL NCT00241254.

So more not good news for SPMS, here is another trial that has failed. Cyclophophamide forms an metabolite that is active and entrers the CNS and can kill B cells as well as any other cell that is dividing including hairs in the follicles. There was a hint of activity but the trial was terminated because there were not enough volunteers.

Saturday, 18 February 2017

#ResearchSpeak: when best practice clinical guidelines our out of date

Is your neurologist a sheep or a wolf, a herder or an independent thinker? #ResearchSpeak #MSBlog

The following study looks at decision-making by neurologists in relation to a simple case scenario. The researchers come to the conclusion that neurologists display herd behaviour, i.e. they follow the crowd rather deciding independently. The study is based on a simple case scenario of a 40-year-old woman with MS who has been stable for 3 years on subcutaneous interferon and developed a self-limited neurological event. I assume this was a relapse. There were no new magnetic resonance imaging (MRI) lesions. Her neurological examination and disability scores were unchanged. She was advised by her MS neurologist to switch from interferon to fingolimod against best practice guidelines

What this scenario doesn't explore is that we all know the EDSS is not fit for purpose and the fact that it was unchanged is neither here nor there. You can still have a relapse despite an unchanged EDSS. Similarly, the there were no new lesions on the MRI. The scenario doesn't mention whether or not a spinal cord MRI was done. May her relapse due to a spinal cord lesion. The researchers assume that if the MRI shows no new lesions then this person has not had a relapse. A significant number of relapses occur without new MRI lesions. The MRI only detects lesions that are ~4mm in size or larger. A small lesion in a critical area can cause a relapse without being detected on MRI.  They also assume that the MRI and EDSS are the disease, when in fact they are not the disease. The disease is biological and hence needs to be thought of as a biological process. They also assume the 'best practice clinical guidelines' are set in stone and to be obeyed at all costs and are current and up-to-date.  Most guidelines take so long to produce and get consensus that when the come out they are usually out-of-date. Guidelines are usually reached by consensus and hence are typically behind the adoption curve and not at the vanguard of new treatment paradigms.  

I assume that the neurologist who read this scenario interpreted the 'self-limited neurological event' as a relapse and advised the patient be switched to a more effective treatment. Unless these investigators can provide evidence that this was not a relapse how can the expect the neurologists they surveyed not to switch treatments? In an era of treat-2-target of NEDA it is clear that the 'best practice clinical guidelines' our out of date. In my opinion this study shows that the neurologists who applied the 'best practice clinical guidelines' were the herders, blindly following guidelines and the ones that elected to switch treatment were the independent thinkers, acting in their patient's best interests. My conclusion on reading this paper is the exact opposite to the researchers' conclusions. 

What do you think? 

Saposnik et al. Herding: a new phenomenon affecting medical decision-making in multiple sclerosis care? Lessons learned from DIScUTIR MS. Patient Prefer Adherence. 2017 Jan 31;11:175-180. doi: 10.2147/PPA.S124192. eCollection 2017.

PURPOSE: Herding is a phenomenon by which individuals follow the behavior of others rather than deciding independently on the basis of their own private information. A herding-like phenomenon can occur in multiple sclerosis (MS) when a neurologist follows a therapeutic recommendation by a colleague even though it is not supported by best practice clinical guidelines. Limited information is currently available on the role of herding in medical care. The objective of this study was to determine the prevalence (and its associated factors) of herding in the management of MS.

METHODS: We conducted a study among neurologists with expertise in MS care throughout Spain. Participants answered questions regarding the management of 20 case scenarios commonly encountered in clinical practice and completed 3 surveys and 4 experimental paradigms based on behavioral economics. The herding experiment consisted of a case scenario of a 40-year-old woman who has been stable for 3 years on subcutaneous interferon and developed a self-limited neurological event. There were no new magnetic resonance imaging (MRI) lesions. Her neurological examination and disability scores were unchanged. She was advised by an MS neurologist to switch from interferon to fingolimod against best practice guidelines. Multivariable logistic regression analysis was conducted to evaluate factors associated with herding.

RESULTS: Out of 161 neurologists who were invited to participate, 96 completed the study (response rate: 60%). Herding was present in 75 (78.1%), having a similar prevalence in MS experts and general neurologists (68.8% vs 82.8%; P=0.12). In multivariate analyses, the number of MS patients seen per week was positively associated with herding (odds ratio [OR] 1.08, 95% CI 1.01-1.14). Conversely, physician's age, gender, years of practice, setting of practice, or risk preferences were not associated with herding.

