Tag: smouldering MS

Beyond NEDA: protecting the end-organ or your brain

Barts-MS rose-tinted-odometer: zero-★’s 

It became clear to me at least 6 years ago that we need to go beyond NEDA (no evident disease activity) when treating MS and we have to focus on protecting the end-organ, i.e. normalising the brain volume loss that occurs in people with MS (pwMS). To do this you really need to diagnose and treat MS as effectively as possible early on. From a research perspective, this means a focus on smouldering MS and the mechanisms responsible for the smouldering disease or the ‘real MS’.

This study below is another study showing a link between brain atrophy and cognitive impairment and supports the therapeutic strategy above. The criticism that is alway levelled at the flipping-the-pyramid argument is that too many pwMS will end up on high-efficacy DMTs and then what? My response to this is that if the majority of pwMS end-up on high-efficacy DMTs eventually is a testament to fact that the majority of pwMS need high-efficacy DMTs and hence it is best to get them there as soon as possible (#TreatMSASAP). 

This #TreatMSASAP principle underpins our #AttackMS trial design of using natalizumab ASAP after presentation and is aping the management of stroke. 

Another argument about flipping the pyramid is safety, i.e. we are putting pwMS at risk of severe adverse events. Yes, we are, but we can derisk a lot of the anticipated adverse events, i.e. the known-knowns and the unknown-knowns (anticipated AEs based on the mode-of-action of DMTs). In any event it is not for the neurologist or HCP to make the call on risk; surely it is up to the person with the disease to make the call? 

The following is a recording of my presentation from ACTRIMS-ECTRIMS 2020 that discusses these issues. Please note the presentation is targeting HCPs, but most pwMS should understand it. 

Golan et al. The association between MRI brain volumes and computerized cognitive scores of people with multiple sclerosis. Brain Cogn 2020 Sep 11;145:105614. doi: 10.1016/j.bandc.2020.105614. Online ahead of print.

Background: Computerized cognitive assessment facilitates the incorporation of multi-domain cognitive monitoring into routine clinical care. The predictive validity of computerized cognitive assessment among people with multiple sclerosis (PwMS) has scarcely been investigated.

Objective: To explore the associations between brain volumes and cognitive scores from a computerized cognitive assessment battery (CAB, NeuroTrax) among PwMS.

Methods: PwMS were evaluated with the CAB and underwent brain MRI within 40 days. Cognitive assessment yielded age- and education-adjusted scores in 9 cognitive domains: memory, executive function, attention, information processing speed, visual-spatial, verbal function, motor skills, problem solving, and working memory. The global cognitive score (GCS) is the average of all domain scores. MRI brain and lesion volumes were assessed with icobrain ms, a fully automated tissue and lesion segmentation and quantification software.

Results: 91 PwMS were included [Age: 52.1 ± 11.7 years, 64 (70%) female, EDSS: 3.4 ± 2.0, 79 (87%) with a relapsing-remitting course]. Significant correlations were found between the GCS and whole brain, white matter, grey matter, thalamic, lateral ventricles, hippocampal and lesion volumes (Correlation coefficients: 0.46, 0.40, 0.25, 0.42, -0.36, 0.21, -0.3, respectively). Regression analysis revealed that lateral ventricles and thalamic volumes were the most consistent predictors of all cognitive domain scores.

Conclusion: Computerized cognitive scores were significantly associated with quantified MRI. These findings support the predictive validity of multi-domain computerized cognitive assessment for people with multiple sclerosis.

CoI: multiple Twitter: @gavinGiovannoni  Medium: @gavin_24211

Dodging COVID-19 to fly to Copenhagen

I arrived late last night in Copenhagen to give a keynote lecture at their Danish MS Society’s annual conference. Copenhagen airport was eerily quiet; COVID-19 is clearly having a dramatic effect on flying.

I was asked to give an overview of emerging treatment targets and outcomes in MS. My focus is going to be smouldering MS. I had to cut the section on prevention from my talk; prevention always seems to be short-changed. Maybe not for much longer?

You can download the slides from my DIY-slideshare site.

CoI: multiple

MS@theLimits 2020

Barts-MS rose-tinted-odometer ★★★

The Barts-MS team is heavily engaged with the 2020 MS@theLimits meeting at the Royal College of Physicians. Two things to note is the gender bias in favour of female speakers. This was in response to criticism about the male dominance at the last MS@theLimits meeting in 2018.

I am speaking today about some of my ideas around ‘the real MS’ or ‘smouldering MS’. I hope to challenge the current clinico-MRI worldview of MS and to get the MS community to think about MS as a biological disease.

