Category: Archive

Do you know what GROLDI means?

Several things often happen together for a reason and then make you sit up and think. 

Firstly, I got a tragic email from a young woman, who lives in Los Angles, who was recently diagnosed with MS. Unfortunately, she is unable to get herself onto a DMT due to being uninsured. She describes having quite active MS and unless she is treated early and effectively will almost certainly be unable to continue working. She was desperate enough to ask about what would be required for her to move to the UK to live, work and have her MS treated in the UK. Although moving to the UK is possible she would need to have a work permit and a job.  Instead of the latter, I put her in contact with a very compassionate neurologist in LA who I am sure will be able to weave some magic and help get this poor lady on one of the compassionate access programmes the Pharma companies run in the US. 

Only weeks after receiving this email the BMJ has run a feature on US Healthcare focusing on the 27 million people who are uninsured. Jullie Rover, Chief Washington correspondent, Kaiser Health News,  describes how healthcare is a partisan issue in the US and that is unlikely to be sorted out by the respective political parties in the near future. This is despite healthcare costs becoming a major political issue for Americans (see an excerpt from her article below).

Excerpt: “In 2003, according to the Kaiser Family Foundation, a non-partisan policy analysis group, 60% of Americans surveyed said insurance coverage was the most important health matter, with 33% saying the cost was the most important. In 2018, by contrast, that had almost exactly reversed, with 59% saying the cost was the most important health matter in their lives, and only 26% saying coverage. A separate poll by researchers from the Harvard TH Chan School of Public Health and elsewhere also found healthcare costs near the top of voter concerns, with 70% calling health affordability ‘a very big problem’. ” Julie Rovner. The complicated, political, expensive, seemingly eternal US healthcare debate explained. BMJ 2019;367:l5885 (Published 10 October 2019).

Now one could argue, and many do, that affordability and access to high-cost DMTs is a rich-world issue and has little relevance to middle- and low-income countries. However, you would be wrong. 

I recently had an email from a neurologist in Venezuela asking for advice about how to manage one of her patients with active MS when there were almost no available DMTs in her country. After email ping-pong, we settled on low-dose methotrexate as being the only immunosuppressive or immunomodulator available to her. There was no supply of azathioprine, leflunomide or parenteral cladribine. In other words, Venezuelan neurologists and doctors have to make do with what was is available. Surely treatment with an off-label medication is better than no treatment?

What about the Syrian refugee with MS living in a refugee camp in Lebanon? The email I received from her sister, brought tears to my eyes. I have lost contact with them, but after speaking to a friend and colleague in Beirut I was led to believe that the Lebanese government and healthcare system would help them. However, the subsequent email exchange I had with this poor patient’s sister implied that they would have to pay for the DMT privately. I, therefore, recommended off-label parenteral cladribine or leflunomide (pro-drug for teriflunomide).  I am not sure if this was ever taken up.

I could go on with case histories of this kind that I have been asked advice on either from the patients themselves, their families and friends, or their neurologists. A list of the countries that come to mind are Tunisia, Morroco, India, Pakistan, Chile, South Africa, Botswana, Tanzania, Egypt, Columbia, Brazil, Lithuania, Ukraine, Poland. Romania, Bulgaria, Serbia and Mexico.  

The problem in low- and medium-income countries is access to high-quality MS services and affordable DMTs is highly variable. This is a problem that is not going to be solved easily. One solution we recently explored, unsuccessfully, was the WHO essential medicines list or EML. The MSIF coordinated a multi-stakeholder application, which I co-chaired with Brenda Banwell, to get glatiramer acetate, fingolimod and ocrelizumab/rituximab onto the WHO Essential Medicined List. 

The WHO acknowledged our approach but noted that some relevant therapeutic options for MS were not included in the application (azathioprine and natalizumab) or were not given full consideration (rituximab). For the committee to recommend we look at azathioprine again, when they rejected azathioprine in 2015, was odd. To the best of my knowledge, nothing has changed in terms of new data since 2015 to change Azathioprines position as a potential off-label treatment for MS.

As for natalizumab, we did not add it to the EML application because it is still on patent, i.e. expensive, it needs to be given as a monthly infusion, which adds to its expense, and is associated with a high monitoring burden for PML. The latter would be very difficult in resource-poor environments. At the moment the PML JCV serology assay is controlled by Biogen so when natalizumab comes off-patent, and say natalizumab biosimilars emerge, what will happen to the international JCV serology monitoring system that currently exists? Would the WHO take it over from Biogen? Would it be distributed to national labs? Will resource-poor countries be able to incorporate this into their already over-stretched lab systems?

