Saturday, 31 January 2015

B cell depletion in progressive MS appears to be marginal

Castillo-Trivino T, Braithwaite D, Bacchetti P, Waubant E. Rituximab in relapsing and progressive forms of multiple sclerosis: a systematic review. PLoS One. 2013 ;8(7):e66308

BACKGROUND:Rituximab is an anti-CD20 monoclonal antibody approved for non Hodgkin lymphoma and rheumatoid arthritis. It is being considered for the treatment of MS.
OBJECTIVES:To evaluate the efficacy and safety of rituximab for MS treatment.
DATA COLLECTION:Studies were selected if they were clinical trials, irrespective of the dosage or combination therapies.
MAIN RESULTS: Four studies with a total of 599 patients were included. One assessed the efficacy of rituximab for primary progressive (PP) MSwhile the other three focused on relapsing-remitting (RR) MS. In the PPMS study, rituximab delayed time to confirmed disease progression (CDP) in pre-planned sub-group analyses. The increase in T2 lesion volume was lower in the rituximab group at week 96 compared with placebo. For the RRMS studies, an open-label phase I study found that rituximab reduced the annualized relapse rate to 0.25 from pre-therapy baseline to week 24, while in the randomized placebo-controlled phase II trial, annualized relapse rates were 0.37 in the rituximab group and 0.84 in the placebo group (p = 0.04) at week 24. Rituximab dramatically reduced the number of gadolinium-enhancing lesions on brain MRI scans for both RRMS studies. Off-labelrituximab as an add-on therapy in patients with breakthrough disease on first-line agents was associated with an 88% reduction when comparing the mean number of gadolinium-enhancing lesions prior to and after the treatment. Although frequent adverse events classified as mild or moderate occurred in up to 77% of the patients, there were no grade 4 infusion-related adverse events. A

UTHOR’S CONCLUSION: Despite the frequent mild/moderate adverse events related to the drug, rituximab appears overall safe for up to 2 years of therapy and has a substantial impact on the inflammatory disease activity (clinical and/or radiological) of RRMS. The effect of rituximab on disease progression in PPMS appears to be marginal.


I am really happy that the blog is empowering you guys. 

However, with all this knowledge you  can ask some tough questions that we can't answer, because we don't know the answer. (Does this make us look stupid..or just human)  or we can't answer because the blog is not the correct forum for us to answer. 

However the musing of scientists can obviously get you guys thinking and you can put "2 and 2 together".

Whilst ProfG has built up the idea that MS DMT may be killing a causative infection that prevent relapsing MS, some other scientists have come up with the idea of B cells in the brain causing progressive MS, because they find progressive MSers having B cell clusters in their brains. 

Therefore pwMS may think about giving up their T cell therapies in favour of anti-B cell treatment is the way because of we have present the argument that way, but there are always differences in opinion.

However it has to be said that some pathologists think this is just the product of the BBB, not the blood brain barrier but the British Beer-drinking Body (pathologists & nothing to do with me:) seeing things that others can't see. 

This has given people the thought that depleting B cells is going to be good for PPMS. However the data at present does not support this idea.  It is clear that RRS responds to CD20-B cell depletion and whilst some PPMSers respond to anti-CD20 depletion, to date it is only relapsing PPMSers or PPMSers with gadolium-enhancing lesions who show clear benefit.

Some people think that this is because immunosuppression of the white cells in the blood can inhibit relapses but the drugs can't reach the immune response within the brain, because of the BBB (blood brain barrier) and so don't work. Therefore some people think if they inject anti-B cell therapy into the brain it will work.

Cyclophosphamide is an anti-B cell drug and is one of the few MS drugs that can get into the brain in high concentrations to have an effect.  This is used at very high concentrations in HSCT to kill immune cells and get the stemcellsto come into the blood.This ose is effective at inhibiting relapsing EAE. This is the exclusively-immunology world-view held by many senior people. I no longer buy into this idea and think that the immune response preconditions a neurodegenerative effect that no longer responds to immunotherapy that blocks relapses ( I could be wrong). So you need to think outside the immunological box if you want to really get to grips with progressive MS. 

This concept is supported by the HSCT as it appears that progressive MS responds poorly. Likewise so does progressive MS respond poorly to B cell depletion as shown in this analysis.

In reality I believe that the immune response is part of the problem and solution of PPMS/SPMS and optimal therapy will require combinations of treatment to protect and repair and stop immunity in the CNS

20 comments:

  1. Does this point to them not being the same disease, so two diseases with similar symptoms but different causes?

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    1. The same disease but different mechanisms of damage within a continum some people have more of one than the other. If I am right then they both have the same root treatment if you start early enough but how early i early?