I am hoping to make a compelling case for tackling smouldering MS with combination therapies and will be giving several examples in the presentation. Please note my talk includes Brain Health that will become increasingly important in the future.

CoI: multiple

Premature Ageing

One of my colleagues, with whom I was co-authoring an editorial on smouldering MS, demanded I delete the section on premature ageing being a factor driving delayed worsening of disability in people with MS (pwMS). I refused so we had to pull the editorial. The fact that he is quite old and doesn’t like the hypothesis of brain & cognitive reserve being neuroprotective explains his position. He criticised my theory for being ageist.

I am more convinced than ever that premature ageing is a big driver of delayed worsening in MS. 

A few years ago I was asked to see a patient from the North of England who has presented in her early 60’s with SPMS. She had had three spinal cord attacks in her late teens and had been in remission until her late 50’s when she noticed increasing weakness in her weaker leg with foot drop. In the intervening 40 years since her last attack, she had been relapse-free and fully functional apart from mild persistent weakness in her one leg that prevented her from running. 

As part of her work-up, I repeated her MRI of the brain and spinal cord and we performed a lumbar puncture. Her CSF showed local synthesis of oligoclonal IgG bands consistent with her diagnosis of MS and her neurofilament levels were low. Her MRI showed no active or new lesions and apart from some brain and spinal cord atrophy, there was nothing extraordinary about her imaging. When I saw her in outpatients I explained to her that she did not have active MS and that her diagnosis was now non-relapsing or inactive secondary progressive MS; I now refer to this as smouldering MS.

She then volunteered that she didn’t think her worsening was due to MS, but rather ageing. I couldn’t disagree with her and explained that her previous MS attacks had probably reduced the number of axons or nerve fibres in the motor pathway to her leg, which was now ageing as the surviving nerve fibres were gradually dying off she was seeing increasing weakness in the leg. This is called the premature ageing theory of progressive MS. Is there any proof for it? 

We know from other neurological diseases that ageing can cause delayed worsening. The most well know one is post-polio syndrome. This is when people who have had polio notice increasing weakness in previously affected muscles decades later as they start to age. In HIV we see age-related neurodegenerative diseases present decades earlier than one would expect. The theory being that HIV infection of the brain reduces reserve and triggers premature ageing mechanisms. Even with Alzheimer’s disease factors that are associated with reduced brain reserve result in an earlier age of onset of dementia. 

I suspect MS is not and exception and that ageing, or premature ageing, is part of the disease. The problem we have is that disease duration and disability are strongly correlated with ageing. This makes it difficult to unentangle ageing from disease duration. One way to look at this is to use biomarkers of ageing. As you get older the ends of your chromosomes or telomeres get shorter. Telomere length is used as a biomarker of physiological and not chronological ageing. By using telomere length instead of your age we may be able to unpick the impact of ageing on disease worsening. 

In this study below there was a clear gradient in terms of disability and telomere length. Shorter telomere length was associated with disability independent of chronological age, suggesting that biological ageing is contributing to neurological injury in MS. 

The implications of this are enormous and imply that we should be targeting age-related mechanisms as a therapeutic strategy in MS. This is why I also include ageing in my holistic management of MS talks and why focusing on all of those lifestyle issues and comorbidities is so important in MS. Interestingly, I made this a major theme in my talk at ACTRIMS last year when I had to predict what was going to happen in MS in 5 years time (slides below). 

So the time for biohacking (diet) and aggressive lifestyle interventions have arrived in the MS space. The million-dollar question is how to we get the MS community to buy into this as a therapeutic strategy. 

Krysko et al. Telomere Length Is Associated With Disability Progression in Multiple Sclerosis. Ann Neurol, 86 (5), 671-682 Nov 2019. 

Objective: To assess whether biological aging as measured by leukocyte telomere length (LTL) is associated with clinical disability and brain volume loss in multiple sclerosis (MS).

Methods: Adults with MS/clinically isolated syndrome in the University of California, San Francisco EPIC cohort study were included. LTL was measured on DNA samples by quantitative polymerase chain reaction and expressed as telomere to somatic DNA (T/S) ratio. Expanded Disability Status Scale (EDSS) and 3-dimensional T1-weighted brain magnetic resonance imaging were performed at baseline and follow-up. Associations of baseline LTL with cross-sectional and longitudinal outcomes were assessed using simple and mixed effects linear regression models. A subset (n = 46) had LTL measured over time, and we assessed the association of LTL change with EDSS change with mixed effects models.

