Tag: worsening MS

My ‘Smouldering MS Clinic’

I finished yesterday emotionally burnt-out; “broken and useless, no longer working or effective” or “kaput” as the Germans would say. I did an all-day clinic with my registrar off sick; it was hard and brutal. 

On my way home I wondered to myself if I should change the name of my MS clinic to the ‘Smouldering MS Clinic’. Virtually all of my patients had smouldering MS or as some of you would prefer me to call it PIRA (progression independent of relapses).

With our aggressive campaigns of treat-early-and-effectively, treat-2-target, zero-tolerance, NEDA (no evident disease activity) I think we have exposed the real MS, i.e. smouldering disease. Almost all my follow-up patients were NEDA yesterday and doing ‘well’. However, when I interrogated them almost all of them had subtle symptoms and signs of disease worsening. Worsening fatigue, cognitive slowing, reduced walking distance, dropped feet on exertion, nocturia, sexual dysfunction, numbness and clumsiness of the hand, subtle unsteadiness of gait, poor balance in the dark and when tired, increased leg spasms at night, reduced auditory discrimination, problems with night vision, etc. 

The new norm is smouldering MS or more likely the realisation that MS is smouldering MS. Our anti-inflammatory DMTs are doing what we say they should do, i.e. they are stopping focal inflammatory lesions and relapses, but are they getting to the core of the disease, ‘smouldering MS’? I suspect not.

I have argued several times before on this blog that focal inflammation is not MS and that the real disease is what is driving the immune system to produce the focal inflammatory events. I suspect that effective DMTs are simply converting relapsing-forms of MS into what we used to call primary progressive MS.

If you have MS this post will be very depressing, but as soon as the MS community faces up to the above the better. We would then start directing our limited resources to tackle smouldering MS. 

I would encourage the funders (government, charitable, private and pharma) to start to divert their R&D spend to addressing smouldering MS. What needs to be done? I would encourage out-of-the-box thinking and support alternative hypotheses of MS. We need deep phenotyping and biomarker studies. More trials on drugs targeting CNS B-cells and plasma cells, microglia inhibitors or activators (both need to be tested), drugs that target astrocyte and oligodendrocyte biology, antiviral trials and trials targeting ageing mechanisms. I would also include systems biology and the impact of diet, etc. on smouldering disease. We need a “Smouldering MS March of Dimes” event to raise the money to get on top of the real MS. 

I would like to thank you all for helping out with our grant naming survey. It is clear that from a scientific perspective PIRA (progression independent of relapses) won out. However, smouldering MS came a close second and most commentators prefer this name to describe PIRA to people with MS and their families, i.e. smouldering MS is a lay-term for PIRA. I, therefore, suggest we keep both names in the MS lexicon and use them interchangeably when discussing the real MS. 

Results of the blog survey.

Don’t be fooled into a false sense of security that because you are NEDA that your MS is under control. We clearly need to go beyond NEDA to tackle MS. 

CoI: multiple

Smouldering MS: does it exist?

… by taking an MRI-centric view of MS we may have lulled ourselves into a false sense of security. … an MRI worldview of MS has framed, and continues to frame, our perspective of MS and has created a cognitive bias.

I have recently posted on why you can have MS and have a normal MRI or a very low lesion load. I made the point that MS is a biological disease and not an MRIscopic disease, i.e. what you see on MRI is the tip of the tip of the iceberg and that most of MS pathology is hidden from view with conventional MRI. To capture this pathology we need to use unconventional imaging techniques or look at end-organ damage markers, i.e. whole brain, or preferably grey matter, volume loss or atrophy. Another option is serial CSF or possibly peripheral blood neurofilament levels. At least the end-organ damage markers will capture the end-result of MS pathology; the loss of neurones and axons.

In another recent blog post, I explained how someone with MS can still be deteriorating despite being NEDA (no evident disease activity). The NEDA here is referring to focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind this worsening despite being NEDA could be driven by the delayed neuroaxonal loss from previous damage, ongoing diffuse inflammation which has become independent of focal lesions (innate activation), ageing mechanisms or focal inflammatory lesions that are too small to be detected with our monitoring tools. Of all the processes listed here, the last one is the only one that is modifiable by our current DMTs. Therefore I think we should reserve the term smouldering MS to this process, i.e. one that is modifiable by current DMTs.

The really important question this raises is when you treat someone a DMT and they become NEDA how do you know they don’t have smouldering MS and would benefit from being escalated to a more effective DMT? One commentator asked specifically about cladribine.

‘If a patient was treated with cladribine and was rendered relapse and MRI activity free how can we be sure that this patient did not have smouldering MS?’

This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. We may then be able to answer this question. However, this won’t necessarily tell us if escalating people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab will result in them doing better than them simply waiting for their smouldering MS to become overtly active MS before making a switch in their treatment.

A point has been made that primary progressive MS (PPMS) is simply smouldering RRMS and that all we are doing with our DMTs is converting people with RRMS to PPMS and delaying the inevitable progressive phase of the disease.  I don’t buy this because a proportion of pwMS who have been treated early on with an immune reconstitution therapy or IRT in particular with alemtuzumab or HSCT appear to be in very longterm remission and may even be cured of their MS (please read my previous post on this topic). Some would argue, I included, that this group of patients has not been followed up for long enough to be sure they have been cured. I agree with you and this is why I have proposed doing a deep phenotyping study to assess whether or not these patients have any evidence of ongoing MS disease activity. This study would help define smouldering MS, by looking for its absence.

What this post is telling me is that by taking an MRI-centric view of MS we may have lulled ourselves into a false sense of security. In other words, an MRI worldview of MS has framed, and continues to frame, our perspective of MS and has created a cognitive bias. Dare I call it an MRIscopic bias?

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