Tuesday, 21 April 2015

Inflammation occurs in both relapsing and progressive MS

Komori M, Blake A, Greenwood M, Lin YC, Kosa P, Ghazali D, Winokur P, Natrajan M, Wuest SC, Romm E, Panackal AA, Williamson PR, Wu T, Bielekova B. CSF markers reveal intrathecal inflammation in progressive multiple sclerosis. Ann Neurol. 2015 . doi: 10.1002/ana.24408. [Epub ahead of print]

Objective The management of complex patients with neuroimmunological diseases is hindered by an inability to reliably measure intrathecal inflammation. Currently implemented laboratory tests developed more than 40 years ago are either not dynamic or fail to capture low levels of central nervous system (CNS) inflammation. Therefore, we aimed to identify and validate biomarkers of CNS inflammation in two blinded, prospectively-acquired cohorts of untreated patients with neuroimmunological diseases and embedded controls, with the ultimate goal of developing clinically useful tools. 

Methods Because biomarkers with maximum utility reflect immune phenotypes, we included assessment of cell-specificity in purified primary immune cells. Biomarkers were quantified by optimized electrochemiluminescent immuno-assays. 
Results Among markers with cell-specific secretion, soluble CD27 is a validated biomarker of intrathecal T cell activation, with an area under the receiver-operating characteristic curve of 0.97. Comparing the quantities of cerebrospinal fluid (CSF) immune cells and their respective cell-specific soluble biomarkers (released by CSF cells as well as their counterparts in CNS tissue) provided invaluable information about stationary CNS immune responses, previously attainable via brain biopsy only. Unexpectedly, progressive and relapsing-remitting multiple sclerosis (MS) patients have comparable numbers of activated intrathecal T and B cells, which are preferentially embedded in CNS tissue in the former group.

We have been saying for some time that progressive MS and RRMS are just parts of a continual spectrum and there is active inflammation going on in progressive MS. This ideally needs to be dealt with just as it needs to dealt with in RRMS. Dealing with the immune response in the Periphery can stop relapsing disease but we also want to stop inflammation in the brain and spinal cord. Most MS drugs are relatively poor at getting into the CNS, and whilst Gilenya easily gets there, its function is to trap the white blood cells in the lymph  glands. So a treatment that gets rid of inflammation in the CNS would be useful.

61 comments:

  1. Replies
    1. *choke* hammer to crack nut* choke* side effects* choke* :-)

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    2. Someone else put the link to this paper elsewhere in the comments on this blog: http://www.ncbi.nlm.nih.gov/pubmed/17293360

      *cough*cough*splutter*...flatline_____________ .

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    3. Haha - MD 1 & 2, you pair of cynics!! This is what too much cannboid-laced cheese and heavy metal will do to you!! :-)

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    4. To Anon - Yeah I read this some time ago (pre HSCT) in the imaginatively named journal, 'Brain'! I asked the question to a couple of the docs/researchers I consulted with at the time. The gist of it was as follows:

      Firstly and foremost, the 5 patients in this study were all SPMS and PPMS patients with high EDSS of 6-8. We know that HSCT (and all current MS treatments) are less effective in patients with progressive disease and high EDSS - which is why most HSCT trials these days have an upper cut-off of EDSS 6, and the majority only treat RRMS'ers or transitioning SPMS'ers. That being said, some SPMS/PPMSe'rs have still seen clinical stabilisation & improvements - but that's an argument for another day!

      4 of the 5 patients had the mega-toxic Busulphan in their protocols, and the one that didn't had Total Body Irradiation instead (which, let's face it, is what made The Hulk happen. Not good.). Both of these protocols are highly neurotoxic and linked to atrophy - even in non-MS patients (not to mention serious TRM). Neither of these are used in the modern non-myelo or BEAM protocols. It's also well documented that chemo leads to some increased atrophy for up to 2 years, before normalising.

      In addition, 4 out of the 5 patients died very shortly post-transplant (days/months), presumably due to the extreme protocols they received. In Moscow, I think they're at about 400 MS patients treated now, with zero fatalities, thanks to the milder protocols used today which deliver substantially similar benefits, with much reduced risk.

      Next up, if you google the work of Prof Muraro @ Imperial in the UK, on T cell repertoire post-HSCT, you'll see how the reconstituting immune system shifts over the months post-HSCT. In effect, the "immune reset" is not fully complete for several months/a year/maybe longer. In these cases of early fatality post-treatment, we don't know what would have happened given time for the process to complete. It is well documented that many MS'ers see significant and ongoing EDSS/symptomatic improvements for 2 years and beyond, post HSCT.

