Saturday, 30 September 2017

#ClinicSpeak & #ResearchSpeak: breast implants not associated with multiple sclerosis

Silicone breast implants not associated with a higher incidence of autoimmunity. #ClinicSpeak #ResearchSpeak

Summary: A large study in over 55,000 women undergoing breast augmentation with saline and silicone implants demonstrates that breast implants are not associated with a higher risk of developing MS. 

Theoretical ClinicSpeak scenario: A patient with MS asked me to write a letter to her plastic surgeon about her planned breast augmentation surgery. Her surgeon was reluctant to do the surgery on the off chance that it would make her MS worse. I dutifully wrote the letter stating that to the best of my knowledge I was not aware of any reason why she shouldn't undergo the surgery because of her MS. 


Interestingly, a few years ago there was a crisis about the possibility of silicone breast implants triggering, or causing, autoimmunity. This was thought to relate to ruptured silicone implants. Therefore the large study below is reassuring that both silicone and saline breast implants are not associated with a higher incidence of multiple sclerosis if anything the risk was lower. 


Singh et al. Five-Year Safety Data for More than 55,000 Subjects following Breast Implantation: Comparison of Rare Adverse Event Rates with Silicone Implants versus National Norms and Saline Implants. Plast Reconstr Surg. 2017 Oct;140(4):666-679. 


BACKGROUND: The U.S. Food and Drug Administration has required postapproval studies of silicone breast implants to evaluate the incidence of rare adverse events over 10 years after implantation.

METHODS: The Breast Implant Follow-Up Study is a large 10-year study (>1000 U.S. sites) evaluating long-term safety following primary augmentation, revision-augmentation, primary reconstruction, or revision-reconstruction with Natrelle round silicone breast implants compared with national norms and outcomes with saline implants. Targeted adverse events in subjects followed for 5 to 8 years included connective tissue diseases, neurologic diseases, cancer, and suicide.

RESULTS: The safety population comprised 55,279 women (primary augmentation, n = 42,873; revision-augmentation, n = 6837; primary reconstruction, n = 4828; and revision-reconstruction, n = 741). No targeted adverse events occurred at significantly greater rates in silicone implant groups versus national norms across all indications. The standardized incidence rate (observed/national norm) for all indications combined was 1.4 for cervical/vulvar cancer, 0.8 for brain cancer, 0.3 for multiple sclerosis, and 0.1 for lupus/lupus-like syndrome. Silicone implants did not significantly increase the risk for any targeted adverse events compared with saline implants. The risk of death was similar with silicone versus saline implants across all indications. The suicide rate (10.6 events per 100,000 person-years) was not significantly higher than the national norm. No implant-related deaths occurred.


CONCLUSIONS: Results from 5 to 8 years of follow-up for a large number of subjects confirmed the safety of Natrelle round silicone implants, with no increased risk of systemic disease or suicide versus national norms or saline implants.

Friday, 29 September 2017

Education: B cells are not a single subpoulation

Lehmann-Horn K, Kinzel S, Weber MS. Deciphering the Role of B Cells in Multiple Sclerosis-Towards Specific Targeting of Pathogenic Function.Int J Mol Sci. 2017 Sep 23;18(10). pii: E2048. doi: 10.3390/ijms18102048.
B cells, plasma cells and antibodies may play a key role in the pathogenesis of multiple sclerosis (MS). This notion is supported by various immunological changes observed in MS patients, such as activation and pro-inflammatory differentiation of peripheral blood B cells, the persistence of clonally expanded plasma cells producing immunoglobulins in the cerebrospinal fluid, as well as the composition of inflammatory central nervous system lesions frequently containing co-localizing antibody depositions and activated complement. In recent years, the perception of a respective pathophysiological B cell involvement was vividly promoted by the empirical success of anti-CD20-mediated B cell depletion in clinical trials; based on these findings, the first monoclonal anti-CD20 antibody-ocrelizumab-is currently in the process of being approved for treatment of MS. In this review, we summarize the current knowledge on the role of B cells, plasma cells and antibodies in MS and elucidate how approved and future treatments, first and foremost anti-CD20 antibodies, therapeutically modify these B cell components. We will furthermore describe regulatory functions of B cells in MS and discuss how the evolving knowledge of these therapeutically desirable B cell properties can be harnessed to improve future safety and efficacy of B cell-directed therapy in MS.
I am doing a presentation and am trying to see where the road blocks are to the understanding of MS. 

Reading through this review on B cells, which you can read if you are interested, it gives me the feeling that I am banging my head against a brick wall. 

I think there is a failure to appreciate that you cannot simply view B cells as a single population. Because if you do you cannot hope to understand what is going on.

For years we have been viewing T cells as a mixed group of cells, T helper cells (CD4), cytotoxic (CD8) and regulator cells and more, but the biggest road block to understanding MS is viewing B cells as a single cell population, which many studies do.

As a card carrying T cell immunologists, I must admit I do not understand the complexities of the B cell response, but I am trying to learn. So maybe you can learn too.

There are many, many subtypes of B cells and here are a few


B cells are born in the bone marrow from stem cells and then go through a series changes in their coats and expressing some markers. The graph below is simplified as is much more complex 

It is clear that pre-B cells form immature B cells in the Bone Marrow, these change into mature B cells, which shuttle between the bone marrow and lymphoid tissue, such as the spleen and lymph nodes. 

In some studies they are called follicular cells. Following stimulation, they proliferate in structures called germinal centres.

Germinal centre cells differentiate into either memory B cells or plasmablasts that can turn into antibody forming..plasma cells,....

When B cells are depleted they repopulate in a stereotyped way. 


The immature cells enter the blood to fill the space and then there is maturation This masks the very slow repopulation of memory cells, from the lymphoid organs, which is where we have said the action is. All drugs that work in MS deplete memory B cells, except natalizumab which get trapped in the blood so they can't get into the brain.



Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis.


Clearly not many people buy it...until they do. They may be clutching at straws


I will explain how this happens,  but I hope you can see that alemtuzumab wipes out memory B cells, but if you look at the CD19 population it is relatively meaningless in terms of understanding what is going on. So MS B cells are not a single population

Thursday, 28 September 2017

#ClinicSpeak: how early is too early?

Cognitive impairment may begin before the first attack of MS. #ClinicSpeak #ResearchSpeak

Summary: The following post makes the case to change the MS diagnostic criteria to include asymptomatic MS. This will allow us to identify high-risk patients for treatment at an earlier stage. 

I was at a meeting early this week I voiced my disappointment that the new diagnostic criteria for MS will not extend the diagnosis of MS into the asymptomatic phase. That is the radiologically isolated syndrome or RIS, will not be defined as a disease. This has implications for people with RIS (pwRIS). Because they don't have a disease they won't be eligible for treatment. 

