Wednesday, 3 June 2015

Head of NICE on the Radio


                     Head of NICE on PM 
                (BBC Radio 4 about 5:35)
          Sorry to Say Don't waste your Time 
                       it's a MS-free Zone

                 It sounds like a stuck record
                   The Question to Pharma
How Do You Come Up with Cost of Drugs?
 This is a waste of time 
as its a Rhetorical Question. 
We know the Answer
It's what the (US) Market will Pay

Didn't hear my or your Questions
So no news of The White Knights Tale

We have a Three Tier Health System
   Private Outside NHS
   Private inside NHS
    Public inside NHS

PoliticalSpeak: preventing MS - teenage smoking

Calling all parents with teenage children; I need your help #MSPolitics #MSBlog #MSResearch

“Preventing, or at least reducing the incidence of, MS and other autoimmune diseases sounds relatively easy. Simply identify the risk factors and get the population to avoid them. Take smoking for example; it increases your risk of getting MS by approximately 50%, not to mention rheumatoid arthritis and a whole lot of other allergic diseases. Why then do people still smoke despite the negative publicity? My wife would say marketing, the power of branding and money. I note the Canadians have just given BAT (British American Tobacco) a whopping CAD$10.4bn (£5.5bn) fine; it was large enough to wipe 2.5% off the stock market value of BAT. Good on the Canadians. But is it enough?

I was doing an end-of year assessment with one of my academic trainees yesterday and said to him that the most important thing doctors can do is practice what they preach. You can’t tell your patients to exercise and lose weight if you are obese and a couch potato. You can’t tell your patients to stop smoking , and to try and stop their kids from smoking, if you smoke and your children smoke. This is why I am so disappointed that my daughter who is 18 smokes, and so do all her friends. Why? You don’t have to look too far to find out. It is cool to smoke; a large number of the role models that teenage girls idolise smoke. Girls also smoke to lose weight and stay thin. Smoking is an appetite suppressant; if you smoke you will be thinner. As Kate Moss says ‘nothing tastes as good as thin feels’. The corollary is nothing tastes as bad as kissing a smoker, when you are a non-smoker. 


Kate Moss - pretty, young and skinny; a smoking icon! 
My daughter is well educated; she finished A-levels last year with stunning marks and has just finished first year University. She knows a lot about the effects of smoking on health. She is aware about the link between smoking and MS; I have drummed it into her for years. She also has first-hand experience with MS and has seen what MS can do to someone. She has attended one of our MS research days and has spoken to and seen many MSers. She attended my inaugural lecture and heard about MS. One of our neighbours has MS. When we moved into the area 12 years ago he was walking. He is now wheelchair bound, disinhibited with a severe speech impediment. When you speak to him now, it is hard to have a meaningful conversation; his speech is very slurred and laboured. Prior to his wheelchair we saw him fall several times in public. I have even seen him being incontinent in public once. He always used to be accompanied by friends; both girlfriends and boyfriends. When you see him now, you only see him with one of his carers. Social isolation has struck. My daughter knows him well; they are alumni of the same school. Surely the image of him has imprinted itself on my daughter’s brain. How could my daughter ignore my advice regarding smoking and MS? I suspect the attitude that 'it won’t happen to me' is hardwired into the teenage brain. 

The public health figures regarding teenage smoking are sobering. Interestingly, teenage boys seem to be smoking less, but the trend in girls remains upwards. 

Source: http://www.hscic.gov.uk/catalogue/PUB14988/smok-eng-2014-rep.pdf

Source: http://www.hscic.gov.uk/catalogue/PUB14988/smok-eng-2014-rep.pdf
One of the reasons we launched digesting science (www.digestingscience.co.uk) was to educate children of MSers about environmental risk factors linked to MS; in particular the link between low vitamin D levels and MS. We have always planned to add smoking to the mix, but have always wondered how responsive 6-12 year olds would be to an anti-smoking message. A better plan may be to finesse digesting science to cover teenagers? However, the coverage of digesting science is small and the message is unlikely to get to the general public.