Results: Included were 356 women and 160 men (mean age = 43 years, median disease duration = 6 years, median EDSS = 1.5 [range = 0-7], mean T/S ratio = 0.97 [standard deviation = 0.18]). In baseline analyses adjusted for age, disease duration, and sex, for every 0.2 lower LTL, EDSS was 0.27 higher (95% confidence interval [CI] = 0.13-0.42, p < 0.001) and brain volume was 7.4mm3 lower (95% CI = 0.10-14.7, p = 0.047). In longitudinal adjusted analyses, those with lower baseline LTL had higher EDSS and lower brain volumes over time. In adjusted analysis of the subset, LTL change was associated with EDSS change over 10 years; for every 0.2 LTL decrease, EDSS was 0.34 higher (95% CI = 0.08-0.61, p = 0.012).

Interpretation: Shorter telomere length was associated with disability independent of chronological age, suggesting that biological aging may contribute to neurological injury in MS. Targeting aging-related mechanisms is a potential therapeutic strategy against MS progression. ANN NEUROL 2019;86:671-682.

CoI: multiple

Will the real MS say hello?

The difference between religion, a belief system, and science, an experimental system, is that you can falsify the latter, but not the former. So when KoL (key opinion leaders) say they believe something they don’t really mean it literally. What they are really stating is a hypothesis that needs to be interrogated. 

So when I say that relapses and focal MRI activity are not MS, but are occurring in response to the cause of MS I am stating a hypothesis that needs to be falsified. Underpinning science are philosophical constructs on which to test hypotheses. One such construct, or system, is the Prentice criteria for defining a so-called surrogate endpoint in clinical medicine. 

According to the Prentice criteria for a surrogate endpoint to be considered as a substitute for the disease (or is the disease), it requires that (1) the baseline measurement of the endpoint is predictive of outcome, (2) changes in the measurement of the endpoint over time is predictive of outcome and (3) changes in the measurement of endpoint in response to a therapy is also predictive of outcome (Prentice, 1989). I would add a fourth criterion that (4) the measurement of the endpoint should predict outcome independent of treatment, i.e. it should behave in the same way whether a subject is on placebo or active treatment. 

When you apply these four criteria to relapses and/or focal MRI activity (new and/or enlarging T2 lesions or Gd-enhancing lesions) they don’t predict disability outcomes. This is why I state that the real MS is smouldering MS and the focal inflammatory activity is the immune system’s response to what is causing the disease. Suppressing the immune system’s response to the cause of MS may modify the course of MS, but it does not stop MS from smouldering away. 

The analogy I use is one put forward way back in 1994 to Ed Thompson my supervisor when I was a PhD student. I subsequently felt confident enough to present it at a European Charcot Foundation meeting in Lausanne under the title of ‘The yin and yang of inflammation in multiple sclerosis’. I subsequently published the hypothesis as a book chapter in 2004 (see below). 

It is interesting that my ideas, or hypotheses, about MS from 25 years ago haven’t changed very much. This is called cerebral stagnation. Maybe it is time to move on? 

The primary neurodegenerative hypothesis (1994): Although multiple sclerosis is a clinically heterogeneous disease it can be viewed as an inflammatory neurodegenerative disease with the clinical spectrum or phenotype determined by the presence or absence of focal inflammation, similar to that which occurs in infectious diseases, e.g. leprosy. The underlying neurodegenerative component of the disease may or may not be ongoing but it is modified by superimposed focal inflammatory events. The focal inflammation may be an appropriate host response directed at an unidentified aetiological agent or an inappropriate autoimmune response. These focal inflammatory events are responsible for clinical attacks and MRI disease activity. Although damaging in themselves the focal inflammation provides the biological substrate in the form of trophic and growth factors which promote repair and clinical recovery. Inhibiting the focal inflammatory events, e.g. with generalised immunosuppression, would reduce the relapse rate and MRI activity and remove the important trophic and growth factor support provided by the inflammatory infiltrates, but it may not affect the underlying primary neurodegenerative processes. This strategy would simply convert relapsing-remitting disease into non-relapsing progressive disease. There is evidence from infectious diseases that this phenotypic variability is linked to genetic susceptibility. 

Why use leprosy as an analogy? Leprosy is an infectious disease caused by a bacterium with a well-defined set of antigens that can be used to interrogate the adaptive immune systems responses to antigens. Depending on the immune response you get a different clinical picture. If you a brisk inflammatory response you get tuberculoid leprosy and it presents with very inflamed lesions. On the other side of the spectrum, you get lepromatous leprosy that is more of a smouldering disease with low-grade inflammation. Between these two extremes, you get a grey zone that is referred to as borderline subtypes. Interestingly people can convert from having lepromatous to tuberculoid leprosy if the shift their immune response to a so-called type 1 immune response that is driven by a cytokine called interferon-gamma.  