Is this a problem? The study below shows that over 25% of pwRIS have significant cognitive impairment. These findings underpin the observation that one of the major hidden burdens of MS is the early impact it has on cognition. Fortunately, most of you won't notice early cognitive impairment as your brain has the remarkable ability to compensate for damage. The consequences of this adaptation are increased energy consumption and the need for greater concentration and attention to complete cognitive tasks. As you know pwMS are easily distracted and find it difficult to multi-task cognitively. Compensating with cognitive impairment is associated with mental fatigue and other hidden symptoms such as depression and anxiety. 

The argument against diagnosing MS earlier is the possibility of over-diagnosis, over-medicalisation and over-treatment of pwMS. I agree that this is potentially the downside of defining asymptomatic MS as a disease. Interestingly, with the other neurodegenerative diseases, in particular, Alzheimer's disease and Parkinson's disease, the diagnostic criteria are evolving to diagnose the diseases earlier. Why? So that disease-modifying therapies can be tested at an earlier phase, before too much brain has been lost. Is MS any different? We know that a proportion of pwRIS already have significant brain atrophy and cognitive impairment, why wouldn't we want to protect their brains? 

A small number of people diagnosed with MS initially present to memory clinics with dementia and are subsequently diagnosed with MS. These people must have RIS for many years prior to developing frank dementia. The question we need to ask is do we want to protect the group of people who won't develop MS, or problems from their RIS, or do we want to identify the pwRIS who are likely to develop problems in the future, for example, dementia? 


Please note that is many areas of the country neurologists don't treat CIS. Do you think they would treat RIS? The good news is that there are two trials of DMTs in patients diagnosed with RIS. A US trial testing DMF (Tecfidera) to placebo and a European trial testing Teriflunomide (Aubagio) to placebo. The primary outcome in these trials is time to first attack, i.e. time to CIS or MS. Maybe we will have to wait for the outcome of these trials before we can challenge the diagnostic criteria for MS? Or we could be bold and do a Donald Trump; we could simply ignore the new criteria and define a new set. We could call them the Alternative MS Diagnostic Criteria?

Amato et al. Association of MRI metrics and cognitive impairment in radiologically isolated syndromes. Neurology. 2012 Jan 31;78(5):309-14.

OBJECTIVE: To evaluate cognitive changes in a cohort of radiologically isolated syndromes (RIS) suggestive of MS and to assess their relationship with quantitative MRI measures such as white matter (WM), lesion loads, and cerebral atrophy.

METHODS: We assessed the cognitive performance in a group of 29 subjects with RIS recruited from 5 Italian MS centers and in a group of 26 patients with RRMS. A subgroup of 19 subjects with RIS, 26 patients with RRMS, and 21 healthy control (HC) subjects also underwent quantitative MR assessments, which included WM T1 and T2 lesion volumes and global and cortical brain volumes.


RESULTS: Cognitive impairment of the same profile as that of RRMS was found in 27.6% of our subjects with RIS. On MR scans, we found comparable levels of lesion loads and brain atrophy in subjects with RIS and well-established RRMS. In subjects with RIS, high T1 lesion volume (ρ = 0.526, p = 0.025) and low cortical volume (ρ = -0.481, p = 0.043) were associated with worse cognitive performance.

CONCLUSIONS: These findings emphasize the importance of including accurate neuropsychological testing and quantitative MR metrics in subjects with RIS suggestive of MS. They can provide a better characterization of these asymptomatic subjects, potentially useful for diagnostic and therapeutic decisions.


CoI: multiple

Wednesday, 27 September 2017

#ClinicSpeak & #BrainHealth: poor sleep and increased mortality

Poor sleep is the Big Elephant in the room; we need to do something about it. #ClinicSpeak #BrainHealth

Summary: We as a society are chronically sleep deprived. Sleep deprivation is associated with a large number of medical problems. Improving your sleep hygiene should reduce these problems and improve your quality of life. 

One of my patients sent me the link to the Guardian article below. I suggest you read and digest its contents; it is medical writing at its best. It summarises the science about poor sleep hygiene and discusses a list of common maladies that are associated with poor sleep. The following is a short list:

1. Obesity, metabolic syndrome, hyperglycaemia and hypertension
2. Stress, anxiety and depression
3. Reduced concentration, poor memory and dementia (Alzheimer's disease)
4. Cardiovascular disease: myocardial infarction
5. Increased risk of common infections
6. Reduced quality of life
7. Increased risk of making errors of judgement 
8. Reduced reaction times

The article highlights that at a population level we are chronically sleep deprived. Some of the factors driving this epidemic are cultural, i.e. 24/7 entertainment, stimulants (caffeine) and macho culture of burning the candle at both ends. It is quite clear that sleep deprivation is reducing our productivity and making us sick. 

I sent the article to my wife to read and she said that she hopes I take note. I am a veteran insomniac and have very poor, in fact shocking, sleep hygiene. I probably have 4-5 hours of sleep a day during the week and slightly more on weekends. In short, this is not good for me. I always feel tired and to get through a typical work day I have to consume 8-10  Nespresso capsules; any more than this and I get a caffeine tremor and anxiety. I am typically so wired by the end of the day that when I get home it takes me several hours to relax. Day 1 of restricting myself to two cups of coffee per day. 

I find exercise really helps reset things. When I was training for marathons I would be forced to go to bed early and would sleep like a baby and wake refreshed. The problem is that my exercise patterns have also become erratic; I have become a weekend warrior. 

Why I am telling you all this? Sleep hygiene is one of the issues that we address as part of our Brain Health initiative and is central to the holistic management of MS. I believe that I should practice what I preach; i.e. if I am to tell my patients to improve their sleep hygiene I need to improve my own. I am saying this to you, as I am making multiple typos having just completed an overnight trans-Atlantic flight during which I only got 3 hours of restless sleep. Time to have a sleep? 

Poor sleep is a major problem for pwMS. When I did a survey on sleep problems in pwMS on the blog a few years ago it showed that the majority of pwMS have sleep problems. The reasons for poor sleep were numerous with many people having more that one problem. I spend a lot of my clinic time addressing poor sleep in pwMS. I, therefore, urge you to assess your own sleep, if it is disturbed to identify why you are sleeping poorly and to then try and address the problems. 

When we get our group clinics off the ground one of them will be dedicated to sleep hygiene. Sorting out poor sleep usually means we have to sort out all your other symptomatic problems. 


Rachel Cooke. The shorter your sleep, the shorter your life: the new sleep science. The Guardian Sunday 24 September 2017 08.00 BST.

Neutrophils lost after alemtuzumab

Marked neutropenia: significant but rare in people with multiple sclerosis after alemtuzumab treatment. David Baker, Gavin Giovannoni, Klaus Schmierer Mult Scler Rel Disord. 2017 .