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    5. Then there is the question of microglia (which is what they believe was causing the damage in these patients). They've a much slower turnover time than peripheral blood immune cells. Once activated by T-cells or whatever triggers them (pre-HSCT), how long until they deactivate or are replaced?

      And last but not least (hopefully the MD's will back me up on this based on their work with the cheese-eaters), if you can stop immune-mediated inflammation early enough into the course of the disease, at least in EAE, you can "cure" the disease. But if you leave it too late, neurodegeneration sets in. HSCT trials are generally shifting, for that reason, towards early active disease.

      Personally, I hope I (and many others) have caught it early enough. The results in terms of long term stabilisation and improvement are very promising - though I guess without more time or an autopsy (the latter of which I'm not really up for right now) I can't conclusively prove it. This is the "big 20 year experiment" with all of the induction therapies (HSCT & Alemtuzumab) that Prof G speaks of so often.

      To summarise, the paper you've posted raises more questions than it answers and, when you actually read the full paper, does not disprove that HSCT is highly effective (the most effective, in fact) at halting inflammation and progression in early, active MS. In the same way as the Lemtrada results in SPMS/PPMS patients does not prove that treatment as a dud either.

      Either way, whether or not HSCT "cures" MS by eradicating all inflammation (jury is out), it remains the most effective treatment currently available - as evidenced by NEDA rates and improvement in EDSS. You only need glance at the recent results to the Alemtuzumab results published on the blog the other day to see that.

      Maybe the likes of Ofatumumab, or combo therapies with the neuroprotectives will change that one day soon. But that day is not today...!


      ________/\_____/\____/\_____/\_____ [no flatline]!

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    6. "This is what too much cannabinoid-laced cheese and heavy metal will do to you!!"
      That's just like your opinion, dude, now where the hell did I put that cheese? ;-)

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    7. Matt Perry - there is no way, come hell or high water, that I personally would go through HSCT. You can find arguments for and against it, but this, for me as someone with PPMS, is sledgehammer therapy. I'll wait for a more intelligent key to my disease that doesn't essentially mean destroying my immune system to hope that it rights itself.

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    8. HSCT relies on the assumption that T cells are driving all phases of the disease. The fact that all humans have autoreactive T cells clearly indicates this is an immune supressive therapy.

      This being the case it has no effect on the chronic microglia activation that is a problem with progressive disease which is why these therapies have to be pursued. HSCT is far from being a cure:

      http://mobile.journals.lww.com/jneuropath/_layouts/oaks.journals.mobile/articleviewer.aspx?year=2007&issue=07000&article=00009#ath

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    9. Are you the same Anon, or a new Anon? :-)

      Either way, I think you misunderstand HSCT. Yes everyone has some autoreactive lymphocytes but they don't normally permeate the BBB and they don't usually have a rapidly expanding autoreactive epitope. Nor are they in such high numbers as in MS'ers.

      The work of Muraro clearly and definitively demonstrates that HSCT is not purely an immunosuppressive therapy, as the new immune system which reconstitutes post treatment expresses a profound shift.

      If what you were saying was true, when the immune system reconstitutes at 12-18 months, MS activity would resume (for Lemtrada as well).

      The fact that both HSCT and Lemtrada show a sustained remission AFTER immune reconstitution is complete would suggest this is not purely immune suppression.

      I met Prof Muraro (author of this study) to discuss HSCT. His view was pretty much as per the conclusion of the article you've posted re mice. Intervene in early disease and it appears to be highly effective. Leave it too late, and it's less so.

      Nobody is disputing the benefit of research into new therapies. But HSCT (and Lemtrada - which is basically a weaker HSCT) both have patients with 10 years+ of NEDA, and counting.

      If you have PPMS I can understand your reticence and why it may not be right for you, but in early RRMS it's proving to be highly effective (92% PFS at 3 yrs in Moscow for patients <EDSS 3.

      I like to think of it like a busted microwave. No idea how to fix it, but getting a new one seems to sort the problem.

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    10. Will it last forever? Nobody knows yet. Hope so, though. Either way, gives me the best chance at sustained NEDA until your "more intelligent" solution arrives.... But given that nobody knows the trigger, target or exact pathology of MS, waiting for this "key" could be a long wait!

