Natalizumab is unable to stop the shredder

N
Is the treatment aim of ‘maximising the lifelong brain health of every person with MS’ realistic?


In this study below pwMS stable on natalizumab (one of our most effective DMTs) are still losing brain volume way and above what you would expect for age. Is this premature ageing or is this the slowly expanding chronically active lesion shredding the brain? 


We know that over many years brain volume loss, or brain atrophy, correlates with poor outcome; i.e. cognitive impairment and physical disability. What this study indicates that we clearly need something additional to an anti-inflammatory to treat MS and prevent end-organ damage. What it is telling me is that we are going to need additional add-on treatments to really make a difference for pwMS. What these add-on treatments turn out to be is speculative. At the moment we talk about add-on neuroprotective, remyelinating and neurorestorative therapies when what we may need are antivirals to suppress EBV and HERVs that are driving the slow burn and gradual loss of brain and spinal cord. 

It is clear that unless we normalise brain volume loss in pwMS they will not be able to age normally and nor will be able to ‘maximise‘ their brain health. 

One interpretation of this data is that the focal inflammatory lesion, and relapses, are not MS, but are simply the body’s response to what is really causing the disease. We need to ask the question what is MS and what is driving this accelerated brain volume loss in the absence of focal inflammation? 

Natalizumab continues to make me think about MS and continues to challenge the scientific dogma that MS is simply an organ-specific autoimmune disease. MS is clearly not an organ-specific autoimmune disease; it is a whole lot more complex than that. 


For more information please read my recent blog post ‘explaining why you get worse despite being NEDA‘. 


Koskimäki et al. Gray matter atrophy in multiple sclerosis despite clinical and lesion stability during natalizumab treatment. PLoS One. 2018 Dec 21;13(12):e0209326.

BACKGROUND: Brain volume loss is an important surrogate marker for assessing disability in MS; however, the contribution of gray and white matter to the whole brain volume loss needs further examination in the context of specific MS treatment.


OBJECTIVES:  To examine whole and segmented gray, white, thalamic, and corpus callosum volume loss in stable patients receiving natalizumab for 2-5 years.

METHODS: This was a retrospective study of 20 patients undergoing treatment with natalizumab for 24-68 months. Whole brain volume loss was determined with SIENA. Gray and white matter segmentation was done using FAST. Thalamic and corpus callosum volumes were determined using Freesurfer. T1 relaxation values of chronic hypointense lesions (black holes) were determined using a quantitative, in-house developed method to assess lesion evolution.

RESULTS: Over a mean of 36.6 months, median percent brain volume change (PBVC) was -2.0% (IQR 0.99-2.99). There was decline in gray (p = 0.001) but not white matter (p = 0.6), and thalamic (p = 0.01) but not corpus callosum volume (p = 0.09). Gray matter loss correlated with PBVC (Spearman’s r = 0.64, p = 0.003) but not white matter (Spearman’s r = 0.42, p = 0.07). Age significantly influenced whole brain volume loss (p = 0.010, multivariate regression), but disease duration and baseline T2 lesion volume did not. There was no change in T1 relaxation values of lesions or T2 lesion volume over time. All patients remained clinically stable.

CONCLUSIONS: These results demonstrate that brain volume loss in MS is primarily driven by gray matter changes and may be independent of clinically effective treatment.

CoI: multiple

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

22 comments

  • Okay. But why do. Brain atrophy normalise with Alemtuzumab? What does this drug do Natlizumab or Ocrelizumab doesn't do that stops Brain atrophy?

    • Re: "But why do. Brain atrophy normalise with Alemtuzumab?"

      Alemtuzumab and HSCT (immune system rebooters) and not ocrelizumab and cladribine (B-cell depleters). Herein lies the rub.

      I have hypothesised based on this this observation that we probably need both T and B cell depletion to affect both the afferent (messenger) and efferent (effector) limbs of the immune system. B-cell depleters seem to predominantly affect the afferent systems only.

      This is why B-cell depletion therapies are not the holy grail of MS treatment. We need to tread carefully so as not to create the next generation of under-treated pwMS.

      More than ever I want to tackle the deep phenotyping of alemtuzumab treated patients who have been NEDA for 10+ years. Are they cured?

    • Thanks Prof G. Reading following comments. I don't think this article is depressing. Any improvement in understanding MS. Is a step towards cure. The fact you see CDI in Alemtuzumab at level like no other drug used. Hints it's doing its job. Let's hope it is a cure. Thanks again rof g for efforts. Merry Christmas and Happy New year to all your team.

    • How can we make Alem. a first line -first choice drug for MS? How can we make it safer but also make doctors think the future of the patient and be more drastic?

  • This post is very disconcerting. I thought MS was simply an autoimmune disease and that if you switched off the inflammation you stopped the damage from accruing. This post suggest something much sinister is going on.

    • Sorry to disappoint you. I have never thought that focal inflammatory lesions or relapses are the disease. We now have lots of evidence to the contrary. Focal inflammation is simply a response to what is causing MS.

  • Cheery Christmas post from Prof G.

    "What it is telling me is that we are going to need additional add-on treatments to really make a difference for pwMS. What these add-on treatments turn out to be is speculative." They key point is that there are no add-on treatments ready to prescribe, nor any on the horizon. We've been going round this buoy for the last 20 years.