HIGHLIGHTS

  • Neutropenia occurred in 20-25% of people in the 2 year phase III, pivotal trials of alemtuzumab.
  • However, grade 3-4 neutropenia (neutrophils occurred in only 5/811 people with MS (0.6%) in the year following the first infusion cycle and in 12/808 people (1.5%) in the year following the second infusion cycle.
  • Agranulocytosis was a rare occurrence but this responded to treatment.
Background: Alemtuzumab is a CD52-specific monoclonal antibody that markedly depletes T and B lymphocytes and inhibits relapsing multiple sclerosis (MS). However, polymorphonuclear neutrophils also express CD52 and can be depleted by alemtuzumab, thereby potentially contributing to the infections that develop post-alemtuzumab treatment. Surprisingly, however, the degree of neutrophil depletion in MS was not included in the pivotal trial reports.Methods: The regulatory submission of the Comparison of Alemtuzumab and Rebif® Efficacy in MS 1 and 2 trials was obtained from the European Medicines Agency through Freedom of Information. The data relating to neutrophils was extracted.
Results: Data extraction from the submission was straightforward. In year one 72/811 (8.9%) and in year two 116/808 (14.4%) people with MS (pwMS) developed neutropenia. The degree of neutropenia was generally mild, and only 5/811 (0.6%) in year 1 and 12/808 (1.5%) in year 2 developed grade 3-4 toxicity. Two pwMS developed severe neutropenia-related adverse events.
Conclusions: Treatment with alemtuzumab induces neutropenia, which is mild in the large majority of pwMS treated. Leucocyte levels following alemtuzumab should be monitored as a marker of efficacy and safety; persistent neutropenia may require treatment

Following on from a recent case report indicating that alemtuzumab, marketed by Sanofi Genzyme, can induce neutropenia (loss of neutrophils, which are your first line of defense against fighting infection), this paper was written and submitted within a few hours.

It is all well an dandy to know that something can occur, but surely it is important to know how common the problem is. 


We show that the occurrence of neutrophil loss is frequent but marked loss is not a common problem. This data was in the unpublished phase III trial data set, but as it is now 5 years since the trial report was published and add another few years since the work was done, the manufacturers had shown no interest in publishing the information.

We had it because we had the data set obtained from the European Medicines agency and so we could easily answer the question. Pharma could never write and submit a paper within a few hours.

Will they be miffed, as we have published the information?

Maybe/Probably  but t
he manufacturer has had 7 years to get the data published, as have their academic collaborators, so I should not feel too bad

Some of our colleagues are not too happy with this type of information source and have told us so in no uncertain order, but this is important, safety information.

I am sure the manufacturers are happy that we have put the case report in context.

But, it says to pharma, that the the world order has changed and now the machinery is at hand to get access to trial data. We have led the way.

So they now pharma can get up to 12-18 months to publish what they want, to publish in a way they want to publish the story, but after that it will be fair game. 

The race may be on to get hold of the ocrelizumab data...for example the phase II extension study...oh I forgot I've published the headline result already:-).

Anyway back to the alemtuzumab data set. 


It houses quite a lot of unpublished ideas and I had hoped that by publishing some details, such as the presence of neutralizing antibodies, it may have encouraged the academics & company to come clean.  It didn't, so I tell you here again.

Nearly 80% of people produce neutralizing antibodies and over 30% had pre-existing neutralizing antibodies and over 70% have binding antibodies by 12 months after the second cycle.  So if you need a third cycle there could be issues.

Will it be part of the CARE-MS extension data reporting?

It is important as the question is....How many people got anaphylactoid (allergic) responses during infusion? 


In the first two years it was very low and you take preventative medicine to prevent this


Importantly how often does the antibody stop working? 


These are theoretical problems based on immunological principals

and are a problem for all therapeutic proteins, but is alemtuzumab
extra special? 

One wonders whether the dosing schedule was developed because an issue of neutralizing antibodies was recognised (only 2 course as standard and only retreat at the year end and not when disease activity occurs, as you need to wait for the neutralizing antibodies to subside).


If you are paying $60,000-$80,000 for treatment, you would expect it to work, wouldn't you? 


But I know it doesn't always, however what is the scale of the issue?


I don't know, but I can assure you we will get an answer by hook or by crook, with or without company assistance. 


Maybe it is not an issue, but let's see the data!


As MD2 will testify, once the ferret's jaw locks...it locks..and with no costs and no resource to data crunch we can bide our time.


This is important because omissions by pharma are in the news at present so let's hope this is not a repeat case.


A report in the  Telegraph says


"Medical experts were “complicit” in allowing thousands of children to suffer deformity after resisting warnings on epilepsy drugs, campaigners have said.

"A hearing in London heard that regulators knew in 1973 that taking the anti-epilepsy drug in pregnancy could cause babies to be born with disabilities, but waited 40 years before alerting the public to the risks".  (The regulators have the data to see that there could be an issue of neutralization with alemtuzumab..if they had any immunological knowledge)

"Estimates suggest that around 20,000 babies in the UK suffered harm as a result of sodium valproate which can also cause brain damage and problems such as autism".

"Sanofi, which manufactures the drug, has said it has always been transparent with regulators about the risks of the medicine".

I think this apparent ignorance of the knowledge is rather odd, because when I have been teaching epilepsy since 2006 to our second year medical student's, one of the central topics in the course notes that is covered is the use of these types of agent during pregnancy and the risks of birth defects.

Why is this interesting to MS?

It shows the importance of disclosure and importantly.... dissemination of problems. 

In the telegraph article Medical Experts seem to have been suppressing the information flow.

In addition this interesting to me because our potential MS drug acts on the opposite side of neurological control (to promote relaxation/inhibition) to agents like valproic acid (blocks excitation). If blocking excitation causes autism. Will our drug inhibit autism and epilepsy?  

We will have to wait and see.

Tuesday, 26 September 2017

#GuestPost & #PoliticalSpeak: How Brexit made me even more uncertain about my MS

Can we really ignore the impact that Brexit will have on the NHS? #Brexit #GuestPost #PoliticalSpeak

Summary: A perspective from someone with MS on Brexit and its potential impact on his/her life. The author is a professional journalist, who frequently visits our blog and volunteered this piece; it was not commissioned. For obvious reasons, he/she wants to remain anonymous and has penned this under his/her blog pseudonym iaino.


How Brexit made me even more uncertain about my MS

by iaino

In the far-off Pacific, in the islands of the Trobriands, there is a language called Kilivila. And that language possesses a word that struggles to be translated into English - or any other language, for that matter.

Mokita.