CONCLUSION: Herding was a common phenomenon affecting nearly 8 out of 10 neurologists caring for MS patients. Herding may affect medical decisions and lead to poorer outcomes in the management of MS.

CoI: multiple

Meta analysis points a finger at a virus.

Morandi E, Tanasescu R, Tarlinton RE, Constantinescu CS, Zhang W, Tench C, Gran B.The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis. PLoS One. 2017 ;12(2):e0172415.

BACKGROUND:The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS.
OBJECTIVE: To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients.
METHODS:Medline, Embase and the Cochrane Library were searched for published studies on the association of HERVs and MS. Meta-analysis was performed on the HERV-W family. Odds Ratio (OR) and 95% confidence interval (CI) were calculated for association.
RESULTS: 43 reports were extracted (25 related to HERV-W, 13 to HERV-H, 9 to HERV-K, 5 to HRES-1 and 1 to HER-15 family). The analysis showed an association between expression of all HERV families and MS. For HERV-W, adequate data was available for meta-analysis. Results from meta-analyses of HERV-W were OR = 22.66 (95%CI 6.32 to 81.20) from 4 studies investigating MSRV/HERV-W (MS-associated retrovirus) envelope mRNA in peripheral blood mononuclear cells, OR = 44.11 (95%CI 12.95 to 150.30) from 6 studies of MSRV/HERV-W polymerase mRNA in serum/plasma and OR = 6.00 (95%CI 3.35 to 10.74) from 4 studies of MSRV/HERV-W polymerase mRNA in CSF.
CONCLUSIONS:This systematic review and meta-analysis shows an association between expression of HERVs, and in particular the HERV-W family, and MS.

We all have endogenous retroviruses in our genome, it makes up about 5% of our genome. There is a suggestion that these can be reactivated to be a target in MS. This study does a meta analysis of data out there and concludes that HERV-W is associated with MS. However, how many papers are related to the fact that there is commercial development of an anti-HERV-W antibody.

The problem with meta analysis is publication bias, as there is bias towards positive data being published, and if you don't understand the biology then you can't sort out the "wheat from the chaff".

This is why meta analysis of EAE data is largely futile, there is a dearth of negative studies and there is such over-interpretation of results to make them look interesting. 

The number of studies where drug X or compound Y is reported to save nerves, cause remyelination, when the drug never gets into the CNS. So if you see that there is an immunosuppressive action, it will be neuroprotective and stop demyelination and even allow remyelination because inflammation is stopped. You claim your drug to be neuroprotective and pro-remyelination and the person doing the meta analysis buys it. 

Therefore, be careful all sorts stuff can be believed of as fact.

If we did a meta analysis on whether T or B cells are the important target in MS, I bet T cells will win hands down.

Fingolimod works by trapping white blood subsets in lymph glands...if you did a meta analysis on that, we would all agree  that this is so. Are there any decenting ideas or data...I think there is.

Therefore careful understanding of the facts, probably gives us greater insight. We need more thinkers than herders

Friday, 17 February 2017

#ResearchSpeak: are polyunsaturated fatty acids intake a preventable risk factor for MS?

PUFAs supplements may reduce your risk of getting MS. #RsearchSpeak #MSBlog

The study below shows that high intake of polyunsaturated fatty acids (PUFA) reduces your risk of getting MS. This observation is independent of other identifiable risk factors. Is this association or causation; chicken or egg? The only way to do this is by doing a randomised controlled population study to see if PUFA supplementation reduces the risk of getting MS, compared to a suitable control substance (placebo or another fatty acid). Another strategy would be to confirm this finding in another cohort of people, which may be difficult, or to try and test the hypothesis using a genomic approach, i.e. Mendelian randomisation. The problem with the latter is that we will need to know a lot about the biology of PUFAs and how subtle genetic variants affect the metabolism and levels of PUFAs. 

What it does suggest that if you are 'at risk' of getting MS, i.e. are a first, second or even a third degree relative of someone with MS it may be a good idea to look at your diet to make sure you are getting enough PUFAs. If not you can easily supplement your diet. In addition to this you need to make sure you are vitamin D replete, you don't smoke and you keep your weight down. 

As with all dietary interventions PUFAs have an up and a down side. Omega-3 PUFAs can increase your risk of bleeding and may interact with other medications.