      At least there now seems to be some good progress on neuroprotectives and potential treatments for progressive disease.

      Best of luck to you :)

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    11. Are the microglia active in progressive MS because they are mopping up the degradation products of degenerating axons? As in, is it all a secondary process or is there strong evidence that it is a primary process completely independent of anything else?

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    12. "Will it (HSCT) last for ever" I think there is enough data to say that for everyone the answer is no...just like lemtrada there are a significant number where disease returns, so this plays into the risk benefit excersise.

      HSTC is immunosuppression perhaps the ultimate immunosuppression, but it is also a rebooting so the immune response that returns is different and it depends what comes our of the bone marrow and the state of the thymus and how good the depletion is. the thymus.

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    13. Are microglia.....Good question and difficult to answer I thing the view at the moment is that they can be both good and bad guys and it is all context dependent

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    14. Out of interest, when you say "depends on the state of the thymus", what influences that? Do MS'ers have dodgy thymuses?

      On your first point, agree. Clearly not effective for everyone. But for early, active MS, 92% PFS is about as good as it gets currently.

      They told me that first 2-3 years appears to be the main risk period for resumption. Of those who make it through that, there's favourable odds of long term remission. Some of the guys over on the forum are 12 years out now with no relapse, MRI activity or progression.

      I hope in 12 years time I'm one of them.... But as with all things MS, time will tell. I

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    15. Thymus what influecnes that ...age it atrophies as you get older

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    16. If you want to understand HSCT, watch this video from Dr. James Bowen who has worked at the Fred Hutchinson Cancer center and is a leading researcher in HSCT.

      https://youtu.be/1EMKoaBysOk

      Cleary, HSCT is immunosuppressive as your CD4+ cells never recover. Since the Thymus becomes less efficient at developing new T-cells as you age this might pose problems down the road.

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    17. Hi Matt Perry - I'm Anon 12:20 and 5:28 (this Anon thing is getting tiresome - I really should get one of these account thingies)! Sorry, I didn't realise you had HSCT, in light of which, my comments appear much too flippant and rather callous in tone. But I can understand why someone with your "kind" of MS might opt for HSCT, and I certainly wish you a long lifetime of benefit from it.

      For me, with my PPMS, which I no longer refer to cosily as a "condition" but rather a "disease" (usually with accompanying expletives), I would run a mile (if I still could) rather than have HSCT. But my disease is very different to yours.

      All the very best.

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    18. That depends on protocol. The HSCT used in cancer can be allogeneic, or at the very least is usually strongly myeloablative. Non-myelo bounces back much more quickly. In fact, even without stemmies you'd recover from a non-myelo transplant. My haemo over here told me 12-24 months for CD4+ to return to normal range.

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    19. Actually, Dr. Bowen is using a specific protocol for MS which is myeoblative (BEAM).

      It is true that your total lymphocyte count returns to normal, but the subset of the CD4+ are the ones in question. They appear to never fully recover with myeoblative HSCT.

      It would be interesting if you could provide a link to a paper that describes the recovery of this subset with non-myeoblative HSCT therapy.

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    20. That's a negative, green leader. I don't have a paper on it unfortunately - I'm just going off conversations with my haemo. BEAM is much higher intensity than the treatment I received, and wipes out the myeloid/blood forming tissue from the marrow as well. The treatment I had broadly leaves that in tact (~15% depletion) but knocks out lymphocytes pretty well... I can't view the video from here, but I'll have a butchers later on. On the graph they showed me, from memory, neutrophils bounced back first, then I think CD8+ overshoots and then normalises, B cells recovered quite quickly, and CD4+ was a much shallower line which took 1-2 years to cross into the lower range of normal. It was the last one to recover. I've not seen anything on more granular subsets of CD4+ though. I'll ask him when I see him.

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    21. "really should get one of these account"
      It is easy to give yourselfa name just scroll down the reply as and go Name/URLlike superman etc

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  2. What about intrathecal rituxan? Some do it now, and there are early studies: https://clinicaltrials.gov/ct2/show/NCT02253264

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    1. Interestingly, the PI of this trial, Ellen Mowry, is also the author of the study on positive effects of coffee mentioned in the previous post! Well, coffee sounds more appealing than intrathecal rituxan; the question is which is more effective? Of course, I am enjoying a cup of strong coffee right now, and it does not seem to help my MS in any way, but it still tastes good.