Mokita means a painful fact that everyone is aware of, but which – out of compassion – no one dares mention. The ability of a group to manage mokita is said to be deeply admired. Multiple sclerosis might be a case in point. People may know you have it, and the flip and the flop of your feet on pavement will testify to it, but – like Voldemort in Harry Potter – it is a thing that dare not be named.

There are, of course, words in English that, like Mokita, do not translate easily. Brexit is one of them.

Like Mokita, Brexit slips through our fingers when we truly try to interpret its meaning. Of course, on a basic level, it refers to the prospective withdrawal of the United Kingdom from the European Union. But on a deeper level, it means so much more. To some, it is a symbol of national pride, hope and of better days ahead. To others, it is a rejection of hard-fought liberal ideals, a slap in the face to multiculturalism and a green card for racism and bigotry.

But to everyone Brexit means one thing: uncertainty. Even Boris Johnson, for all his bluster, cannot know for sure what will come of it. And, to people with Multiple Sclerosis - that most uncertain of diseases - it must mean uncertainty layered upon uncertainty.

Why should this be? Well, on a very simple level, Brexit poses great uncertainties to our future health.

First, Brexit raises the issue of who will treat us after the barriers come down? Screeds have been written about how the NHS is staffed by people from across the European Union. Men and women who have travelled here to the UK, to hoist us onto MRI machines, slide needles into our trembling veins, inspect our Babinski reflexes are many. One of my favourite MS nurses is French-Algerian. My Cladribine research hero is a German. My last brain scan was undertaken by a Pole. Not only has Brexit been a slap in the face to them (ask them - yes, they took it personally), but it also raises the question: if they decide to leave our little island (and who would blame them?), who will take their place? Who, indeed?

Second, there is the issue of the pound. A weak pound does not just mean that sangrias at the pool in Ibiza have become eye-wateringly costly. A weak pound also hikes up our drug prices. The policy director of the Health Care Financial Management Association, the professional association for NHS financial staff, has told the BBC he expects there to be an impact on the NHS caused by the increasing cost of imports. "Efficiencies one way or another" are expected. And you know that when someone starts talking about efficiencies, it doesn’t bode well for a disease renowned for making people notably less-than-efficient. In the US, Ocrelizumab (Ocrevus), the first disease-modifying treatment that has been seen to have an impact on primary progressive multiple sclerosis, is tagged at a costly $65,000 per year. Will efficiencies mean that this drug will be restricted in the UK to the very few? After all, only this week tens of thousands of Parkinson's disease patients with a mixture of dementia and psychosis were denied an effective drug due to its cost.

Third, Brexit brings uncertainty to our economy as a whole. Britain’s credit rating has just been downgraded by Moody's. Nobel laureate economist Paul Krugman says there is 'zero chance' leaving the EU will make Britons better off. What impact Brexit might have on employment prospects is – yes – very uncertain. And if you are the person in the office who keeps on having to take time off for duvet days, or neurologist appointments, and all the rest, well… we won’t have the European Court of Human Rights to defend us if we are the first to be sacked.

Fourth, it brings uncertainty to scientific research, and this isn’t just because mice might go up in price. As the prestigious Royal Institution states: “the ramifications of Brexit are still unknown, but it is certain to affect jobs, funding and collaborations for decades to come.” Will funding streams dry up? Will cross-border collaborations wither on the vine? What possible cure might be lost in the maelstrom?

Finally, Brexit has fostered the shadow child of insecurity: namely, intolerance. It cannot be denied that Brexit was partly born from a fear of ‘the other’. When Nigel Farage stood in front of a poster of male migrants, supported by the tag-line ‘Breaking Point’, he used the age-old trope of ‘the other’ as the threat. The barbarians were at the gates. It’s the daily fodder for the pro-Brexit papers. Refugees are turned into migrants and migrants has turned into a dirty word. To me the issue is this: when we get into the politics of explicit bias – where ‘the other’ becomes a potent symbol for people to be distrusted and reviled, then where does that lead? Because we, people with disabilities, are ‘the other’. We are the ones that need the support of the state at exactly the same time when the state wants to demonise those who might seek support. It begins with migrants, it shifts to people of colour, then the impoverished, then the mentally ill… there is always ‘the other’. And when intolerance becomes a politically acceptable creed, those who should be most concerned are those who are least able.

So, perhaps we should strive not to apply the Kilivilian word of mokita to Brexit. Perhaps those with MS, the charities that support those with MS, the partners of people with MS, perhaps we should really begin to debate more fiercely what Brexit might mean for us. For our access to NHS staff, our access to drugs, our access to employment rights, our access to the benefits of research: all of this is now uncertain.


I do not know what this disease will do to me and I try not to worry about it, but I do worry about what Brexit could do to those with this disease. And you should too.

Should RIS (radiologically isolated syndrome) be treated?

Mult Scler. 2017 Sep 1:1352458517729462. doi: 10.1177/1352458517729462. [Epub ahead of print]

Radiologically isolated syndrome should be treated with disease-modifying therapy-Yes.

Okuda DT


Radiologically isolated syndrome should be treated with disease-modifying therapy – No

Andrés Labiano-Fontcuberta, Julián Benito-León First Published September 14, 2017


MS treatments are a caveat emptor. Global consumerism has hit the MS market succeeding in banishing moderation, thereby legitimising price hikes in the name of competition. It, therefore, falls to the responsible clinician to take the moral and ethical high ground. So, if science gives us the opportunity to treat early, regardless of cost, wouldn't it be wrong not to follow its instruction? Is, there an alternative viable option - realistically speaking? A transformative approach to early treatment in MS should therefore not be swept under the table. A pragmatic approach that demands an unequivocal demonstration of efficacy is not an approach to take in the path to a cure.

Okuda, above argues that MRI lesions in radiologically isolated syndromes (RISs) are very typical to those seen in MS in terms of appearance, frequency and distribution in the brain. Of those scanned 24% demonstrate contrast enhancing lesions on their baseline scan - it is well know that this cohort has further increased risk for future contrast enhancing lesions on subsequent head scans (Hazard ratio=3.4). Early DMT use, therefore, is a sound strategy for preventing further disease evolution.

"An estimated 11,000 axons are transected per cubic centimeter of contrast enhanced tissue".

Okuda, however, concludes with the realities of DMT use in MS: "Relating radiological features specific to in situ demyelination may be challenging at times. However, how truly accurate are clinical descriptions of experiences by patients that we routinely use to fulfill the clinical component of the diagnostic criteria in those with established MS? Would our concerns for treatment in RIS subjects be different if the costs of DMT were not so exorbitant or if the treatments provided were substantially safer than our current offerings?"

The counter argument for not treating RIS is provided by Labino-Fontcuberta and Benito-Leon. They argue on the point that the current risk-benefit ratio of DMTs is unfavorable for treating early. The current evidence is that ~ 7/10 RIS cases may not go onto develop MS in the next 5 years. In this case, a greater number would need to be treated to avoid developing MS, than is necessary. The authors appeal to a greater understanding of the nature of the disease at the RIS stage before we as a community offer treatments for it. 