We went through all these factors in our deliberations and came to the conclusion that 6-monthly ocrelizumab, and rituximab if ocrelizumab is not available, would be a better alternative to natalizumab. Another factor was that ocrelizumab is now licensed to treat PPMS. If we excluded ocrelizumab from the list what message would this send out to PPMSers in the world? In addition, the monitoring requirements for anti-CD20 therapies are much less burdensome than natalizumab, although this may change as the long-term safety profile of anti-CD20 therapies changes with time.

So we can take the punch on the chin, get up and start working on the next application that will be due in 2021, or does the MS community need to do something else? 

The question I have asked myself is “Do we really expect people with MS living in resource-poor environments to wait another 2-3 years for the WHO to deliberate and possibly add MS DMTs to the EML and then for countries to enact changes?” If the drugs are high-cost, and they are likely to be high-cost, then poorer countries will just ignore the WHO EML. This doesn’t help people living with MS now.

I think it is time to act local and to start a grass-roots movement based on local MS champions to get MS diagnosed, managed, and care for properly in these resource-poor environments and to get off-label prescribing high-up on the agenda.

If you are from a resource-poor country the following are the nine options that we at Barts-MS have supported in the past. Not all of these options will be available, or appropriate for your county. For example, rituximab biosimilars are still relatively expensive and require quite a sophisticated infrastructure to deliver them, but this is not insurmountable as many countries, in even high-income countries, have adopted off-label rituximab treatment for MS with gusto. In comparison, in very low-income countries drugs such as leflunomide (class 1 evidence), subcutaneous cladribine (class 1/2 evidence) and possibly azathioprine and methotrexate may be more appropriate. 

  1. Azathioprine*
  2. Cladribine
  3. Cyclophosphamide*
  4. Fludarabine*
  5. Leflunomide
  6. Methotrexate*
  7. Mitoxantrone
  8. Rituximab*
  9. HSCT

*on the 19th WHO Model List of Essential Medicines (April 2015)

So what next? If you live and/or work in resource-poor environments and want to start a grassroots movement can you please register your interests using the google form below. We can then arrange a web-based meeting to formulate a strategy. I envisage us putting in place a simple diagnostic and management algorithms for resource-poor environments and writing detailed protocols for each of the drugs on our essential DMT list. This list is not exhaustive and we can add or even cull agents from this list if they are not appropriate for your country. 

We may feel the need to get your local patient organisations behind this initiative, but unfortunately, many receive a lot of funding from Pharma, are openly conflicted, and hence tend to be against off-label prescribing as a solution to the management of MS. This is why patient organisations tend to prefer and support access schemes.

I have been down the access route. A few years ago I tried with Biogen to implement such a scheme as a test case in Zambia, but we failed to get it off the ground. There were too many hurdles, politically and logistically and there was a question mark about its long-term sustainability. It would have been unethical to provide the free drug to a patient with MS for say 3 or 4 years for the scheme to be discontinued because the local healthcare system couldn’t take over the prescribing and monitoring of the drug sometime in the future. 

Another solution is a market solution, which the  Medicines Patent Pool (MPP), a United Nations-backed public health organisation is exploring. The MPP licenses patents of high-cost drugs from Pharma and then sublicenses them to generic companies to produce a generic equivalent for low- and middle-income countries. This model has worked very well for HIV and more recently for hepatitis C. I am working with the MPP at present on MS. Although the MPP does great work it will take time for this to happen and does not address the unmet need now. 

So if you want to join and help with a Grass Roots Off-Label DMT Initiative (GROLDI) please join by signing-up below. We were planning to start this almost 4 years ago but realised we couldn’t do this on our own. However, recent events, particularly around the WHO-EML debacle, have made it clear to me that we have let so many people living with MS down over the last 4 years that I feel guilty. However, it is not all bad news; in the interim, under the leadership of Prof K, we have developed our subcutaneous cladribine protocol that you can download and start using now (see below).

I have accepted several invitations over the next 12 months to speak about MS and its management in resource-poor countries. I will use these trips to raise off-label prescribing high-up on the agenda and to find as many GROLDI champions as possible.