Figure from the American Society of Microbiology.

Primary progressive MS is lepromatous MS and relapsing-remitting MS is tuberculoid MS and the SPMS sits in the middle. Interestingly, gamma interferon may have the same effect in MS as it does in leprosy. We know that an early trial of gamma-interferon had to be aborted as it triggered relapses. I hypothesise that if you treat PPMS with gamma-interferon you would convert it to RRMS. Unfortunately, this is an experiment that is unlikely to occur but happens naturally when you get a viral infection. Interestingly, infections are a common trigger of relapses. These clinical observations are congruent with the ‘Leprosy Hypothesis of MS‘.

Do these observations support the ‘Field Hypothesis’ and the ‘Viral Hypothesis’ of MS?

Panitch et al. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 1987 Jul;37(7):1097-102.

We treated 18 clinically definite relapsing-remitting MS patients with recombinant gamma interferon in a pilot study designed to evaluate toxicity and dosage. Patients received low (1 microgram), intermediate (30 micrograms), or high (1,000 micrograms) doses of interferon by intravenous infusion twice a week for 4 weeks. Serum levels of gamma interferon were proportional to dose and no interferon was detected in CSF. Seven of the 18 patients had exacerbations during treatment, a significant increase compared with the prestudy exacerbation rate (p less than 0.01). Exacerbations occurred in all three dosage groups and were not precipitated by fever or other dose-dependent side effects. There were significant increases in circulating monocytes bearing class II (HLA-DR) surface antigen, in the proliferative responses of peripheral blood leukocytes, and in natural killer cell activity. These results show that systemic administration of gamma interferon has pronounced effects on cellular immunity in MS and on disease activity within the CNS, suggesting that the attacks induced during treatment were immunologically mediated. Gamma interferon is unsuitable for use as a therapeutic agent in MS. Agents that specifically inhibit gamma interferon production or counteract its effects on immune cells should be investigated as candidates for experimental therapy.

CoI: multiple

What’s in a name?

The Barts-MS team are in the final stages of preparing a UK MS Society grant application to tackle the ‘real MS’ that lives inside you. Our focus is on studying or defining what is smouldering MS. This is a massive unmet need and refers to what we currently call inactive SPMS and PPMS. This is likely to affect a lot of you; at present, you remain in the so-called untreated MS camp. Ocrelizumab and siponimod are only licensed or reimbursed for patients with active PPMS and active SPMS, respectively. We are hoping our grant will be able to identify and/or repurpose drugs to modify this stage of MS or using current terminology inactive worsening SP/PP MS. 

Our campaigns of treat-early-and-effectively, treat-2-target, zero-tolerance, NEDA (no evident disease activity) have exposed the real MS, i.e. smouldering disease. Many pwMS who are NEDA on DMTS and ‘doing well’ are not necessarily doing well. When we interrogate these sorts of patients they almost all have 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. Do you recognise yourself? 

The new norm is smouldering MS or more likely the realisation that the ‘real 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? I suspect not, or at least not in the majority of pwMS.

We 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, by exposing smouldering MS. The one hypothesis that is being explored at present is that if you treat MS early and effectively you may prevent the damage, innate immune activation and B-cell follicle formation that is thought to drive smouldering 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 could then start directing our limited resources to tackle smouldering MS.  This is the purpose of our grant application.

We are proposing to do deep phenotyping and biomarker studies and try and discover new treatments directed at 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 in the future drugs targeting ageing mechanisms. 

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) only just won out. However, as PIRA only refers to relapse-onset MS we prefer the name smouldering MS. We will keep you posted on how things turn out. We are interested to know what the reviewers will say about the terminology and the concept of smouldering 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

What’s in a name?

You will have noticed that a lot of discussion on this blog has recently been devoted to the topic of secondary progression or smouldering MS or whatever else you want to call it. At the moment there is no standard terminology for describing the scenario of someone with MS who is NEDA-2 (no relapses and no activity on MRI) who is getting worse. The getting worse could be overt, i.e. worsening EDSS, or a more subtle deterioration, which can only be detected using more sensitive outcome measures, or asymptomatic.

Can you let us know which term you prefer?