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    2. So like Epstein Barr can cause both CD20 expressing and none CD20 expressing lymphomas by infecting B cells.? And rituximab does not affect the second type.

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  2. Prof M,

    Thanks for your post and honesty. In reality, I don't feel empowered and knowledge doesn't equate to power (you see this on lots of MS society websites). We have been sold a pup by the MS societies with the 'there's never been a better time to get MS'..... 'Research is accelerating at a rapid pace'.... 'Big breakthroughs are just around the corner'. In reality, good progress has been made with anti-relapse drugs, but we don't seem to be any nearer to a drug to stop progression or to encourage repair. Even the very basic questions (auto-immune or viral / primarily inflammatory or primarily neuro-degenerative are still not answered). At the start of each year my hope rises and then falls away. Gilenya for PPMS, anti-lingo for repair of ON damage. This year I'm pinning my hopes on the Charcot Project and Phenytoin. In reality the best I can hope for is that the results show a non-statistical i.e. they don't have much effect. I know we can come across as sourpusses, but we are living with a grim disease 24/7 and just want some hope. If i knew sometime good was coming in 3 years (highly effective neuroprotective drug or a drug which encouraged some repair) it would lift my mood immensely. I live in hope.

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    1. You feel empowered when your knowledge can allow you to make decisions, however until we give real positive choices to progressive MSers the science words can have the empty rhetoric.

      20 years ago there were only the "placebo plus" compounds, now there is more choice...and treatments that make and impact that is unless you are prisoner to NICE prescribing guidelines, If you are empowered with knowledge you should be thinking I want ZeTo (zeroTolerance of disease activity) as soon as possible rather than waiting and see.

      There are protection and repair studies ongoing which would not have been thought about 20 years ago. The repair studies would no have been thought about 5 years ago and now I know more potential candidates than I can shake a stick at. I personally know of three repair studies in MS and then there is the stuff I don't know about, and one of them is by pharma.

      Last year we had stem cells allowing a bloke to walk again..progress is slow,but there is progress. But breakthroughs is media babble that has done us no favours with the public at all.

      Was the anti-LINGO-1 a failure not necessarily as I have posted they did a trial where the odds were stacked up against them and they got a hint of activity, because they didn't deal with the inflammatory response adequately before trying to repair.....I bang my head against the wall as treatments get flushed down the toilet by poor choices but the polypill has not yet filtered to pharma and pharma knows best :-)

      If you pin hopes on Charcot and phenytonin you can be disappointed because even if (hey lets be upbeat and say when) they are positive they are still going to be small steps forward, Charcot 1 is an imaging study so we would need to see a clinical response, eg. beta interferon is good at getting rid of lesions but not so good at getting rid of relapses. "OK ProfG & ProfG down under I accept that if Charcot 1 works it should be a game changer"..but only a start. Are enough anti-virals getting to the virus in the CNS, is this needed?

      Then there is the phenytonin study. What has happened to simvastatin which showed promise 2 years ago. Sir Jeremy is off doing MS-SMART which will occupy a lot of his time. There will be lots of good stuff appearing this year but progress will never be quick enough, but if phenytonin is positive it shows us we can slow nerve damage....would this be a breakthrough or a step forward?

      In the beasties we have very effective immune control and we know we can save nerves with a whole host of things, others can show repair these things have been there for years, however they take time to filter through...I hope 2015 brings good cheer for both of us and predict that some good will occur but like you I say this every year..

      ProfG mentions ASCEND (above) whilst I have predictions of the outcome, I think I can say it will not stop progressive MS, at least for every one as one can see progressive MSers on tysabri that get worse. However if it slows the rate of worsening this really says we need to deal with the peripheral immune response in progressive MSers too, which i suspect we do.

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    2. Many thanks for taking the time to respond.

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    3. Thanks Mouse - that was honest and very clear.

      Charcot ... it would be a game changer even with marginal results simply because it would change the paradigm and point towards viruses - I so much hope it will because the viral meds are so much better researched.

      from a personal point of view I would love my MS to have a viral cause because then I would have a cause at least and would stop blaming myself and the world and its cat for my illness.

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    4. Really well said, MouseDoc. Thank you.

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    5. Great reply, MouseDoc.

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    6. Very well made point, MouseDoc.

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    7. I have to agree with many of the sentiments expressed by Anon at 8:23am, and in some ways the "pup" we are sold has a case of parvovirus, which is why I tend to ignore most of the MS Society websites for anything except basic info. However, since discovering this blog I do feel more empowered, even if the news is not good, as at least an effort is made to tell it like it is. I have learnt stuff which helps me deal with the platitudes and "soft fuzzy" information given to me by MS nurses et al although I have no wish to malign the generally positive role that they play for many people, which is really far more focussed on practicalities such as self-injection techniques etc. Some of us just want/need to know more than others do - this blog helps meet that need. Keep up the excellent work.