Bjørnevik et al. Polyunsaturated fatty acids and the risk of multiple sclerosis. Mult Scler. 2017 Jan 1:1352458517691150.

BACKGROUND: Results from previous studies on polyunsaturated fatty acid (PUFA) intake and multiple sclerosis (MS) risk are conflicting.

OBJECTIVE: To prospectively investigate the association between dietary intake of PUFA and MS risk.

METHODS: We followed 80,920 women from Nurses' Health Study (1984-2004) and 94,511 women from Nurses' Health Study II (1991-2009) who reported on diet using a validated food frequency questionnaire every 4 years and identified 479 incident MS cases during follow-up. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs), for the effect of PUFA intake on MS risk adjusting for age, latitude of residence at age 15, ancestry, cigarette smoking, supplemental vitamin D intake, body mass index, and total energy intake.

RESULTS: Higher intake of total PUFA at baseline was associated with a lower risk of MS (HR top vs bottom quintile: 0.67, 95% CI: 0.49-0.90, p trend = 0.01). Among the specific types of PUFA, only α-linolenic acid (ALA) was inversely associated with MS risk (HR top vs bottom quintile: 0.61, 95% CI: 0.45-0.83, p trend = 0.001). The long-chain fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were not associated with MS risk.

CONCLUSION: Low dietary PUFA intake may be another modifiable risk factor for MS.

Not in My Name. Time to Stop -. Stem cells

Papers are getting assessed on altmetrics and one of the outputs are blog posts, so anyone who has clicked on the altmetric link to get here you are in for a on

Jiang H et al. Amelioration of experimental autoimmune encephalomyelitis through transplantation of placental derived mesenchymal stem cells.Sci Rep 2017 Feb 10;7:41837. doi: 10.1038/srep41837.

Placental derived mesenchymal stem cells (PMSCs) have been suggested as a possible source of cells to treat multiple sclerosis (MS) due to their immunomodulatory functions, lack of ethical concerns, and potential to differentiate into neurons and oligodendrocytes. To investigate whether PMSCs share similar characteristics with embryonic mesenchymal stem cells (EMSCs), and if transplanted PMSCs have the ability to integrate and replace degenerated neural cells, we transplanted rat PMSCs and EMSCs into the central nervous system (CNS) of Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Our findings demonstrated that transplanted PMSCs, similar to EMSCs, were effective in decreasing infiltrating inflammatory cells, preserving axons, and ameliorating demyelination, thereby improving the neurological functions of animals. Moreover, both PMSCs and EMSCs had the ability to migrate into inflamed tissues and express neural-glial lineage markers. These findings suggest that PMSCs may replace EMSCs as a source of cells in MS stem cell therapy.

The blog is a site that allows us to talk about research, and some of it is good news and some is bad news. We hope some of the readers are scientists and neurologists as we feel it has educational content for all..but also we need to educate the public about the type of things scientists do.

We can do the rose-coloured tinted glasses approach, which you get in most Science websites where every thing is great. But if every thing was great, we would have cured something by now.

As a card carrying vivisectionist,  we have to take the flank from parts of Society that do not like or want animal experiments. However, the UK Government want us to be open about working with animals, and this is why we post on animal studies.

I have decided against doing "cure of the week" which happens every week as I realize many animal studies are years away from offering something of use. 

Anyway back to the post

If you poll pwMS about where we should be putting their research resources?. I bet high on the list will be people wanting stem cell trials. 

This is because science has promised that we can reverse the effects of time, and the media and public have bought into this view, so you rightly say trials, trials, trials!

Indeed the MS Societies listen and put their resource behind their members wishes. Trials have been initiated and everybody's hopes are high. The hope you are being sold is that the stems cells turn into myelinating cells and new nerves and then we can turn back time.

Mesenchymal stem cells, or MSCs, are multipotent stromal cells that can differentiate into a variety of cell types. Mesenchyme is embryonic connective tissue that is derived from the mesoderm and that differentiates into haematopoietic and connective tissue, whereas MSCs do not differentiate into haematopoietic cells.

Everyone gets on the band wagon, and even we dipped our toe in the stem-cell waters. 

I know you like to hear about this stuff, but I need to put this into perspective, because if the stem cells trials don't work you will be blaming the animals.....Don't!