Mao et al. Cladribine: Off-label disease modification for people with multiple sclerosis in resource-poor settings? Mult Scler J Exp Transl Clin. 2018 Jun 26;4(2):2055217318783767.

BACKGROUND:  A considerable number of people with multiple sclerosis (pwMS) live in low- and middle-income countries (LMIC), where lack of resource adversely affects access to effective disease-modifying treatment.

OBJECTIVE: The objective of this commentary is to propose a useful cost-effective disease-modifying treatment option for pwMS in LMIC with potential high efficacy and high convenience to the pwMS and treating physician.Viewpoint: We propose using generic 2-chloro-2′-deoxyadenosine (cladribine), a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II and III trials to be a highly effective disease-modifying treatment for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high-income economies where an oral preparation has recently been licensed by the European Medicines Agency.

CONCLUSION: Our viewpoint takes into account experience we have gathered over the past three years in the use of generic cladribine to treat pwMS. Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.

CoI: multiple

Oh, George!

The last time I saw George Ebers was at the European Charcot Foundation meeting in Baveno in 2017. I sat next to him and we had a long chat about MS and his new life in Canada. George had lost his anger and was very content with life. I learnt about all his projects on his farm; his windmill restoration project, his fence building, on being a carpenter and the summer water sports on his lake. I was slightly envious of his lot. I sincerely hope that I will be able to do something completely different, i.e. outside of MS when I retire.

George complimented me on my presentation at the meeting that was addressing social determinants of health and addressing poor access to DMTs in resource-poor environments (see below). He didn’t question whether or not these treatments were effective or not. I think he now realises that as new data and more effective DMTs have emerged that the natural history of MS has changed. In other words, DMTs are delaying the onset of the clinically apparent phase of SPMS and possibly preventing SPMS in some cases.

As for George’s personal attacks on his peers and his rant about the pharma industry, journals, universities and no doubt the regulators these need to be taken in the context of greater social changes. He may be right, but what has happened in MS is simply a representation of what has happened in greater society. Over the last 40 years, we have seen the rise of capitalism and the neoliberal philosophy and its impact on social mores. Everything has a price the debate is how much. Almost everyone is on the take. As the saying goes in America, “If You’re So Clever Why Aren’t You Rich”?

However, there is definitely a change in the tide. Rising inequality is ripping our society apart and is impacting massively on the provision of healthcare services and health outcomes. It is clear the neoliberalism, in its purest form has had its day, and socialism is on the rise again. I don’t think George has to worry too much; the medical profession and the MS Community will find its soul. It is our job to make it happen sooner than later. There are hundreds of thousands of people with MS living in resource-poor environments who need our help.

CoI: multiple

8 picograms

What does your DMT say on the tin? 

Some advice on what to say to your neurologist, or HCP, the next time you see them; “I now know why I am not expecting to get anything more out of this DMT than what it says on the tin”. 

Our current crop of DMTs can only do what they are designed for, i.e. stopping the focal inflammatory activity or new lesions from forming.  They are not designed to switch-off smouldering MS, restore neurological function or scrub the brain clean of the damaging B-cells and plasma cells. Based on this we need to readjust our treatment goals for DMTs. 

This is why one of my #ECTRIMS2019 highlights was as a post-hoc analysis that showed the best predictors of treatment response to natalizumab was (1) MRI activity (Gd-enhancing lesions and new T2 lesions),  (2) neurofilament levels and (3) relapses. All the other factors did not contribute anything to predicting treatment response. Why not? The answer lies in the biology of MS. Relapses, focal MRI activity and raised neurofilament levels are the triumvirate of inflammatory disease activity. 

Calabresi et al. Disease control beyond NEDA: The value of non-clinical disease activity measures to determine treatment response to natalizumab. ECTRIMS Online Library. Calabresi P. Sep 13, 2019; 278615; P1415

Based on the analyses in this poster our treatment goal with anti-inflammatory DMTs should be NEDA based on these three variables. All the other factors (EDSS, 9HPT, 25TW, BVL, PASAT) that we analysed added zero to the predictive model. The reason for this is that all these additional variables measure disability worsening or end-organ damage that is the consequence of the previous inflammatory activity. 

This is why we should not expect our DMTs to do more than what they are designed to do. If you want to prevent worsening from occurring you have to get your MS treated early and effectively and prevent the accrual of early damage. 