"Emerging data suggest that in RIS, the clinical and pathological damage of magnetic resonance imaging (MRI) lesions might be compensated by more efficient reparative mechanisms".
 
I leave it to you to draw your own conclusions - are you for or against early treatment in RIS?

Monday, 25 September 2017

#ThinkSpeak & #NewsSpeak: social medicine the great disruptor

We are in the process of 'professionalising' the Barts-MS blog, by reducing the number of posts and improving the quality and relevance of each post for pwMS. As part of this transition, I will be moving all of my #ThinkSpeak posts, which are not directly relevant to MS onto Medium, a relatively new and evolving social media platform. Although the #ThinkSpeak post '#SocialMedicine the great disruptor' that I posted on Medium is underpinned by many ideas that I have developed on this blog I don't think its content is appropriate for this site.


#NeuroSpeak: treating MS in patients with PML

Teriflunomide is the drug of choice for treating MS in patients recovering from PML. #NeuroSpeak #CharcotProject

Summary: This post summarises the scientific principles for treating multiple sclerosis in patients who have PML as a complication of natalizumab treatment. I make the case for using DMTs that are not immunosuppressive and highlight the antiviral effects of Teriflunomide that make it the DMT of choice. 

At the grand round at Imperial College on Friday, a case of natalizumab-associated PML was presented. The patient had developed IRIS and was deteriorating. The question was posed about MS rebound contributing to some of the later deterioration in functioning and how to treat MS in this situation. 

It is clear that you cannot use an MS DMT that causes immunosuppression, particularly one that targets T-cells, in this situation. Patients with PML need their CD8+ cytotoxic T-cell to recover from PML. In my opinion, this only leaves 4 drugs that have a suitable profile:

(1) Interferon-beta: IFNbeta is not immunosuppressive and has many activities that are anti-viral. However, a lot of people who are on natalizumab may have failed IFNbeta in the past. IFNbeta has also been shown not to be that effective in preventing MS rebound post-natalizumab. 

(2) Glatiramer acetate: GA is not immunosuppressive, is only moderately effective in treating MS, is not effective in preventing MS rebound post-natalizumab and has a delayed onset of action. Therefore, it would not be the ideal agent to prevent MS rebound post-alemtuzumab in a patient with PML.

(3) Teriflunomide: Teri is not immunosuppressive as defined by the regulators, it has a complex mode of action that includes general anti-viral activity. Interestingly, leflunomide, a prodrug that is converted into teriflunomide, has been shown to have antiviral effects against BK virus (see below), that is very closely related to JCV, the cause of PML. In addition, there is some emerging evidence that Teri may cross the blood-brain barrier and hence may be able to inhibit JCV with the CNS. At the last AAN there was a poster of a switch study showing that Teri, post-natalizumab, was able to hold back rebound MS disease activity in the majority of patients and overall these patients did well.

(4) Daclizumab: Dac is not immunosuppressive, as defined by regulators, and only drops CD8 cell numbers by ~10%. Therefore, antiviral responses, for example against JCV should be intact. Dac also expands the NK, or natural killer, cell population that have anti-viral effects. We are in the process of doing a switch study to assess the effectiveness of Dac post-natalizumab to see how effective it is in preventing post-natalizumab rebound. Daclizumab also has a rapid-onset of action making which makes it an ideal agent post-natalizumab. However, as Dac reduces IL2 signalling in activated T-cells it may blunt effector T cell responses, i.e. reduce their reactivity, which makes me concerned about using it in patients with active JCV infection and PML. 

My recommendation, therefore, to the team looking after this patient particular patient was to use high dose Leflunomide (40mg per day) until JCV was not detectable in her CSF and then to switch her to Teriflunomide 14mg per day. The choice of Leflunomide dose is based on that used to treat BK-virus associated nephropathy. In my opinion, the team looking after this patient have little to lose; her JCV viral load in the spinal fluid was dropping so the IRIS (immune reconstitution syndrome) was at least taking care of the JC virus. However, she needs something to take care of MS without impacting on her immune system and at the same time assisting with the treatment of her PML.


With regard to Teriflunomide, there is an increasing number of reports of how well pwMS are doing on teriflunomide long-term. Teriflunomide is the only DMT that works significantly better second, or third, line than it does as a first-line treatment (see figure below). I have hypothesised that these observations may be due to teriflunomide's mode of action as an anti-viral agent. Professor Julian Gold and I are in the process of exploring this hypothesis under the umbrella of the Charcot Project. We will let you know as soon as we have data available.  




Josephson et al. Treatment of renal allograft polyoma BK virus infection with leflunomide. Transplantation. 2006 Mar 15;81(5):704-10.



BACKGROUND: Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals.

METHODS: We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy.

RESULTS: In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added.

CONCLUSIONS: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Morita et al. Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review. J Clin Virol. 2016 Sep;82:133-8. doi: 10.1016/j.jcv.2016.07.015.

Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomidetreatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.


CoI: multiple

Delayed Repopulation white cell population after stopping DMF

Bhupendra O. Khatri, Sergey S. Tarima, Benjamin Essig, Jean Sesing, Tayo Olapo. Delayed lymphocyte re-population following discontinuation of dimethyl fumarate and after switching to other disease modifying drug therapies MSARDS DOI: http://dx.doi.org/10.1016/j.msard.2017.09.014

Background:Dimethyl fumarate (DMF) reduces absolute lymphocyte counts, CD4, and CD8 counts, without significantly affecting total white blood cell counts. However, the recovery rate of these cells after discontinuation of DMF is unknown. The effect of subsequent disease modifying therapies (DMTs) on re-population rate is also unknown.
Objectives:To study the re-population rate of absolute lymphocytes, CD4, and CD8 counts back to baseline after discontinuation of DMF. 2. To measure the effect of subsequent DMTs on the re-population rate of these cells after DMF therapy. 3. To study the effect of the duration of exposure to DMF on repopulation of these cells.
Methods:A retrospective chart review of subjects who had discontinued DMF and in whom, CBC with differential, CD4 and CD8 counts were available at baseline, discontinuation and at follow-up (n=113).
Results: DMF causes a significant drop in absolute lymphocyte, CD4, and CD8 counts. Re-population of these cells after discontinuation of DMF is significantly delayed, irrespective of whether or not a subsequent DMT is used, although there is a difference in re-population rate among DMTs. The re-population rate is also dependent on the duration of time patients have been exposed to DMF; longer exposure was associated with more delayed recovery.
Conclusion:During this 30 month study period, re-population rates were significantly delayed post-DMF, irrespective of what subsequent DMT the patients received. Furthermore, no recovery of lymphocyte counts occurred in patients who were started on fingolimod or alemtuzumab after DMF was discontinued; in fact there was a continued decline in all of the cell populations studied.