  1. Non-relapsing SPMS
  2. Inactive SPMS
  3. Hidden SPMS
  4. Hidden progression
  5. Silent progression
  6. Progression independent of relapses (PIRA)
  7. Smouldering MS
  8. Worsening MS
  9. Festering MS

I personally don’t like the use of secondary progression in the term. This excludes MSers with a primary progressive course who have the same pathology and entrenches the dogma that relapse-onset MS and PPMS are different and separate diseases.

Hidden is another term that I don’t like; what is hidden for some MSers may not be hidden for other MSers. For example, cognitive impairment only becomes a problem when you stress your brain. Some MSers may be in a life stage when cognitive stressors are rare and others may stress or test their cognitive abilities on a daily basis.

The term PIRA seems to have the lead at the moment and is being used more and more in abstracts and meetings. Worsening MS is a catch-all phrase that by definition can occur in the presence or absence of relapses and hence according to the Lublin classification you can have active-worsening and inactive-worsening MS. Please note that according to Lublin the worsening has to be overt, i.e. captured using an objective outcome measure.

I like smouldering MS because it creates a visual analogy of what is happening to the brain and spinal cord of MSers. In other words, the flames or relapses and focal MRI activity have been quelled, but the embers continue to burn. It also implies that the embers can fire-up and reignite the flames at any stage. I have a potential conflict in that the term ‘smouldering MS’ may have been used first on this blog and hence we have a vested interest in this term being selected. 

What do you think?

CoI: multiple

What is MS?

The more I read,  think and assimilate information the more I realise that the real pathology behind MS is not the new acute lesion or relapse, but what is going on behind the scenes in the so-called slowly expanding chronic MS lesion or SEL. 

MS is a smouldering disease. 

In an analysis of the ocrelizumab-PPMS or ORATORIO trial, it is clear that SELs already existed in the brains of PPMSers when they started the trial and best predicted their clinical course during the trial. In contrast, brain atrophy or brain volume loss and new lesion activity did not predict disability progression. What is nice about this analysis is that it is in a PPMS population with a very low relapse rate, which excludes relapses as a confounder. 

I am not that concerned about brain volume loss not predicting outcome in this population, because it is out of sync with clinical outcomes; i.e. brain volume loss today is caused by pathology 2-3 years ago and hence needs to be correlated with clinical outcomes in the past. 

What is important in this study is that new MRI activity in the form of new T2 lesions did not predict disability worsening. In other words, focal inflammation is not associated with clinical outcome. In comparison, SELs or smouldering MS predicted clinical outcome. Based on basic medical philosophical principles around the definition of surrogate markers it is clear that new T2 lesions can’t be the disease we call MS, but SELs can. 

It is clear to me 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 when using conventional MRI. This is why you still deteriorate despite being NEDA (with no evident new disease activity). The NEDA in this context is referring to the absence of focal MS inflammatory activity, i.e. relapse(s) and new or enlarging lesions on MRI. The biology behind the worsening despite being NEDA is 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 realistically modifiable by our current DMTs. 

The really important question this analysis raises is that when you treat someone with a DMT and they become NEDA how do you know they don’t have ongoing smouldering MS and hence would benefit from being escalated to a more effective DMT or should be included in add-on combination therapy trial? This is why we need to start using end-organ damage markers and more sensitive inflammatory markers to look for and define smouldering MS. Only then will we be able to start answering important questions. For example, does changing treatment in people with smouldering MS to more effective DMTs, for example, natalizumab, alemtuzumab or ocrelizumab result in them doing better? The ORATORIO analysis below would suggest the treatment effect in this situation is small. This is why we are going to need a new generation of add-on treatments that target CNS pathology, for example, hot microglia, antivirals (EBV and HERVs), CNS-penetrant anti-B-cell and plasma cell agents, neuroprotectives, etc. 

I have made the point 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, alemtuzumab or HSCT, appear to be in very longterm remission and may even be cured of their MS (see the 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 and this is why we need 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. 

The MRI-centric view of MS has lulled many of us into a false sense of security and has resulted in us classifying MS as a focal inflammatory autoimmune disease of the CNS. In reality, MS is a diffuse disease of the CNS and the focal inflammatory events are simply the immune response to what causes MS. This is why the field hypothesis of MS is so relevant and fundamentally challenges our worldview of MS. 

If we don’t change our worldview of MS and explore what is happening in the trenches alongside the one we currently have our heads buried in we will be letting down the next generation of MSers. 

Image from ‘when is a paradigm shift required‘.

Elliott et al. Chronic white matter lesion activity predicts clinical progression in primary progressive multiple sclerosis. BRAIN 2019: 142; 2787–2799. 

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/ evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1- weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum.

CoI: multiple

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