Another message from this analysis is that relapses were the weakest member of the triumvirate; MRI and NFL levels trumped relapses. The implications of this are that you need to have your disease activity monitored; yes, measured on a regular basis. If your neurologist suggests that you don’t need an MRI, or in the future peripheral blood NFL measurements, can I suggest you tell them they are wrong? 

Another implication of this study is potentially a cut-off for what is an acceptable peripheral blood neurofilament level, i.e. you need your NFL levels kept below 8pg/mL. This cut-off will separate the ‘men from the boys’; the only DMTs that are effective enough to reduce average levels consistently below this point are the high efficacy DMTs. 

One final message. Natalizumab continues to teach us about MS. It is the one drug that has transformed MS in so many ways and it has taught me more about MS than anything else. As I have said before there are two phases to the history of MS; the phase before natalizumab and the phase after natalizumab. 

CoI: multiple

Plea

I am at the European Academy of Neurology (EAN) congress in Oslo. It is quite clear that in the message of brain health and the holistic management of MS has moved center stage. Everyone is talking about #BrainHealth. 

The emphasis is now on early diagnosis, early effective treatments and maximising brain health as a treatment goal. To do this we need a full toolbox of treatments, new therapies and to manage MS holistically with a focus on the individual with MS.

In terms of getting these messages across Genzyme-Sanofi have commissioned an art installation on their EAN stand; a large brain ice sculpture that is gradually melting over course of the Congress. Embedded in the ice sculpture are items that are meaningful to MSers, for example, a wedding ring to symbolise relationships, a cocktail glass for social activities, a passport for travel, a teddy bear for children and family and various other work and other activity related items. As the ice sculpture melts these items will emerge to remind us why protecting the brain for the individual with MS is so important. On the plinth of the ice sculpture, it states ‘there is no MRI for quality of life’ to remind us that behind every MRI scan is a living person with hopes and aspirations. It is also suggesting that we need a person-focused, and not an MRI-focused, view of MS.

On the stand, there is a photographer who is taking pictures of Congress attendees alongside the ice brain sculpture holding various pledges in connection with brain health in MS. I took a pledge. 

My concern is that the regulators, in particular, the EMA and the FDA, don’t see it this way. The EMA is currently reviewing alemtuzumab’s risks and benefits, under an article 20 procedure, to see if it needs to change alemtuzumab’s license. At the moment it has put temporary handcuffs on alemtuzumab recommending that it is only used third-line, i.e. after MSers have failed at least two prior DMTs. The problem I have with this is that the average MSers spends about fours years on each tier of DMT, in addition to the many years lost in the asymptomatic and diagnostic phases of the disease. In other words, most MSers would have had MS for more than 10 years before they can access alemtuzumab 3rd-line. In 10 years many MSers would lose more than 10% of their brain volumes, become cognitively impaired, developed bladder dysfunction and have walking problems; not to mention the impact that undertreated MS has on their social and occupational functioning. Limiting alemtuzumab, our most effective DMT when it comes to ‘normalising’ brain volume loss in MS, to these sorts of patients is wrong and makes no sense.

So a plea to the EMA to think very carefully before taking away the option of using alemtuzumab early in the course of MS. 

My interpretation is that we have found ourselves in this article 20 position because the American neurologists are having to use alemtuzumab 3rd-line and later in the course of MS; i.e. in older patients with more comorbidities. This almost certainly explains some of the vascular complications of alemtuzumab. Alemtuzumab was never tested in this population and therefore we don’t really know its risks and benefits in an older more disabled population of MSers. 

I predict that if the EMA makes alemtuzumab a 3rd-line agent then we will start to see the same problems the Americans have seen with alemtuzumab. Forcing us to keep our most efficacious DMT for last flies in the face of conventional wisdom and current thinking about how to manage MS. 

Another issue I have is that the EMA and FDA think they need to protect MSers from risky therapies and irresponsible neurologists and HCPs. In other words, the regulators don’t trust MSers to be able to make their own decisions about the treatment they receive. In short, the EMA is saying to you that you can’t assess what risks you are prepared to accept and as a result, you can’t choose the most effective DMT 1st-line. I would argue that this is patronising and not in keeping with the wish to empower MSers.