As I have been saying for some time, when you start a DMT you have to think of what next after the DMT, as many will fail particularly the lower efficacy agents. DMT is higher efficacy agent. It is an immune depleting agent, which is pretty good at getting rid of CD8 T cells. It is moderate at removing memory B cells so that affects its ranking in my mind. But what else does it do. It is evident that some people who take DMF, deplete their cells and they do not functionally recover for some time, suggesting that DMF must hit the baby T cells so that there is little to repopulate with.
This offers a conundrum of when is best to start, because you don't want to wait too long before starting the next treatment so rebound does not occur, but if you are adding a lymphopenia inducing drug when you are lymphopenic are you going to be more susceptible to infections?
Worth knowing and discussing with your neuro before the switch.  ProfG maybe can expand on the DMF switch when he wakes up in Trumpland.

Sunday, 24 September 2017

Up in Smoke

Palacios N, Munger KL, Fitzgerald KC, Hart JE, Chitnis T, Ascherio A, Laden F. Exposure to particulate matter air pollution and risk of multiple sclerosis in two large cohorts of US nurses. Environ Int. 2017 Sep 19;109:64-72.

BACKGROUND:Air pollution is thought to raise the risk of neurological disease by promoting neuroinflammation, oxidative stress, glial activation and cerebrovascular damage. Multiple Sclerosis is a common auto-immune disorder, primarily affecting young women. We conducted, to a large prospective study of particulate matter (PM) exposure and multiple sclerosis (MS) risk in two prospective cohorts of women: the Nurses Health Study (NHS) and the Nurses Health Study II (NHS II).
METHODS: Cumulative average exposure to different size fractions of PM up to the onset of MS was estimated using spatio-temporal models. Participants were followed from 1998 through 2004 in NHS and from 1988 through 2007 for NHS II. We conducted additional sensitivity analyses stratified by smoking, region of the US, and age, as well as analyses restricted to women who did not move during the study. Analyses were adjusted for age, ancestry, smoking, body mass index at age 18, region, tract level population density, latitude at age 15, and UV index.
RESULTS: We did not observe significant associations between air pollution and MS risk in our cohorts. Among women in the NHS II, the HRs comparing the top vs. bottom quintiles of PM was 1.11 (95% Confidence Intervals (CI): 0.74, 1.66), 1.04 (95% CI: 0.73, 1.50) and 1.09 (95% CI: 0.73, 1.62) for PM10 (≤10μm in diameter), PM2.5 (≤2.5μm in diameter), and PM2.5-10 (2.5 to 10μm in diameter) respectively, and tests for linear trends were not statistically significant. No association between exposure to PM and risk of MS was observed in the NHS.
CONCLUSIONS: In this study, exposure to PM air pollution was not related to MS risk.

Phew pollution is not a risk factorof MS,...an makes a change from finding risks...what next?

Can we find something else that doesn't link with MS:-)

But wait like buses, no sooner than one paper on pollution we have two.

Amy M. Lavery, Amy T. Waldman, T Charles Casper, Shelly Roalstad, Meghan Candee, John Rose, Anita Belman, Bianca Weinstock-Guttman, Examining the Contributions of Environmental Quality to Pediatric Multiple Sclerosis

Background Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade.
Objective:To examine potential environmental factors in pediatric MS using geographic information systems (GIS).
Methods:Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects’ geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or ≥20 miles from the recruiting center), using logistic regression.
Results Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p=0.90 <20 miles from center; p=0.43 ≥20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR=2.83; 95%CI 1.5, 5.4) and those who reside ≥20 miles from a referral center (OR=1.61; 95%CI 1.2, 2.3).
Conclusion: Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures.

So in this study in childhood MS, risk was not associated with environmental (air, water etc) quality per say..so I thought replication within a day of the above and hopefully the need for no more studies on this:-), but then we had the air quality bit and it says in children living in poor air quality are affected so I spoke too soon. 

You were 3 times more likely to have MS if you live near to the MS hospital in a poor quality area the risk and was one and half times if living more than 20 miles (32km) away. 

So I'm not sure what to make out of this.....numerous other studies on air pollution on the way....:-( 

Do parents with kids with MS move to be nearer treatment centres?

or is it god forbid cars and all the air pollution they cause. 

We have been demonising the hubble ciggie for along time, but should we be ditching the motor...as driving kills!

Will new car adverts have to feature the pictures of car accidents and ill children as a health warning.

Should America start to use public transport for the sake of their children or...Maybe too much heresy for one day:-). 

Saturday, 23 September 2017

#ClinicSpeak: hospice care the underbelly of MS

Why is death and dying with MS such a taboo amongst MS stakeholders? #ClinicSpeak 

Summary: As multiple sclerosis advances people may enter a phase when the complications of MS become life-threatening. This phase is referred to as the terminal phase of MS. This post discusses a hotline service provided by the German MS Society to help German MSers with advice about palliative care and hospice.


Just over a year ago I bought a pair of rose-tinted glasses to improve my outlook on the world. Several commentators on the blog thought some of our posts were too morbid and not positive enough. I responded that we don't pull our punches and tell things as they are. If people don't want to know the truth they can go somewhere else; there are plenty of sights on the web dedicated to alternative facts. 

The following study addresses the underbelly of MS, its terminal phase. It describes the experience of a German MS hotline dedicated to palliative care and hospice care. The hotline received 222 calls over a 27 month period; i.e. ~8.2 calls per month. Germany is a large country with a population of ~83 million, therefore this is probably the tip of the MS iceberg. What this study shows is that there is a need for information and advice about terminal care. 


Just yesterday I was asked to comment about a person with MS who was locked-in and was being managed in an intensive care unit as a result of severe brainstem disease. This person was in her late 50's and had MS for ~20 years. The patient was conscious and was actually not quite locked in as she could still twitch one of her fingers. She was using this finger twitch to communicate. I made the point that this is the exact situation when having an advanced directive or living will in place is helpful.  It provides clear instructions to your family and medical team years before they need it to guide their treatment decisions in the future. I would recommend you all address this issue in advance. The NHS Choices has very good advice on end-of-life issues and advanced directives. 

End-of-life issues that are highlighted on our MS Tube map that possibly need consideration are:


  1. Palliative care
  2. Legal aid
  3. Social services
  4. Hospice
  5. Respite care
  6. Dignitas
  7. Assisted suicide
  8. Funeral planning
  9. Dignified dying
  10. Mortality (cause of death)
  11. Living will



Did you know that one of the MS Society's asked me permission to use my tube map, but wanted to remove the terminal line? They felt it would not be appropriate to inform or remind pwMS that MS has a terminal phase. On principle I said no; if they wanted to use the map they needed to take it as is, warts and all. Was I wrong? I feel the days of the patronising HCP, deciding what information to give pwMS, are over. To be honest, life has a terminal phase and the issues being discussed here are not unique to MS and apply to everyone so I am not sure we need to be overly sensitive about these issues.

