Managing expectations: can we cure MS?

When I was at the ANZAN meeting in Darwin I was shown the results of a recent survey of Australian people with MS regarding their research priorities. The number one unmet need was for researchers 'to find a cure for MS via repair and regeneration of cells'. This is easier said than done. I also have problems linking 'an MS cure' with the concepts of 'repair and regeneration'. In this post, I try and explain why.

Although a large part of this post is repetitive from past posts, sometimes it is helpful to repeat oneself. 
How will we know if we have cured MS?

The current thinking is that MS is an autoimmune disease of the central nervous system that is driven by MS lesions. We think the MS lesion is responsible for both acute (now) and delayed (in the future) neuronal loss. The permanent loss of neurological function (impairment or disability) is due to neuronal loss, which can be measured clinically (neurological examination and cognitive testing), electrically with evoked potentials, using MRI (brain atrophy or loss of brain volume) and/or biochemically using spinal fluid neurofilament levels. 

Acute Neuronal Loss (the Shredder or Scissors): Inflammation in the active MS lesion transects neuronal processes, or axons, acutely that results in loss of function. If the lesion is an eloquent site it causes a relapse. Loss of function is then restored by the surviving axons taking over the function of the lost axons, or other areas of the brain taking on new functions, we call this axonal and cortical plasticity, respectively. Recovery can only occur if there is sufficient reserve capacity. The accumulation of damage and ageing reduces reserve capacity, which explains why recovery from relapses tends to fail with more advanced disease and with advancing age. This is why it is important to treat MS early so as to protect reserve capacity.

Delayed Neuronal Loss (Slow Burn): Neuronal processes (axons) that survive being transected are compromised and never recover fully. They may remain demyelinated, or if they are remyelinated the myelin sheath never gets back to what it was in health. In addition, the so-called microenvironment within the chronic MS lesion is stressful to the axon. All these processes program the previously damaged axons to die off over time. This is why anti-inflammatory therapies that switch off the development of new focal MS lesions may not prevent the delayed neuronal loss that characterises progressive MS. Even if we were able to cure MS as an autoimmune disease we may not be able to stop, or prevent, progressive disease from occurring in the future as it may already be programmed to occur from previous damage that has accumulated in the past. 

In other words, progressive MS is like a ticking ‘time bomb’ in people who have acquire d a lot of damage from MS in the past.

Premature ageing: We also seem to forget that as we get older we lose brain; this is what we call age-related cognitive, or neuronal, decline. From the age of 35 our brains start to shrink and our neuronal systems start to fail. The manifestations of this are not that subtle; how often do you battle to find the right word, or remember an important fact, only to find that your memory has failed you. Similarly, your balance is just not as good as it once was; you realise that you can’t put on your trousers standing-up unsupported and you have to resort to sitting down, or holding onto to a piece of furniture, for balance. If we all lived long enough we would all dement from natural ageing. Evolution never designed our brains to function for as long as we are living today. 

What protects us from the ageing process is brain reserve; the more brain reserve we have the later we will present with our dementia. As MS reduces brain reserve we hypothesise that people with MS (pwMS) will notice age-related cognitive decline earlier than their peers in the general population. So even if we cure you of your MS you may still get a drop off in neuronal function earlier than expected that is simply due to ageing. This early drop-off in your neuronal function will probably be interpreted as MS-related, and not age-related decline.

The insights above highlight some of the reasons why we started the ‘Brain Health: Time is Brain’ campaign and why it is going to be so hard to prove that we have cured MS. However, if we don’t define what a cure looks like we won’t find it.

Defining a cure in MS: Based on what I have said above you may be cured of our MS, but still, have progressive disease. The difference between progressive disease, which is due to previous MS damage and that which is due to premature ageing is that the former should burn-out, i.e. after a period of time, your worsening disability should stop (flat-lining). In comparison, premature ageing is unlikely to stop. In comparison defining a cure in people who are young, with reserve capacity, who have been treated earlier would be easier. 

I hope you can see that this definition of a cure is incompatible with the terms 'repair' and 'regeneration'. The latter are separate processes that are independent of a cure. We clearly need repair and regeneration agents to treat pwMS who have accumulated a significant amount of damage to their nervous systems. In comparison, in pwMS who have been cured of their MS and have not had any significant damage will not need to undergo treatments to repair and/or regenerate their nervous systems. 

Importantly, a cure can only really occur in relation to IRTs (immune reconstitution therapies; e.g. alemtuzumab, cladribine & HSCT), i.e. treatments that are given as short courses that address the underlying ‘cause’ of MS. Maintenance treatments that need to be given continuously can’t cure MS, because when you stop the treatment MS disease activity tends to return. 

Let’s say we have treated a group of pwMS early in the course of their disease with an IRT and they have gone into long-term remission with no evident disease activity (NEDA). How long should we wait before declaring a victory over their MS; 15, 20 or 25 years? In the past, I have proposed defining a cure as NEDA at 15 years post-treatment as a starting point. Why 15 years? This is the most commonly accepted time-point used for defining benign MS and therefore it is a standard end-point that should be accepted by the wider community; this may be wishful thinking many in the field are saying that we can’t cure MS, therefore, we should not be having this discussion. 

In addition, the average time to the onset of secondary progressive MS is ~14-15 years so one would expect to see a significant proportion of people manifesting with SPMS in this timeframe. If we had got the autoimmune hypothesis wrong and the IRTs don't work then I would estimate at least a third should have SPMS if our hypothesis is wrong. The problem with 15 years is that it is too long to wait; some pwMS want to know 'now' if an IRT offers a cure, therefore we need data to convince the naysayers to support the ‘cure hypothesis’. Hopefully, convincing data will change their minds and get them to at least offer IRTs to more of their patients.

Deep phenotyping: We are therefore proposing a deep phenotyping project to look at pwMS who are NEDA-2 post-IRT to see if we can find any evidence of ongoing inflammatory, or neurodegenerative, MS disease activity. We propose interrogating them in detail and comparing them to a similar cohort of pwMS who are being treated with maintenance DMTs. Deep phenotyping is simply a term to interrogate brain and spinal cord integrity in a lot of anatomical and functional detail to see if an IRT has stopped ongoing damage and protected reserve capacity. At the same time, we plan to look for evidence of ongoing inflammation in the spinal fluid. 

One of the problems I am finding with pwMS who have had an IRT and are now in long-term remission is that they forget that they have MS and simply get on with their lives. They disengage from the MS community; they stop reading MS blogs and stop coming to MS research meetings. In short, these people act as if their MS has gone away. They act differently and start to believe they have been cured of MS. Therefore, I see the biggest problem of doing this study will be difficult recruiting subjects; who will want to take a day off work and come into a research unit to be interrogated in detail? 

Deep phenotyping will include quantitative neurological examinations, multiple questionnaires (PROMS), multidimensional MRI scans, a full set of sensory evoked potentials and central motor conduction times, detailed neuropsychological testing, a large number of blood tests and a lumbar puncture. The latter is to make sure spinal neurofilament levels are normal and to see if the oligoclonal bands (antibodies) have disappeared. I am hoping they will have disappeared. If we can show that the majority of the subjects in an IRT cohort has stabilised with no evidence of progressive disease compared to the maintenance DMT group we may convince the field of the value of IRTs. 

What do you think? Will you be convinced?  


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