I am sure that if we are forced to stop offering alemtuzumab first-line more of my patients, who can afford it, will seek HSCT and other risky treatments abroad. Is this what we want? I have learnt that all decisions have unintended consequences and the EMA may in fact put more patients at risk of off-label treatments as a result of the unintended consequences of their decision(s) and they will entrench inequalities, i.e. the rich will simply travel abroad to get treated and the poor will be left to fester.  

The EMA needs to understand what it is really like to be someone with MS, staring down a barrel playing Russian roulette on low efficacy DMTs, whilst their brains are being irreversibly shredded by MS. The brain is the most precious organ we have and we need to do everything we can protect it so we can have some resilience in old age. 

I, therefore, call upon you the MS community to prevent the EMA from handcuffing alemtuzumab and denying neurologists and their patients the option of using alemtuzumab, our most effective DMT, early on in the course of MS. We will all be worse off for not having the option of using alemtuzumab the way we use it now. 

CoI: multiple

Does your neurologist walk the talk?

Thanks to Daniel Kahneman and Amos Tversky behavioural psychology and behavioural economics have become very sexy. Kahneman & Tversky have spawned an industry of nudge theorists; people who devise ways of getting populations of people to do things that are good for them.

People with MS are no different from the general population when it comes to doing what they are told to do. We have major issues getting MSers to adhere to lifestyle interventions.

In this long-term follow-up study below MSers who report higher levels of health promotion activities and greater functional ability tend to experience lower levels of fatigue, pain and sleep disturbance and higher levels of cognitive abilities in subsequent years.

Is this the chicken or the egg; i.e. did MSers who were simply doing better more likely to engage in healthy activities compared to those doing less well? The only way to sort this out is to do a randomised controlled trial, which is virtually impossible for lifestyle interventions. What we need are ways of getting MSers to adopt a Brain Healthy lifestyle as part of their routine management plan. The following is the list of things to do:

  1. Smoking – if you are a smoker stop smoking.
  2. Exercise – try and do 5x 30 min aerobic sessions per week. If this is too hard and you are not too disabled you can try HIIT (high-intensity interval training) instead.
  3. Diet – eat a healthy diet. My philosophy is to eat ‘real-food’ that is culturally compatible with your family and friends. Avoid ‘fad diets’ and processed foods, particularly processed carbohydrates.
  4. Alcohol – don’t consume too much alcohol, it is neurotoxic even in relatively small amounts.
  5. Sleep – please make sure you don’t have a sleep disorder and make sure you get good quality sleep.
  6. Comorbidities – make sure you are screened for co-morbidities (hypertension, diabetes, impaired glucose tolerance, high cholesterol levels and dyslipidaemia) and get them treated.
  7. Infections – try and make sure you don’t get recurrent avoidable infections. The big one in MSers is UTIs.
  8. Concomitant medications – review your medications and try and reduce your anti-cholinergic burden as much as possible.
  9. Stress, depression and anxiety –  if you suffer from these get them treated and managed actively. If you haven’t tried mindfulness therapy it is worth giving it a go.
  10. Social capital – work on your social networks. Make sure you have time for friends and family.
  11. Menopause – if you are menopausal you may want to consider hormone replacement therapy. The evidence on whether HRT makes a difference to MS outcomes is weak but interesting enough to consider it if you are a woman.
  12. Wellness – this not only refers to your lifestyle but how it relates to the environment and your spirituality. Many argue you need to live in harmony with the environment to be truly well. I tend to agree. For example, my problem is my carbon footprint, which is impacting on my wellness.

If you have any suggestions to help other MSers with adhering to these principles, or you have any other to add to the list, please feel free to comment. Don’t be shy.

I also think you need to find yourself a neurologist and/or HCP who walks the talk. It is difficult to take a neurologist who is obese, smokes and clearly does not look after himself or herself, seriously when they tell you to improve your lifestyle. Or maybe I am wrong?

Becker et al.  Functional and health promotion predictors of PROMIS® scores in people with multiple sclerosis. Health Psychol. 2019 May;38(5):431-434.

OBJECTIVE: The purpose of this study was to examine the impact of perceived functional abilities and health promotion activities on subsequent symptom experience among those who have lived with multiple sclerosis (MS) for many years.