So to describe the paper in this study creates mesencyhmal stem cells from embryos and placenta and show that they inhibit EAE and stop demyelination and nerve loss when transplanted into the brain.

Yeah we say.

However, how many more of these studies are we going to see? 

MSC made from this or that cell. 

I wonder whether we should call time? 

Are we going to want to use stem cells from embryos or someone else's placenta, when one can make stem cells from yourself.  
Technology has moved on

There have been endless studies of mesenchymal stem cells and EAE. The results are remarkedly consistent (As seen below, from this study).

The effects are pretty uninspiring.

The benefit is a small diminution, and sometimes a delay, due to a small inhibitory effect. Perhaps much of the benefit of demyelination and nerve loss reported can be then be downstream of this, because the damaging inflammatory response has not arrived in the CNS to cause damage. 

It is often impossible to work out if it was in fact a diminution of the severity of disease or was it because a few animals in the experiment didn't get disease. 

I maintain that we need to see this data. 

However, this minor effect in the most optimum of conditions can easily be bettered by most current DMT. 

If this is good as it gets, then the chances of this being useful in MS is really rather dubious. 

If all they really do is have an immunosuppressive action then is this the way to go?. 

I'm yet to be convinced.

However, do we need these types of study? Mesenchymal trials in humans are well underway. 

Therefore, do we need more animal experiments for the  time being? Perhaps the time for these types of animal experiments has passed.

The success or failure of trials in humans will determine whether this approach is developed or not. 

It will probably be safe, but will it work?....I suspect something towards a failure or something wishy-washy as the trials are based on data made of quick-sand.

Remember this is an opinion and I could be wrong.

Trials in humans are done due to opportunity and public pressure, where we are running before we can walk. How do we guide the mesencymal cells to become oligodedrocytes etc, can they do anything when given systemically? Do they really convert into useful cells? (answer in animals is generally no), there are so many unknowns. This means that the chance of success are slim.

I am there to be proved wrong and then I will eat humble pie when I am.. I don't mean to dash hopes. Stem cells do have potentials 

Am I wrong to be a cynic? and burst some bubbles or should I have a rant and say "Not in my name"

I have to justify what I do, but I am not going to defend all the work of others and this paper happened to come into my firing line.

Am I sorry for doing this in public...No. 

The 3Rs of animal use is supposed to a core principle of working with animals in Europe.

In the experiment above, there is a group where experiment healthy animals are followed and show nothing. They,
 are sometimes injected with adjuvants that serve essentially no useful function excepts it wastes animals. It is no longer an experiment, we know it is not going to induce neurological signs...stop it!

Next up, For anyone reading this study, the method of disease induction and method of killing are no longer allowed in the UK. 

To kill animals they chop their heads off. 

This is not worse thing...a Japanese person once said they throw rats into liquid nitrogen to freeze the brain quickly....non-sense it would not be the quickest way of doing it!- This was stupidity and animal abuse

Anyway "This technique should only be used in rare circumstances and where there is exceptional scientific justification" The animals must be dead before being decapitated. (

However, if you call people on things does it make them hide the truth.

In the study they only state they inject the adjuvant subcutaneoulsly, but where is this? 

I guessed they have been rejected for saying where, so they don't say it. However, they give a reference  which says the same thing and gives a reference from the yesteryear and it states that the adjuvant is put subcutaneous in the feet.

This practice was likewise outlawed in the UK over twenty-25 years ago as being inhumane, as putting the adjuvant into the feet you get swelling and so pain and the animal has problems walking. This can be put under lose skin and this does not seem to cause the animals the same problem. Therefore, the foot pad injection has no place in science, at least in EAE science. Maybe they did not do this, they selected the wrong references

I personally refuse to accept this work if they do use injection in feet, it is bad science.This is the way to make people change practise..maybe not they just hide things:-). 

It is obvious there are some people that do not care about this and they are based in prominent countries that should know better! 

This is perhaps what happens when you move your research to places, where they do not give a stuff about the beasties they work with. Remember this,  as UK science based on animals closes down

Perhaps it is about time that Journals state producing a list of procedures that they will not accept on ethical grounds.

Yes, EAE will eventually end up there, but if we continue to undertake bad practices then we will hasten this process and so a good reason to speak out...the animals can't 

However, killing off animal work in the UK is going to mean that you get more of this guff.

Some people out there will be saying shut you whining minnie, 
"This is why we move out of the UK you are too Regulated"