On reflection the fine imposed on the BAT by the Canadians did not go far enough. May be the Canadian Government should have linked the fine to a defined target, for example if the rate in teenage smoking does not drop below 10% by 2025 they will double, triple or quadruple the fine. Nobody knows the black art of marketing to teenagers better than the tobacco industry; we should harness that expertise. A one off fine is unlikely to change their behaviour. Simply reducing teenage smoking to less than 10% will reduce the incidence of MS by 10-20% and in some countries by more; not to mention the impact on other autoimmune diseases.

Can anyone help? We need a prevention strategy that works. I hope there are some politicians reading this post.”

Daclizumab inhibits accumulation of cells in the CNS

Lin YC, Winokur P, Blake A, Wu T, Romm E, Bielekova B.
Daclizumab reverses intrathecal immune cell abnormalities in multiple sclerosis.Ann Clin Transl Neurol. 2015;2:445-55

OBJECTIVE:Novel treatments such as natalizumab and fingolimod achieve their therapeutic efficacy in multiple sclerosis (MS) by blocking access of subsets of immune cells into the central nervous system, thus creating non-physiological intrathecal immunity. In contrast, daclizumab, a humanized monoclonal antibody against the alpha chain of the IL-2 receptor, has a unique mechanism of action with multiple direct effects on innate immunity. As cellular intrathecal abnormalities corresponding to MS have been well defined, we asked how daclizumab therapy affects these immunological hallmarks of the MS disease process.
METHODS:Nineteen subpopulations of immune cells were assessed in a blinded fashion in the blood and 50-fold concentrated cerebrospinal fluid (CSF) cell pellet in 32 patients with untreated relapsing-remitting MS (RRMS), 22 daclizumab-treated RRMS patients, and 11 healthy donors (HDs) using 12-colour flow cytometry.
RESULTS:Long-term daclizumab therapy normalized all immunophenotyping abnormalities differentiating untreated RRMS patients from HDs. Specifically, strong enrichment of adaptive immune cells (CD4+ and CD8+ T cells and B cells) in the CSF was reversed. Similarly, daclizumab controlled MS-related increases in the innate lymphoid cells (ILCs) and lymphoid tissue inducer cells in the blood and CSF, and reverted the diminished proportion of intrathecal monocytes. The only marker that distinguished daclizumab-treated MS patients from HDs was the expansion of immunoregulatory CD56(bright) NK cells.
INTERPRETATION:Normalization of immunological abnormalities associated with MS by long-term daclizumab therapy suggests that this drug's effects on ILCs, NK cells, and dendritic cell-mediated antigen presentation to CD4+ and CD8+ T cells are critical in regulating the MS disease process.

How does daclizumab work.....The other DMT wipe out B cells, which may be the home of EBV. In contrast daclizumab augments natural killer cell activity, does that mean it has anti-microbe activity? Others says that the DMT affect T cell function and daclizumab could affect T cell function but also antigen presenting cell function. However, it appears to limit either the accumulation of cells within the CNS or controls the cells within the CNS so that fewer are found in the spinal fluid. This is a central hallmark of effective DMT,which is to limit activity of immune cells in the CNS. Where is this drug going to figure in the treatment of MS?

Biogen will have more different DMT that their competitors with ocreluzimab soon to follow one suspects. Is their motto escalate from one of our drugs to the next...or we don't care just buy our drugs. 

CoI: None

When will you risk drug induced death

Fox RJ, Salter A, Alster JM, Dawson NV, Kattan MW, Miller D, Ramesh S, Tyry T, Wells BW, Cutter G. Risk tolerance to MS therapies: Survey results from the NARCOMS registry. Mult Scler Relat Disord. 2015 May;4(3):241-9.
BACKGROUND:There is little information about risk acceptance of multiple sclerosis (MS) patients to various MS therapies.
OBJECTIVE:To determine MS patients׳ tolerance to risky therapies and identify associated characteristics.
METHODS: MS patients from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry׳s online cohort were invited to complete questionnaires on decision making and risk tolerance (RT) to two therapeutic scenarios: a theoretical cure for MS [CureMS], with permanent reversal of all MS symptoms but a risk of immediate painless death; and natalizumab [NAT], a real-life scenario with benefits and risks as defined by Phase III trial results.
RESULTS: The median RT for both scenarios was 1:10,000; 15-23% of respondents were not willing to take any risk for their MS therapy. Participants with greater disability or not taking any MS therapy showed a greater RT, while females and those caring for dependants had a lower RT. Females and older age were predictors of lower RT, while increasing disability and greater blunting attitude with respect to information seeking behaviour were predictors of higher RT.
CONCLUSION: MS patients displayed a wide range of RT for MS therapies. Our study identified gender, age, disability and information seeking behaviour to be associated with RT.