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  3. Prof mouse, obviously as a guess as you don't have the data yet! but if you were a betting man would you gamble on success or failure for raltegravir (charcot 1) ?

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    1. I have no idea of the data, this is a study for the ProfGs.

      One thing is that I don't bet, unless I know the answer. I went to Vegas and didn't spend a penny in the casinos...maybe a flutter on the Grand National every now and again but my choices often end in cans (sorry poor taste joke, but you get the gist of my betting skills).

      To answer your question I think history would suggest that the first trials on new targets in MS tend to fail (e.g loads of immunosuppressives were thrown away e.g Azathioprine), we are in the process of throwing away my work on neuroprotectives e.g. cannabinoids and cupid and repair agents are just beginning. However at some point Neuros get it right and find differences and then it becomes easy to find efficacious treatments, so now we can spot a drug that inhibits relapsing MS within 6-12 months. So on the plus side there is anecdote for efficacy.

      However I suspect if may not be straight forward. This week one student was presenting on Neuro-HIV as part of their course work and I was marking their presentation. They said that HAART (HIV treatment of which rategrovir is one aspect) doesn't get in the brain, so if that were true there could be a problem if that is where raltegravir targets.

      After a bit of research it seems there can be a lot of variation of penetration of the amount of raltegrovir getting out of the blood in a group of people with HIV the ratio went from no inhibition of penetration to 99.5% exclusion with the average about 20% penetration. But in people with HIV sometimes the drug levels were not high enough to get rid of the HIV intergration.There are genetic variants of the ACBG2 drug transporter on blood vessels that can make a difference on how much raltegravir gets in the brain. This transporter is present in MS and this transporter has been implicated in various responses to mitoxantrone so some people could respond and others may not respond as well. However if the action is in the blood then this is all irrelevant, However, I am sitting on the fence

      Simple answer is I don't know and there is not point guessing, I like you will have to wait and see....frustrating...but this science.

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    2. P.S. I really like an idea of Charcot 2 presented by ProfG down under this week, so if Charcot (1) doesn't deliver there are more ways forward and if charcot (1) does deliver this could make it even better. What is the idea....the G's will launch it when its ready

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  4. Mouse Dr many thanks :)

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  5. I see a chink in the Team G armor where members of Team G are starting to express differing opinions. You may have to break the voice coming out of this blog into different subsets; Team G, Team Mouse, Team Leave Me Alone, etc., etc.

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    1. We are not all robots and if we all thought the same we would not get debate amongst ourselves and we could all end up do the same blind alley. However the data will hold the key.If ProfG thought there was no chance of things working he may be reluctant to be involved in a trial like ASCEND or the ocreluzimab trial and would rob his patients the opportunity to try something rather than nothing years before anything becomes available. Remember he is all sort of committees, that I am not party to, and he may be in the know.

      The issue of oligoclonal bads is an interesting one but there are more cases where oligoclonal bands have apparently gone and the agents doing that have not stopped progression, although they did not build in the therapeutic lag idea. However the point of my post was to show people that if they were thinking of B cell depletion as a justification of HSCT to replace their immune system they they have to prepare for less of an effect that they may be expecting.

      I hear so many rumours about the progress of ocreluzimab...both good and bad I wonder how reliable the sources are. Maybe the spies are double agents

      for reliable sources:-) i.e. drug reps

      t the even of the day,the clinical trials will tell us which view holds more traction.

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    2. I think it is pretty clear HSCT does not eliminate OCB's no matter what type is performed for autoimmune diseases.

      Acording to Dr. James Bowen who is involved with th Halt MS trial which use a my email time protocol, OCB's are present even after this procedure. The only way that might conceivably delete OCB's is through a allogenic bone marrow transplant where a donor is involved. So looking at it from this view the anti-CD20 therapies want halt progression if you believe b cells are the culprit.

      Here is a video by Dr. Bowen that explains this:

      http://youtu.be/1EMKoaBysOk

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    3. Re "if we all thought the same we would not get debate amongst ourselves and we could all end up do the same blind alley" - Hear, Hear
      The dreaded "groupthink" leads only down one pathway - that of mediocrity and closed minds, all under a cloak of consensus and perceived unity, accompanied by group hugs and much patting of selves on the back about "working together without conflict"
      The much maligned "devil's advocate" role keeps people on their toes and is critical for healthy debate
      Healthy debate and independent thinking leads to fresh ideas and new approaches
      So cherish and nurture different viewpoints and keep the debating alive, I say

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