The following is an example of an advanced directive to refuse treatment at the end-of-life. This can be adapted for MS. 


Strupp et al. Evaluation of a palliative and hospice care telephone hotline for severely affected Multiple Sclerosis patients and their caregivers. Eur J Neurol. 2017 Sep 19. doi: 10.1111/ene.13462.

BACKGROUND: Palliative and hospice care (PHC) still highly focus on cancer patients.


OBJECTIVES: To connect severely affected Multiple Sclerosis (MS) patients and caregivers to PHC, a nationwide hotline was implemented facilitating access to PHC.

METHODS: The hotline was designed in cooperation with the German Multiple Sclerosis Society. Self-disclosed information given by callers was documented using case report forms supplemented by personal notes. Data was analysed descriptively.

RESULTS: 222 calls were documented in 27 months. Patients' (mean age 51.12; range 27-84) mean illness duration was 18 years (range 1 month to 50 years). Inquiries included information on PHC (28.8%), and access to PHC (due to previous refusal of PHC, 5.4%), general care for MS (36.1%), adequate housing (9.0%), emotional support in crisis (4.5%). 31.1% of callers reported "typical" palliative symptoms (e.g., pain 88.4%), 50.5% symptoms evolving from MS, and 35.6% psychosocial problems. For 67 callers (30.2%), PHC services were recommended as indicated.

CONCLUSIONS: The hotline provides insight into needs and problems of patients severely affected by MS and their caregivers, some of which may be met by PHC. Future follow-up calls will demonstrate if the hotline helps improve access to PHC beyond providing information. Overall, our hotline seems to be easily accessible for severely affected MS patients whose mobility is limited.

Addendum: Results of blog surveys done in the past related to this topic.

How does Daclizumab work? Can animal studies tell us

Bhopale MK, Hilliard B, Constantinescu CS, Phillips SM, Rostami A. DAB389IL-2 recombinant fusion toxin effect on lymphocyte- and macrophage-producing cytokine subpopulation cells in experimentally induced demyelinating disease in mice. Immunopharmacol Immunotoxicol. 2017 :1-12

CONTEXT: We have reported previously that DAB389IL-2 recombinant fusion toxin targets IL-2R bearing CD4+ cells, and suppresses demyelinating disease in acute (A) - and chronic (C) - experimental autoimmune encephalomyelitis (EAE) animal models of multiple sclerosis.
OBJECTIVES: The present study was undertaken to investigate the effect of DAB389IL-2 treatment on various cytokine-secreting cell populations in A-EAE and C-EAE mice.
MATERIALS AND METHODS:The effects of DAB389IL-2 at doses of 200-, 800-, or 1600 kU administered i.v. on days 11-13 and 15 on the clinical score and cytokine-secreting cell populations were examined using flow cytometry.
RESULTS:C-EAE mice treated with 1600kU DAB389IL-2, but not A-EAE mice treated with 800 kU had significantly reduced disease. The CD3+CD25+ sub-population in spleens and spinal cords of A-EAE mice treated with 800 kU DAB389IL-2 a was increased, whereas in C-EAE mice treated with 1600 kU this population was increased. DAB389IL-2 treatment reduced CD3+CD4+, CD3+CD8+, CD4+CD8+, CD3+IL-2+, CD3+IFN-γ+ and CD3+TNF-α+ T cell subpopulations in the spinal cord in A-EAE, and C-EAE mice on day 16. CD11b+ macrophages that were IL-2-, IFN-γ-, and TNF-α- positive were reduced in A-EAE mice. DAB389IL-2 treatment reduced CD19+ B-cells positive for IL-2 or CD11b+ in the spinal cord in acute and chronic disease. DAB389IL-2 treatment also reduced lymph node CD3+CD8+, CD4+CD8+, CD3+CD25+ populations on day 16, and lymph node CD3+IL-10+ and peripheral blood CD3+CD25+ populations on day 24.
DISCUSSION AND CONCLUSIONS: Our study demonstrates that DAB389IL-2 fusion toxin suppresses EAE in a dose-dependent manner, and alters inflammatory cell sub-populations during disease development



One of the flavors of the decade in terms of disease mechanisms has been the identification of Fox3P, CD25+, CD4 T regulatory cells. You can't see a paper these days where this is not the mechanism of action of EAE inhibition.

This is all well and dandy, but in terms of MS there is one nasty fact. 

People ignore from their world view. 

This is daclizumab. 

This antibody blocks CD25 which is the high affinity interleukin2 (T cell growth factor) receptor. Block this and natural killer subsets increase and MS goes away, but a problem is so do the T reg cells as these are depleted.

I was always of a mind-set that that the inhibitory effect is not surprising because the action of daclizumab is because it is simply killing or blocking activated T cells and have more recently switched to thinking it is because it kills activated memory B cells. The NK story is a smoke screen. ProfG disagrees he thinks that this creates and better anti-viral response, due to more NK cells.

However T regs are dogma. They are there to stop autoimmunity developing, which I totally understand. However, one question I have always posed is why would we want to spend a lot of effort to generate an immune response, outside the control of T reg control to give you life long protection, only to have it reeled back in by T regs. 

Since T regs were discovered, most studies give the interleukin 2 blocker before disease induction and low and behold it blocks T reg function and autoimmunity gets worse.....Hurrah for dogma.

What happens when this is done after disease has become established?

I have often thought of doing this for a student project, we could by the antibody with their lab expenses and see what happens I predicted nothing or it makes EAE better because EAE is driven by T cells and the blocker blocks activated T cells. 

Now I have found a few examples where people block the CD25 molecule after disease has developed and disease gets worse...so hoorah for dogma again. 

However I have also seen studies where cladribine stops mouse EAE, however someone forgot to tell the authors that cladribine does not work properly on rodents (don't believe me ask Merck..I did and they should know) and is not T cell immunosuppressive. This could be deduced by reading the early cladribine studies that showed that rodent metabolise cladribine in a different way to humans. We knew this years ago (experiments done in 2004). 

So on first read of the manuscript I thought has this had been done
and it didn't block the early acute phase but blocked the chronic phase, but on re-read whilst writing this....I must say uuurgh,

In this study they used a toxin linked to interleukin2 so when it binds to the the CD25 it kills the target. Do this and Eh.....the number of T reg cells increases but T cells decrease and EAE is reduced so hooray dogma persists.  

Should I do that study project?

Friday, 22 September 2017

#NeuroSpeak: do you know what an IRT is?