METHODS: This longitudinal mailed survey study examined Health Promoting Lifestyle Profile II (HPLP) scores and MOS SF 36 scores as predictors of PROMIS® Pain Interference, Pain Intensity, Fatigue, Sleep Disturbance, and Applied Cognition Abilities Scoresamong 260 adults with MS. The community-dwelling sample was initially recruited from the mailing list of the MS Society in a large southwestern state. Respondents were predominantly female, with an average age of 67 years. They had been diagnosed an average of 30 years. Forty per cent reported relapsing-remitting MS, and 41% have the more severe progressive form of the disease.

RESULTS: HPLP and SF 36 Role Physical, Role Emotional, and Social Function scores assessed in 2013 were moderately correlated (r > .30) with PROMIS® Fatigue and PROMIS® Cognitive Abilities scores measured in 2014 and were somewhat predictive of PROMIS® Pain and Sleep Disturbance scores (r > .20). These results were replicated in an analysis using data from Years 2016 and 2017.

CONCLUSIONS: Findings suggest that those who report higher levels of health promotion activities and greater functional ability may experience lower levels of fatigue, pain, and sleep disturbance and higher levels of cognitive abilities in the subsequent year.

A quick summary of Prof G’s Twitter activity (17-23 Sept 2018)

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Rachel Horne interviews ProfG to ascertain why the Department of Health and NICE have said no to ocrelizumab for treating people with PPMS. 


“We don’t care a toss about PPMSers, all we are worried about is rationing high-cost drugs and making sure we keep the system simple”, said a DoH spokesperson. “We cannot change the NHS accounting system to have two prices for the same drug”, he added

“Why?”, asked Prof G.

“Don’t you understand, how the NHS works?”, he replied. 




“I am too conflicted to take on this challenge. People without conflicts of interests will need to take the fight to the DoH and Government”, concludes ProfG. 


CoI: multiple

News: Prof G is fuming, why?

I am considering giving up working for the NHS. How can I face my patients with active PPMS and tell them we can’t treat their disease because the Department of Health/NHS won’t come to the table with a deal that involves differential pricing of ocrelizumab?


NICE has just said no to ocrelizumab for treating active PPMS on the NHS. Why? The problem is that the price of ocrelizumab has been set for RRMS and this is too expensive for the NHS; i.e. it is not cost-effective for the treatment of PPMS based on its efficacy in PPMS and the fact that ocrelizumab has to be compared to best supportive care (no treatment) for PPMS. In comparison, in RRMS ocrelizumab was compared to all the other DMTs. To address these issues I have been told that Roche agreed to lower the price for ocrelizumab for the PPMS indication so that it would be cost-effective. This would mean that ocrelizumab would need two prices on the NHS books; a more expensive price to treat RRMS and a cheaper price for PPMS. Apparently, the Department of Health is not prepared to go there. Why not? In short, they don’t give a toss about PPMSers. For the DoH and the NHS, this is just another can of worms they want to be kicked into the long grass. 

This decision creates inequity; those PPMSer lucky enough to be wealthy and have money will get ocrelizumab privately, those lucky enough to have been in clinical trials will get it from Roche as part of the extension study and those lucky enough to live in another EU country will be on it via their healthcare system. There is a chance the Scottish NHS may say yes, then we would end up with the situation that Scotthish PPMSers will have access to ocrelizumab, but not English PPMSers.  

What can we do about it? I think we need to launch a protest campaign that includes the following:
  1. An open petition; we will need 100,000 signatories to trigger a debate in the house of commons.
  2. A passive email/letter campaign; each and every one of you who cares about the treatment of PPMS needs to write to your MP to ask for an explanation.
  3. Street protests; we need to organise a protest and march on the DoH. Do you think they will respond to a 1,000s of MSers, their families and friends outside the DoH’s HQ in Whitehall? We could block Whitehall with wheelchair users. 
  4. We need to media behind the campaign; article after article and TV programmes about the issues raised by this perverse decision. We need the broader public to know about the issues. The implications of the ocrelizumab rejection go far beyond the treatment of a small group of PPMSers. 
If any of you want to help please contact me. I need ideas as well. 


If this decision was about breast cancer or HIV there would be national protests. The pink and red ribbon brigades would be out in force. Let’s make it an orange ribbon day. 


CoI: multiple; I sat on the steering committee for the ORATORIO (ocrelizumab in PPMS) trial and I am the principal investigator of the ORATORIO-HAND trial (ocrelizumab in advanced PPMS). I am conflicted up to my eyeballs, but I am also an advocate for my patients. They need me to stick my head above the parapet and fight for them, which is what I am going to do. 

