Monday, 21 July 2014

ClinicSpeak: smouldering MS

How big a problem is smouldering MS? #MSBlog #MSResearch #ClinicSpeak

"I had a meeting a week ago with a group of science policy makers and writers who want to develop a document to inform MS-related health policy. Someone in the meeting asked me ‘how big a problem is smouldering MS?’. This is a very good question. Although I can’t answer the question I hypothesise that it is a much bigger problem than we realise."



"The uninitiated may ask what is smouldering MS? Smouldering MS simply refers to MS that is clinically silent, but remains active pathologically. Think of smouldering MS as the shredder running on slow. Smouldering MS gradually uses up all your reserve capacity of the brain and spinal cord that you require to adapt to the damage caused by MS. Once this reserve capacity is gone progressive MS becomes clinically apparent. When this occurs it is too late to reverse the process and the moment too late to restore function through repair. “


“Can we monitor smouldering MS? Yes, we can by using biomarkers of disease activity that are more sensitive than our current clinical read-outs (relapses and disease progression or EDSS). MRI is one biomarker that is capable of finding disease activity that is not clinically apparent. However, routine clinical MRI is not good enough; we know it is missing most if not all of the disease activity in the gray matter and it is also missing a large quantity of disease activity in the white matter. This is why we need to find a way of incorporating brain atrophy measurements into clinical practice. At the moment the technique is too variable to be used on an individual MSer level, but it can be used to study populations of MSers. It is quite clear when you study populations of MSers that brain atrophy is a tractable problem in MS. The brain of the average MSer is shrinking at twice the rate of normal and it is now clear that brain atrophy is associated with poor clinical outcomes. Why would anyone want to be losing brain at a rate above normal? It is also becoming evident that only the highly active treatments have a consistent impact on brain atrophy; i.e. from fingolimod upwards. All the low and intermediate efficacy drugs don’t have an impact on brain atrophy at a population level. Herein lays the problem. These drugs all slow the shredder down and reduce clinical disease activity, but are they switching off the disease? These drugs may switch-off the shredder in some MSers but the majority of MSers on these drugs will have their disease converted to smouldering MS.”

“If I was a public health doctor and treating a population of MSers I would want them all to be on highly-effective DMTs. I would want the population to do well. This is why individualised care pathway makes a mockery of the science; if we are simply converting clinically active MS, into smouldering MS, with low efficacy DMTs we are doing the field, and many MSers, a disservice. What we should be doing is switching off the shredder in as many MSers as possible and improving the outcome for everyone. Any thoughts?”


CoI: multiple

14 comments:

  1. Not a lot of point having thoughts when you don't qualify for the second-line therapies.... Deeply depressing!

    ReplyDelete
  2. How common are problems with vision among MSers? Could optic nerves decline be such a bio-marker?

    ReplyDelete
  3. Prof G,

    I really think you are preaching to the converted. You should do a survey as follows:

    What do you want from an MS treatment: (i) shut down all (95%-100%) disease activity (including smouldering MS); (ii) shut down most (75%-95%) disease activity (little impact on smouldering MS); (iii) shut down some (50%-75%) disease activity (would still have some relapses, MRI activity etc.); or (iv) shut down a moderate amount (25%-50%) of disease activity (moderate impact on relapses, MRi activity etc.).

    I’d be surprised if many MSers didn’t vote for (i). Why would we want continuing damage to our brain / spinal cord?

    It would also be interesting to do the same survey for neuros i.e. what do you want to achieve by treating your patients – (i), (ii), (iii), or (iv)?

    It’s neuros who are the problem. Now that high efficacy treatments are available in the UK, there is no excuse. Neuros need to be honest with their newly diagnosed patients as to the real impact of this disease – 10, 15, 20 years down the line. Then be honest about what impact the various treatments are likely to achieve. Pushing the decision to the patient sounds great, but I want a strong steer from the expert.