We are already beyond ECTRIMS and planning for the ECF 2017 meeting in Baveno. #ECF2017 #NeuroSpeak

I am trying to communicate the new treatment concept of using a new class of treatments called the immune reconstitution therapies, or IRTs. If you are an HCP and are attending the European Charcot Foundation meeting in Baveno, Italy (30th November - 2nd December 2017), you may want to consider extending your stay to attend the following satellite symposium. I will be speaking on the topic of IRTs. To attend you need to pre-register online via this URL





CoI: multiple

#ChariotMS & #ThinkHand: therapeutic lag explains why we don't have treatments for progressive MS

We need to do longer studies in progressive MS #ChariotMS #ThinkHand


Summary: This post explains therapeutic lag and why people with more advanced MS don't see an immediate response to DMTs.

I have been invited to give a grand round talk at Imperial College this morning. I have chosen the topic: "Is progressive MS (more advanced MS) modifiable?".  This is an extension of our #ThinkHand campaign to get the wider neurological community to accept that MS is potentially modifiable throughout its course. Despite us posting and reposting about reserve capacity, therapeutic lag, MS being a length-dependent axonopathy and the asynchronous progressive MS hypothesis we still get questions such as: "Why don't pwPPMS, or pwMS with an EDSS >6.0 respond, to HSCT and other DMTs?"


It is the same issue in relation to responders vs. non-responders to ocrelizumab in the PPMS trial. It is very difficult to know who is a responder and non-responder based on the current data from the ocrelizumab PPMS, or ORATORIO, trial. Why? Simply because clinical trials are designed, or powered, to get a significant read-out in a reasonable period of time. It doesn't mean that if someone with PPMS does not stabilise, on a high-efficacy therapy, in say a period of 2 years is a non-responder. Because of therapeutic lag, it may take much longer to see a response to treatment, particularly in pwMS who are older and have less reserve capacity in the particular pathway (usually the legs) being assessed.

I often refer to the study below which showed that interferon-beta treatment, a moderate efficacy DMT, would probably work in PPMS provided the follow-up is long enough; in this case 7 years. In this study PwPPMS who had only been treated with IFNbeta for 2-years clearly did better at 7-years than those people treated on placebo over the same period of time. There was a lag in the impact of interferon-beta on the outcome.

Why a lag? One interpretation is that the impact of anti-inflammatory medications in progressive MS may take several years to play out. In other words progression in someone with PPMS over the next 2 years was primed by inflammation from years ago. Suppressing inflammation today will have no impact over the next 2-years as the damage priming progression over the next 2 years has already occurred. All anti-inflammatory therapies will have a lag in terms of showing a treatment response in progressive MS.

Does this make sense?

To illustrate this concept I drew the picture below, which has now been published in our length-dependent axonopathy paper. Importantly in this study, the actively-treated subjects (INF-beta) only did better than placebo-treated subjects in terms of upper limb function (9HPT), cognition and brain volume loss. There was no difference in terms of the EDSS and T25FW, which assess lower limb. The reason why there was no difference in lower limb function is almost certainly due to loss of reserve, i.e. too many nerve fibres supplying the limbs had been damaged already for an anti-inflammatory to make a difference. The other issue is that in this study the treatment period was too short. Please note this study is only one of many studies showing the same effect, a greater impact of anti-inflammatory therapies on upper limb, compared to lower limb, function and is one of the reasons we are running our #ThinkHand campaign and trying to get support for our CHARIOT-MS study.

In the ocrelizumab PPMS, ORATORIO, trial the treatment effect was almost double in the arms compared to the legs. This is why I have little doubt that ocrelizumab is effective in PPMS. If the trial was extended for longer the treatment effect on lower limb function will have gotten greater simply because of lag; survival or Kaplan-Meier curves diverge further with time.



I am convinced we are correct about 'therapeutic lag' and the MS community is beginning to take this it into account when designing progressive MS trials. This means being clever about our studies and getting the regulators to accept the 9HPT as a primary outcome measure. The MS community has made it clear that they value arm and hand function more than leg function, we now need the wider community to help get this message across. There is also an economic argument for taking DMTs into wheelchair users to protect upper limb function; once people lose their arm function they lose their independence and the costs, both medical and social, for looking after these become very high. 

Just imagine what happens to your self-esteem and quality of life when you can't transfer your self from your wheelchair to the toilet and need a carer to help you go the toilet? When we asked people with MS what hand and arm function they valued most many pwMS stated being able to go the toilet without help.

As you can see we will continue to make the case for doing trials in more advanced MS. This is why we need your help getting the CHARIOT-MS trial funded.  The CHARIOT-MS study will compare subcutaneous cladribine to placebo in subjects with more advanced MS (EDSS 6.0 to 8.0), using the 9-hole peg test as the primary outcome measure.

If you are a wealthy philanthropist reading this post? DrK (@KlausSchmierer) is looking for a large donation of ~£2M to support his application to the NIHR for the CHARIOT-MS study. He needs to bring the costs of the study for NIHR down to under £2.5M to have any chance of getting this trial funded and to help people with more advanced MS.

Tur et al. Interferon Beta-1b for the Treatment of Primary Progressive Multiple Sclerosis: Five-Year Clinical Trial Follow-up. Arch Neurol. 2011 Nov;68(11):1421-7.

OBJECTIVES: To investigate, during the 5-year period without treatment after termination of a 2-year clinical trial of interferon beta-1b for the treatment of PPMS.

MAIN OUTCOME MEASURES: After 5 years without treatment, the EDSS and MSFC measures were scored for 63 and 59 MSers, respectively. Neuropsychological and magnetic resonance imaging assessments were performed for 59 and 50 MSers, respectively.

EDSS = Expanded Disability Status Scale

MSFC = MS Functional Composite ( a composite 3 tests the PASAT, 9-hole peg test and the timed 25-ft walk)

9-Hole Peg Test = test of upper limb function

Word List Generation Test = cognitive task

RESULTS: After 5 years without treatment, the interferon beta-1b group had better 9-Hole Peg Test (p=0.02) and Word List Generation Test (p<0.001) scores, and MRI measures in the normal-appearing white matter were significantly better. During the entire study period (from trial baseline to assessment at 5 years without treatment), the placebo group showed a greater decrease in brain volume (p=0.004). The in-trial increase of lesions correlated with the worsening of the EDSS score during the 5-year period without treatment (p =0.004).

CONCLUSIONS: Modest but beneficial effects of interferon beta-1b on clinical variables and brain atrophy development were observed 5 years after trial termination. Moreover, in-trial lesion activity correlated with EDSS progression after trial termination. Therefore, we provide evidence to consider immunomodulation as a sensible approach to treat primary progressive multiple sclerosis.

CoImultiple