    In reality, the so called experts and research teams don't know that much about this disease (inside or outside, inflammatory or neurodegenerative, virus or auto-immune……). The drugs developed so far are:

    injectibles – modest efficacy at best;
    fingolimod – high risks damaging rebound when you come off them;
    nataluzimab – risk of PML and limited effect on brain volume loss;
    alemtuzumab – risk of many secondary autoimmunites.

    The goods news is that there are plenty of MS websites, blogs.. and hue numbers of research teams and international conferences / workshops. After 60 years of research into this disease, I think the progress has been limited at best. It's still very much an academic disease. While there are treatments for the inflammatory aspect of MS, patients are stuck between a rock and a hard place. There are still no effective (or even partially effective treatments for progressive MS). A patient diagnosed with PPMS today is no better off than a patient diagnosed 30 years ago. Perhaps 2019 will be the year when a real breakthrough is made. 2018 strikes me as a year when MS research has been treading water.

  • The study examined patients in the first 24-68 months of treatment

    Was there any difference in rate of brain volume loss between the first year, second year, etc? Did the loss speed up or slow down?

    Reason I'm asking – how certain are we that brain volume loss will continue?
    Any chance that it may slow down to normal rates?
    On the same lines as your length-dependant theory

  • This is scary. What would the next steps be now to ensure those on Natalizumab, like myself, are on the add-on treatment. I'm guessing not for a very long time as you say it's still speculative right now?

  • This is a real paradigm shift. So how would you define MS now? A quick refresher of the different types of lesions would help in this context. It would seem that no new lesions is no longer enough on the radiology report. I have never seen a reference to brain volume on mine.

  • Another possible explanation…HSCT and Lemtrada only temporarily eliminate immune components from CNS. Tysabri regimen chronically deprives CNS of immune components. Perhaps these components are responsible for performing regular CNS maintenance and w Tysabri are unable to do so. Maybe Tysabri itself causes the volume loss.

  • "Focal inflammation is simply a response to what is causing MS."

    You could stress that earlier in the blog. I think most of your readers will be surprised. Still, I'm happy you have that view.

    "we probably need both T and B cell depletion"
    How safe can that be? T or B cell depletion alone poses great risk already.

  • I also found this post very disconcerting. I have been doing very well on tysabri without any new lesions or anyting clinically the last 3 years. Typically, the MRI scans do not report the brain volume change. How could I confirm that I am really doing well?

  • "VV you need to read the long-term follow-up data on the natalizumab treated pwMS. They do extraordinary well. Not sure they would if they had ongoing damage."

    http://multiple-sclerosis-research.blogspot.com/2018/12/is-it-time-to-slay-gamblers-dilemma.html

    In this study below pwMS stable on natalizumab (one of our most effective DMTs) are still losing brain volume way and above what you would expect for age

    Time to chance view?

    What to do?

    Obrigado

  • To put this into prospective, the people in this study were on average 9 years into MS, compared to 2 years in the alemtuzumab trial and we know that in many cases oligoclonal bands are not removed and so disease activity is ongoing behind the blood brain barrier. This is bound to be causing damage

    Alemtuzumab does not stop the sredder if it is started late (Coles et al. 2006), it doesn't affect the oligoclonal bands if started late.

    • In assessing the effects of a particular drug on brain atrophy, it should be noted that volume
      loss is a result of several dynamic processes, a balance between destructive and reparative
      mechanisms with interaction among neurons, axons, oligodendrocytes, astrocytes, microglia,
      endothelial cells, inflammatory cells, and water distribution. How a particular drug affects a
      tissue compartment can vary depending on what substrate is most affected by that DMT. Pseudoatrophy
      is a good example of how some DMTs can initially affect water distribution. Alternately,
      fingolimod has prominent effects on astrocytes, since they express S1P1 receptors.[57]
      However, over a longer period of observation time, the interactions among various substrates
      involved in injury or repair probably reach homeostasis and the net effect is plateau, progression,
      or continual repair. Furthermore, injury may not have its full effects at the time of occurrence.
      Prior bouts of inflammation may produce substantial injury, which may not be fully
      realized until months later as various cells degenerate at different rates, debris is removed, and scarring sets in. Hence, the effects of a particular drug on atrophy may not be fully attributed
      to that agent due to this carry over effect from prior injury. In terms of MRI analysis of brain
      volume loss, it is best to set the baseline scan 6–9 months after a relapse, contrast activity, and
      start of therapy.
      https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209326

  • "Alemtuzumab does not stop the sredder if it is st/arted late (Coles et al. 2006), it doesn't affect the oligoclonal bands if started late."

    If started early it can remove oligoclonal bands..?

  • A few weeks without reading the blog and when I come back I come across very intriguing publications.

    There are 04 questions that I always ask myself since I was diagnosed with MS (almost 5 years ago) and continue, at least for me, still unanswered:

    – how could one be cured of MS if the oligoclonal bands still remain in CSF without being eliminated ?;

    – why even in the face of more aggressive therapies does the disease continue to progress?

    – why are more women affected than men?

    – What does MS in children want to tell us?

    2019 could give us more answers than questions…

By Prof G

Translate

Categories

Recent Posts

Recent Comments

Archives