    Some questions – would you still prescribe the first line injectables to a newly diagnosed patient? What impact will the drug being used for the Charcot Project have (may have) on smouldering MS? Given that it looks as if the inflammatory aspect of this disease can be addressed with highly effective treatments, should Team G be focusing on other aspects e.g. repair?

    ReplyDelete
  4. You are right Prof G.
    But like Anon 9:13:00 says, high effective treatments are actually considered dangerous, so second line.
    Will Anti CD-20 therapies, Ocrelizumab and Ofamatumab be considered enough safe to change this paradigm?
    Time will tell, I suppose....

    ReplyDelete
  5. After being told by a neurologist I'm doing something right , but he doesn't know what, made me think just get on with it. My RRMS lasted more than 25 years. I ate healthily, exercised, didn't smoke and cut down on alcohol, boring you may think, but I always enjoyed this lifestyle before I developed MS. Now it appears I've had smouldering cancers, appearing on scans as benign for years before they became more sinister. All four cancers were primaries and all removed with surgery. Never been on any treatment. Does anyone investigate these instances? I believe I'm unusual and very lucky. Is it time that the medical profession look outside their speciality?

    ReplyDelete
  6. I thought NICE had said that alemtuzumab could be given as a first line therapy. There is always a balancing act between risk/benefit and the MSer needs to make an informed choice about what they are willing to accept. For MSers diagnosed now, do they want to wait 5-10 years down the line for ocrelizumab/ofamatumab. Time is brain.

    ReplyDelete
    Replies
    1. Nice have indeed given a first line green light for alemtuumab....waiting for NHS England to agree to pay.

      Ocrelizumab/ofamatumab although probably without the autoimmunity risk of alemtuzumab will not be without their risks.....

      Delete
  7. "smoldering" MS may be just inflammatory processes that are not addressed.http://jem.rupress.org/content/early/2014/07/02/jem.20132477.abstract
    Monocyte derived macrophages initiate demyelination at nodes of Ranvier while resident migroglial macrophages function to clear debris. Since monocytes express alpha4beta1 integrins blocking egress with natalizumab may be beneficial. Hopefully, the clinical studies with natalizumab in progressive disease will be positive. I think low efficiency DMTs have seen their day.

    ReplyDelete
    Replies
    1. "I think low efficiency DMTs have seen their day".

      Biggest sellers in MS....Glaterimer acetate $4 billion/year Avonex at $3billion
      http://multiple-sclerosis-research.blogspot.co.uk/2014/02/ms-cash-cow-2013.html


      Delete
    2. Which drugs are best to achieve NEDA? Previous posts have stressed "hit hard hit early" strategy. Using a less effective therapy is like bringing a knife to a gun fight.

      Delete
  8. Do alemtuzumab and tecifdera count as high efficacy in your opinion? They are now first line. Is it too soon to tell?

    ReplyDelete
  9. What I continue to struggle with in MS treatment is why we don't go after it as aggressively as possible - starting with the weakest drug therapy and working our way up to stronger ones as our bodies fail on the others, makes no sense to me. If this were a cancer, wouldn't we also start with the agent that is most likely to kick it? Why don't we do that with MS? I understand the risk/benefit argument, but MSers should be given this option.

    ReplyDelete
    Replies
    1. Lemtrada is a first line therapy and is expected to be available in England and Wales from September 2014 . RRMSers can request it if they fit the criteria and hospitals and NHS Trusts should agree to that request. The criteria is two relapses in the previous two years. This is known as 'Active'. I am going to go on my first DMT which will be Tecfidera. If I don't get on with that I will request Lemtrada. I get the feeling some neurologists will be hesitant to prescribe Lemtrada as a MSers first DMT and save this for futher down the line in an MSers treatment. This may be because of the large lump sum cost in one go for Lemtrada. Also the risks and benefits need to be looked at by the MSer. My MS was severe relapse onset.

      Delete
  10. I think I have a type of smouldering MS, smouldering is a good description for what is happening.

    ReplyDelete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.