So you can read the study which says  if the risk of death you would accepted this in 1 in 10,000 chance of risk of death for a hypothetical cure. Gilenya is associated with relatively immediate adverse effects as is alemtuzumab.  Is this latter a cure? We don't know and certainly not for some as people need retreating. However, are you queuing-up to be treated I don't think so. 

But what about Tysabri. So the risk of death from PML is about 1 in 5 of people affected by PML and the risk of PML is about 1 in 100 for some groups of MSers so about 1 in 500  which is somewhat lower than 1 in 10,000. 

I suspect you will say get the cure and then we can assess risk

ClinicSpeak: natalizumab has a positive effect on attention and depression

How bad is your brain fog? #ClinicSpeak #MSResearch #MSBlog

"I always finding amazing when an MSer with highly-active MS come back to see me in clinic after 6 months of being on natalizumab and states 'I feel normal, my brain fog has lifted and my fatigue has gone'. Why? I suspect one component of cognitive fatigue and the so called brain fog is due to inflammation in the brain. Once MSers start on a highly-effective DMT that switches the inflammation off they notice the difference. We know that the mediators of inflammation affect how the brain functions. MSers describe feeling like they have never ending flu; this is how they describe the fog. The study below formally demonstrates some of the observations; with improvements in attention and depression after starting natalizumab. It is a pity the drug is not 'safe' to use in everyone. Because of the PML risk it is deemed too risky to use long-term in ~50% of MSers, who are positive for JCV. In the other half of MSers it is relatively safe; despite this the European regulators and payers won't allow us to use it first-line with the exception in the UK being MSers with rapidly-evolving severe MS (two disabling attacks in a 12 month period with MRI evidence of active disease). I wonder if and when these treatment guidelines will change?"

Brain fog!

Kunkel et al. Impact of natalizumab treatment on fatigue, mood, and aspects of cognition in relapsing-remittingmultiple sclerosis. Front Neurol. 2015 May 11;6:97. doi: 10.3389/fneur.2015.00097. eCollection 2015

BACKGROUND/OBJECTIVE: Fatigue, cognitive, and affective disorders are relevant symptoms in multiple sclerosis (MS). The treatment with Natalizumab has a positive effect on physical disabilities in patients with relapsing-remitting MS (RRMS). Some studies describe improvements in cognition and fatigue over 1 year of treatment. Only little is known about longer treatment effects especially on fatigue, and also on cognition and mood. Therefore, the present retrospective open label observational study investigates the effect of Natalizumab on fatigue, attention, and depression over a treatment period of 2 years.


METHODS: About 51 RRMSers who were treated with Natalizumab (male = 11, female = 40; mean age: 33. 9 ± 9. 1 years) were included. The neuropsychological assessment consisted of different tests of attention (TAP: alertness, divided attention, flexibility, SDMT, PASAT), fatigue (WEIMuS, FSMC), and depression (CES-D). The assessments occurred immediately before the first administration of Natalizumab, after 1 and 2 years of treatment.

RESULTS: Significant improvements were found in aspects of attention and depression from baseline to follow-up 1 [alertness: reaction time (RT) cued, p < 0.05; divided attention: visual RT, p < 0.05; SDMT: p = 0.05; CES-D: p < 0.05] and from baseline to follow-up 2 (divided attention: visual RT: p < 0.001; errors: p < 0.01, omissions: p < 0.05; flexibility: RT, p < 0.05; SDMT: p < 0.01; CES-D: p < 0.05). No significant changes were detected in fatigue, probably because of the small sample size, especially in the second year of treatment (WEIMuS: N = 16, FSMC: N = 8).

CONCLUSION: The results show a positive effect of Natalizumab on attention in MSers with RRMS, and for the first time, also in depression after 2 years of observation, and support the efficacy of the treatment over 2 years. More research is needed for fatigue.


CoI: multiple