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  3. I see you've discussed the intrathecal rituxan and methotrexate before on this blog. http://www.neurology.org/cgi/content/meeting_abstract/78/1_MeetingAbstracts/P04.139

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  4. So, is this saying that the inflammation in progressive MS is still present but just not easily detectable? Something like the "visual" difference between sheep clustered around a bales of hay in a field (inflammation around a lesion) and a flock of sheep just spread randomly around a field? (think of an aerial view from about three miles up)

    If this is the case, then it certainly puts a different perspective on the use of anti-inflammatories in progressive MS, but I can't really see any decent trials being done.

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    1. If I had progressive MS I would certainly try the following:

      http://activemsers.wssnoc.net/showthread.php?t=1811

      This is my method for RRMS and hopefully it will halt all disease.

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    2. What's your thinking with this for PPMS and what's your success with it?

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    3. I can't say if it will work with PPMS or not. It is interesting that it is being considered for Parkinsons disease if you read the post.

      I just started on this therapy so I cannot give any results, but the add on does not seem to be noticeable in terms of side effects.

      Good luck

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    4. As a sublimgual or inhaler?

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    5. Actually, I take a 4mg oral tablet/day. This is what was used in the trial

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    6. I take a 4mg tablet/4mg. This was what was used in the trial.

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  5. What about steroids? There must be tons of data

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    1. As shown in the optic neuritis trial these are not enough

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  6. Are there any anti inflammatories out there to go along side the sodium channel blockers for PPMS/SPMS ?

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  7. I am sorry to say that we can not give personal advice on the blog.
    If you want personal advice or chats with MSers they need to be offline as you can link to people is they have links embedded in their profile.
    MDs are not clinically qualified to advise and neuros are unlikely to give specific details. You should be able to contact your health care professional for advice.

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  8. Hi Matt
    You seem to be Clued up on hsct
    What would you do as a 30yr old with rapid progressive Ms? Is hsct an option? Sumptoms only started 4 months ago so in very early stages although the disease is very active
    Is HSCT the way of MSCT initially with Hsct in the locker should that not work?

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    1. It's important to remember that Matt is not medically qualified.

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    2. Prof P has a nice ring to it. I'll look into it. Can't be that hard. :-)

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    3. Do you mean the treat PPMS early with neuroprotectives?
      Would hsct not be the ultimate in neuro protection? It's easy to say what to do, but if there's no drug to do it then what do you do?

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    4. What's the verdict then

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    5. "Prof P has a nice ring to it. I'll look into it. Can't be that hard. :-)"

      Yep, should only take you 20 years or so! ;-)

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    6. "Do you mean the treat PPMS early with neuroprotectives?"

      That would be the goal, perhaps combined with a DMT too.

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    7. What neuroprotective? HSCT?

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  9. Ok then mouse what's your take
    I know matts not qualified but he knows what it's like to have the disease

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    1. I'm not medically qualified either so can't comment. Our medics here (though most are currently at the AAN meeting) might like to comment but can't give a consultation as I'm assuming you aren't their patient. Sorry!

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  10. Only a comment is needed thanks again
    There's so much conflicting info
    I'll be rattling with niotin albuterol phenytoin etc

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  11. I've just ordered a pot of tea would you believe it
    No milk no sugar as per wahls protocol
    Great fun this for a 30yr old
    I honestly think MSCT then hsct later is the way to go though early in Ppms

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  12. Oh and testosterone for neuro protective qualities

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    Replies
    1. Actually oestrogen is the true neuroprotectant but there are obvious difficulties with this.

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    2. Neuroprotection and moobs. Double win!

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    3. Moobs - hahaha! :oD

      Sorry.

      My current recipe for PPMS: evening primrose oil (isn't GLA an oestrogen precursor or something?), green tea, 1000mcg biotin (which has demolished my heat sensitivity and fatigue - are massive doses required for remyelination???), nettle tea / nettle soup. Okay, okay... Nutriceuticals or whatever you call them are naughty. (But nice.) Don't even try to burst my bubble on this. I'm happy on it. :op

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  13. Yeah but in males they found test to be the same
    And any unused test gets turned into oestrogen I brlieve ?

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    Replies
    1. In a healthy adult male only 0.3% is metabolised to oestradiol.

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  14. Is testosterone pointless then?

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  15. What about the study showing testogel slowed brain atrophy to normal levels in males

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