Will the Real MS Stand Up-Rebound death indicates peripheral immunity entering the CNS is the culprit

Larochelle C et al. Immunological and pathological characterization of fatal rebound MS activity following natalizumab withdrawal. Mult Scler. 2016. pii: 1352458516641775. [Epub ahead of print]

BACKGROUND: Severe rebound multiple sclerosis (MS) activity is a life-threatening complication of natalizumab (NTZ) withdrawal, for which pathogenesis and treatment are still unclear. We report the immunological and pathological characterization of a case of central nervous system (CNS) inflammatory demyelination after NTZ discontinuation.
OBJECTIVE: To understand the pathophysiology of this neuroinflammatory condition.
METHODS: Antemortem blood and cerebrospinal fluid (CSF) analysis was compared with postmortem pathological studies, as well as with novel flow cytometry characterization of immune cells isolated from the CNS parenchyma.
RESULTS: Pathological analysis of the brain revealed the presence of innumerable active inflammatory demyelinating lesions typical of immunopathological pattern II. Monocytes/macrophages and B cells were enriched in the CNS parenchyma compared to the CSF. Numerous plasma cells were present in the lesions, but CD8 T lymphocytes were predominant in the parenchyma, as opposed to CD4 in the CSF. CNS-infiltrating lymphocytes expressed high levels of adhesion molecules, granzyme B (GzB), interferon-gamma (IFN-γ), and interleukin (IL)-17.
CONCLUSIONS: Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS inflammation.

Apologies as a half-cocked,unfinished post that was launched by mistake last night at 02.30am…..It was full of spelling mistakes as does the figure below. Copaxone is obviously one of my dyslexia (as pointed out by ProfG) words……it is spelt glatiramer acetate apparently…“comming” is another and “soory” is another, as was “Micheal”, I eventually learnt to spell it Michael maybe glaterimer will get same treatment

“Will the real MS stand up” was something that scientists have been asking…open your eyes is what we have been saying.

ProfG has been arguing that rebound post natalizumab is going to be one good way to find out what is driving relapsing MS. In this study one person actually died from the relapse associated with stopping natalizumab treatment. 

The BartsMS team have been very clear how to switch from natalizumab to something different as it seems some neuros are not aware of the risk of rebound activity. One wonders whether this would have happened it the switch was to a more effective alternative

This is actual the MRI. 

Can you see the damage of  about 4 years of MS in the top row and new lesions in the next two rows some are arrowed.

When the pathology was done it was evident that typical MS lesions were present. Yes the ones full of T cells with a few B cells and antibody plasma cells thrown in. This looks just like EAE.

There were more CD8…virus destroying cells in the brain. So relapse is associated with peripheral immune cells entering the CNS and doing damage. This is the real MS that drives relapsing MS. However the lesions could have been up to 3 months old and lesion C above does not look that active (I need a close up).

However, this is the pathologists at work…remember they missed Grey Lesions for years. Have a look..you are not a pathologist but can you see grey matter lesions. (Wonder if its the same ones saying EAE is rubbish:-). You don’t need a microscope. But is dogma is MS is a white matter disease which it was when I came into the field. Is it surprising that animals models don’t always look like MS 

What we should ask is what was the rest of the CNS like, was it full of demyelinated lesions or was it full of remyelination?

Presumably this person has been doing well on natalizumab and there would be ample time to repair old lesions. If repair is the default there should be evidence of remyelination all over the CNS.
Was this absent or missed because they are not looking for repair only damage. If this is the cases then aiming to get repair strategies is of limited value..you just need to treat early and effectively and the body does the rest.

If there were chronic demyelinated lesions then there is a real repair failure and we need repair strategies. There is not mention of the chronic lesions the lateral ventricles should be full of old lesions based on the MRI. Is figure C light blue (remyelination?) or no blue demyelinated? 

Maybe ProfG /DrK can ask them to have a look?

I have heard about one case of post-natalizumab death, where the CNS was full of remyelination.

So the authors give a stock answer that there are T and B cells there so we need T and B cell therapies and there are plasma cells there…..so generic CLADRIBINE in the only current answer:-). However yesterday we had ProfG posting that anti-B therapies were working better at this than fingolimod which is partially anti-T & B. 

In the text the IL-17 was in the CD8 cells, and so the bit in the abstract probably has nothing to do with Th17.

Most of what is in the CNS is probably irrelevant and is dragged in there because they have homing molecules; The trick is to sort the wheat from the chaff, but I think based on pathology and response to treatment the MS relating to relapsing disease stood up a long time ago.

The study demonstrates that white blood cells can be extracted from the CNS, and therefore we can get at their antigen receptors. Which is a step closer to finding the target. There were plenty of T cells in the lesions with a CD4 bias in the blood and CSF but half the numbers of CD8 in the CNS proper.