Should Prof G do less blogging and more walking the talk?

Did you know that approximately 25% of people diagnosed with a radiologically-isolated syndrome (RIS), or asymptomatic MS, already cognitive impairment and smaller brains? This indicates that even before MS has been diagnosed the disease processes are already causing subclinical damage to brains of people destined to develop full-blown MS in the future. The reason you are not aware of this is that the brain has spare capacity, reserve or some redundancy to allows you to compensate for this early damage.


What about hand function (#ThinkHand)?

The study below takes these observations one step further and show that RISers also have deficits in hand function that they are not aware of. Using a super intelligent glove with sensors these researchers showed that finger-to-thumb opposition at maximum speed and paced two-handed movements were abnormal when compared to control or normal subjects. These abnormalities of hand function were related to the number of lesions on MRI or MS disease pathology. In all likelihood, these RISers would not be aware of these abnormalities, unless they were using their hands at a very high level, for example, professional musicians. Or then again they may simply ignore them as something else. Isn’t this disease scary?



What are the implications of this research for the MS community? Firstly, it argues for us changing the diagnostic criteria to allow us to diagnose MS earlier, in the RIS phase, so that we can offer these patients treatment. Some of the naysayers will say that by allowing MS to be diagnosed earlier we will misdiagnose too many people with MS who don’t have the disease. I am not sure if this is correct. If we developed new diagnostic criteria for asymptomatic MS and tested them properly in a prospective group of RISers and compared them to the gold standard, i.e. pathological diagnosed MS, we could assess the sensitivity and specificity of the criteria and their positive and negative predictive value to address this criticism.

Did you know that the various renditions of the current MS diagnostic criteria have never been validated against a pathological gold-standard? We can make some assumptions that they do okay based on the findings of one or two post-mortem studies, but we can’t be confident about their performance outside areas of high MS prevalence. Secondly, this study supports using hand function as an outcome measure in clinical trials, it seems that if we use sensitive tests of hand function we may be able to use these measures to assess DMTs that delay worsening or even improve hand function.



Two things that I could potentially do as a result of this paper. The first is to walk the talk and write a proposal for a new set of MS diagnostic criteria, which will include asymptomatic MS. The proposal will need to include a study to validate the new criteria against a pathological gold-standard and to test the criteria in high, intermediate and low prevalence areas. A pathological (biopsy or post-mortem) gold standard is required because none of the previous MS diagnostic criteria has ever been validated in this way. The reason for studying the performance of the new criteria in different MS prevalence areas is that the positive and negative predictive values of diagnostic criteria, i.e. their ability for them get the diagnose right depends on how common or rare MS is and how common or rare MS mimics are in the particular area. Against me walking the talk is that I am not sure if I have it in me to take on the MS community in terms of redefining MS.



The other action point that I will take away from this research is that we should try and include this glove as part of our ORATORIO-HAND and CHARIOT-MS studies. We could do small add-on studies to test the utility of the glove and compare it to the 9HPT and the ABILHAND PROM. Another proposal would be to use the glove to assess the impact that neuro-rehabilitation has on hand function. Because the glove has a much lower floor effect, i.e. it even detects abnormalities in asymptomatic MSers, it could potentially be a much better outcome measure in disease improvement trials.



Lot’s to do and not enough time to do it all. Maybe less talking (less blogging) and more walking 😉





BACKGROUND: An engineered glove measuring finger motor performance previously showed ability to discriminate early-stage multiple sclerosis (MS) patients from healthy controls (HC). Radiologically isolated syndrome (RIS) classifies asymptomatic subjects with brain MRI abnormalities suggestive of multiple sclerosis.



METHODS: We assessed 17 asymptomatic subjects with radiologically isolated syndrome (RIS) and 17 HC. They performed finger-to-thumb opposition sequences at their maximal velocity, metronome-paced bimanual movements and conventional and diffusion tensor MRI.



RESULTS: Subjects with RIS showed lower (p=0.005) maximal velocity and higher (p=0.006) bimanual coordination impairment than HC. In RIS, bimanual coordination correlated with T2-lesion volume, fractional anisotropy and radial diffusivity in the white matter.



CONCLUSIONS: These findings point out the relevance of fine hand measures as a robust marker of subclinical disability.



By: Gavin Giovannoni


CoI: none in relation to this post