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 their 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 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.