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  • So, what is the answer? Continue on with Tysabri and risk PML, or discontinue and have rebound? I'm needing to come off Tysabri, and I'm scared to death.

    • You will note they switch to glatiramer acetate if this works it takes months to work they had the rebound within a couple of months so they switched to a low efficacy drug, maybe because they were risk averse

    • Hey there, I just recently went from Tysabri to rituximab, after becoming JCV positive. I'm doing great — no relapses and clean MRI 6 months in. The data suggests rituximab is the best at preventing the rebound effect, and it is probably as effective as Tysabri without the PML risk. Other high efficacy drugs are better than glatiramer acetate for avoiding rebound but rituximab appears to be the best. The downside is that it can be hard to get insurance (or the NHS, it sounds like) to pay for it since it is off-label.
      I'd recommend at least asking your doctor about rituximab. There's some data on other (licensed) drug options here: http://www.neurology.org/content/84/14_Supplement/P3.288. And a recent post on this blog here: http://multiple-sclerosis-research.blogspot.com/2016/04/researchspeak-rituxumab-vs-fingolimod.html.

    • Unknown 3:37
      Firstly what is your JC virus status?
      Secondly, there are options tp prevent rebound, if you've visited the blog before you'll be aware that we are big fans of Cladribine here.

  • Tysabri's an excellent way to cook what's left of your brain. Astonishing to me this got re-licensed.

  • 2 questions (probably stupid):
    1. How do they know this was not PML changes related to JCV post Tysabri?
    2. How hard is it for the immuno-pathologist to identify the antigen and APC cell that the CD8 cells are so violent against in this case?

  • Makes me think If I were to go to on natalizumab I would have to plan for my future. Have an idea of the safest drug to change to post natalizumab and discuss this with my neurologist before starting natalizumab. I'm JCV+.

    I am at a decision point currently as I don't think DMF is working out for me.

    • Natalizumab hopefully buys two years disease free but there is the consequence risk. What will come around und in two years

  • So how is alemtuzumab so effective? You do deplete T & B, but they come back in time, B cells really fast… and still 5 years follow up results were great… Why their brains are not full of CD8 virus destroying cells?

    • Alemtuzumab is so effective because it's effectively Roundup for the immune system. Yes the B cells do come back really fast, too fast and at a level higher than baseline pre-treatment, which would explain the problems associated with B cell driven autoimmunity seen in so many pwMS treated with alemtuzumab. The T cells never seen to return to baseline levels, which is intriguing.
      We can do better.

    • So this inmune system after alemtuzumab doesn't react against EBV infected cells? I know this is not the case for 70% of the patients that will continue to experience relapses or MRI activity… I still think this points towards autoimmunity and not a viral infection. I really hope EBV is the main culprit, we would have a chance to prevent MS with a vaccine, but to me it just doesn't fit. I'm not a neuro, jus a GP so maybe you can give me some insight of how EBV hypothesis fit with alemtuzumab trials and real world results.

    • ProfG is more of an EBV fan than me he may see it as a target I see it more as a trigger. NEDA is over 40% on two courses not 30% . once you have alemtuzumab you don't re vaccinate so preexisting immunity is still there but can it be still regulated that is how induction may work but until you follow the fate of antigen specific cells it is difficult to know

  • Because there is this difference between the amount of CD4 and CD8 cells in the CFS and the CSN?

    And against what they are "fighting"?

    Fingolimod is an anti T cells and B. Under this assumption it would act as well as the Natalizumab …

    One hour I think is MS essentially autoimmune, other think it has anything but really of going autoimmunity …

    • Fingolimod does not hit all T cells their are subsets untouched. Same is true for natalizumab but that subsets unlikely to be causing ms

    • MD tganks, more new information to learn.

      I thought the Fingo suppressed all that is subpopulation of T cells. Then starting on the same principle was discovered which subpopulation of T cells are affected by Natalizumab specifically related relapses of the disease could have the answers to many questions…

    • MD thanks, more new information to learn.

      I thought the Fingo suppressed all that is population of T cells Then starting on the same principle was discovered which subpopulation of T cells are affected by Natalizumab specifically related relapses of the disease could have the answers to many questions…

  • I am being weaned off Tysabri right now. This article has me scared to death. I've tested positive for JC for about 6 months. I've been on Tysabri for 4 years. I don't even know if my neuro is aware of this danger. We haven't decided what my next drug will be. Will it matter? My MRI's have been good for a few years now.

    • Surely it is time to have this discussion before weaning and it is important that you switch to something effective and that you do not wait too long before doing so.

      Does it matter which one…I would say yes. In this scenario the patient had failed GA and chose to return when it is argued by some that it takes months to give protection. If you are taking natalizumab is is likely that you had active disease. Those cells or their ancestors are still there waiting to get back n the brain.

      There are a number of posts on the blog by ProfG about this.

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