Nicoletta: Will HSCT work for patients who have secondary progressive MS?
Dr David Rog, Consultant Neurologist: So that obviously is one of the key questions and there are, it’s a difficult question to answer definitively at the moment. So, one of the key general questions for us when we see somebody with MS is how much inflammation does that person have and how much evidence of neurodegeneration does that person have. So what does that mean? So in terms of inflammation we measure inflammation – swelling, if you like – clinically by acute attacks, relapses, and we also measure it to some degree with fairly rapid accumulation of disability, where for example, one relapse might merge into another. In terms of MRI, then we look at the number of white dots on scans, but we also look at something called ‘enhancing lesions’, which are areas where the barrier between the blood and the brain has been broken down and the dye, called gadolinium, which people are given, so usually squirted into the arm, then that dye can leach through those holes in the blood brain barrier. So that’s acute inflammation. Then neurodegeneration would be more along the lines of people where they have a gradual progressive non-recoverable disability over time, so rather than with a relapse where that may happen over days to weeks, then the accumulation of disability with neurodegeneration where nerve cells are lost in the brain and spinal cord, that would happen over months to years. You can measure degeneration to some degree using other MRI techniques, such as atrophy, which effectively is brain shrinkage, if you like, and reduction in spinal cord diameter, again, because of a loss of nerve cells. So, in an individual patient, there’s always that issue about does the patient have ongoing inflammation clinically and radiologically, and do they have evidence of neurodegeneration, so for example, when you look at the scans, do the scans looks as if the brain has shrunk to a degree, or the spinal cord, or indeed, clinically whether the patient’s had a gradual decline over time. And that’s not just in terms of walking ability, but that might also be in terms of upper limb function, for example. It might also be related to, for example, progressive problems with cognition, you know, with memory and concentration.
So, the reason I gave you such a big preamble is because all of the treatments that we currently have that are licensed in the UK – and I’m choosing my words carefully – work on inflammation. So they work on inflammation to reduce the number of new white dots, the number of new enhancing lesions, and the number of new relapses with a view to reducing short-term accumulation of disability from incomplete recovery from relapses. So you have a relapse, you go to the next level, you make some recovery but you don’t get back to where you were originally. And the importance of that is that at the moment we don’t have treatments which unequivocally reduce accumulation of disability, neurodegeneration. Now, you’ll be aware that there have been a couple of clinical trials recently in primary progressive and secondary progressive MS and those trials were set up to determine, to reduce disability in patients with progressive forms of MS and those studies were positive, and the question then is, does that translate into positive longer term outcomes.
You can think of HSCT as being two components. The first component is to give very powerful anti-inflammatory drugs. Some of the conditioning regimes, as they’re called, include a drug which is licensed in its own right to treat MS and others don’t. And so you get a very potent immunosuppressive effect, which is good for clearing inflammation, and then you then infuse the stem cells to recover the bone marrow and start producing the bone marrow cells again, and with a view then hopefully that you’ve switched off the inflammation. The issue is whether you have an effect on the degenerative aspects. So having gone through all of the risks of the stem cell transplant, are you going to have an effect on the neurodegeneration, the loss of nerve cells.
One of the – and admittedly it’s a retrospective study which looked at outcomes of stem cell transplants across multiple countries over a number of years – did seem to suggest that a proportion of patients with so-called progressive forms of MS may have had a benefit over five to six years post-transplant from the transplant in terms of accumulation of disability. The key point to this is to choose the patients very carefully and to avoid exposing patients unnecessarily to a treatment that may not work, but obviously on the other hand, to not miss an opportunity to treat patients where that condition may work… that procedure may work. [06:14] So, I think the short answer to the question is, there may be some patients who will benefit, we don’t know who those patients are yet, that’s why we need to do stem cell transplants as part of controlled clinical trials to understand which patients benefit and get as much information from those transplants and those patients as possible.
Nicoletta: So is it fair to say that this is very much a developing area and patients with secondary progressive MS may well be helped in the future?
Dr David Rog: I think it’s an exciting time for people with progressive forms of MS, period, at the moment, because I think there are all sorts of different treatment strategies which are currently under investigation as part of late stage clinical trials. We may start to think and label forms of MS in different ways, based upon the presence or absence of inflammation rather than more rigid thoughts of secondary progression, primary progression and so on. And also start to measure the impact of MS much more holistically than we did before. Most of our scales at the moment are still based on ability to walk and ability to walk certain distances and whether the person needs support or not. We’re now integrating much more outcomes in terms of upper limb function, cognition, vision and changes in those aspects and measuring people, as I said, much more holistically. So I think it is a developing field and I think that people with progressive forms of MS can be optimistic that there are going to be some breakthroughs in the relatively near future, but they may be in other areas. And I think one of the issues about clinical trials with stem cell transplants is that by necessity you need longer term follow-up. So the bare minimum now that an international group of MS and blood disorder haematology experts have suggested is five years, post-transplant, to draw even short-term conclusions as to the effectiveness of the treatment. We would obviously like the patients that undergo those procedures as part of clinical trials to be followed up for much longer.
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Dr David Rog is a consultant neurologist at the Salford Royal NHS Trust. He gained his MD in liverpool and he completed his neurological training between 2002 and 2006 on the North West rotation at Lancashire Teaching Hospitals Trust and Greater Manchester Neuroscience Centre. Dr Rog is the Chairman of the Clinical Research Steering Group at Salford Royal and the Nervous System Theme lead for Greater Manchester Comprehensive Local Research Network.