Sunday, 19 February 2012

Case Report: Rebound of disease after fingolimod cessation

Havla et al. Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol. 2012;69:262-4.

BACKGROUND: The oral sphingosine-1-phosphate receptor modulator fingolimod (FTY720/Gilenya) was recently approved for the treatment of relapsing-remitting multiple sclerosis. To date, data about a possible recurrence of disease activity after discontinuation of fingolimod treatment are scarce.

OBJECTIVE: To describe a patient who discontinued fingolimod treatment after a local malignant melanoma was diagnosed. Three months after cessation, he had a striking rebound of multiple sclerosis activity.

RESULTS: Three months after discontinuation of treatment with fingolimod, the patient experienced a severe relapse, with Expanded Disability Status Scale score progression from 2.5 to 4.5. On brain and spinal magnetic resonance imaging, he showed a rebound of disease activity, with a drastic increase of gadolinium-enhancing lesions (more than 20).


CONCLUSIONS: Two aspects relevant to any newly approved multiple sclerosis treatment with immunomodulatory properties are highlighted with this case: first, possible rebound of disease activity after discontinuation; second, the occurrence of a tumor as a possible treatment-related complication.

Gilenya works by stopping white blood cells from exiting the lymph glands so it empties the blood of white blood cells. This can stop MS and also immune survellience that could cause cancers. It is possible that once you stop the drug, the cells can leave the lymph glands, enter the blood and then get in the brain to cause disease. Are these two effects linked well we can not say, but it will need more that an observation in one person to give any conclusive views.

A noticable tumor risk has yet to show itself but this is feasible, as is the case of any potent immunosuppressive agent.

12 comments:

  1. I've always wondered about Gilenya. It seems like stopping white blood cells from entering the blood would be very very dangerous.

    Does this literally turn off your immune system or is there some non-blood way that white blood cells still work in the patient's body?

    I don't understand how people on Gilenya don't just get sick and die.

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  2. The way that gilenya is believed to work is that is does not stop the action of all white blood cells from entering the blood by trapping them in lymph glands.

    It affects a subset of white blood cells that are thought to cause multiple sclerosis, whilst leaving a different subset of cells that deals with infections untouched. Therefore it is not a blanket suppression of the immune response, hence the hope that the side-effect problems of immunosuppression are reduced.

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  3. My neuro wanted me to start this drug after taking me off of Tysabri last june. I really am hesitant to begin. Considering heart related deaths, infections, cancers. I think I am going to wait. The reports about side effects etc, were written by the share holders. Well you know? I want a drug that works, nit one that lines the phsrmaceutical pockets. I do not want to be a guinnea pig.

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  4. I figured it worked in some way like that. My understanding is that Tysabri binds to cells' alpha-4 integrin, right? Which has the effect of not allowing these cells to pass though certain substances, like the blood-brain barrier. I image Gilenya works in a similar fashion.

    What surprises me, though, is that my impression is that they maybe aren't sure exactly which cells have an alpha-4 integrin. Some articles talk only about T-Cells, but it sounds like many other white blood cells may have an alpha-4 integrin and may also be affected which could be a good thing, or in some cases a bad thing. That's something I got from this blog, hopefully I didn't massacre the idea too much.

    What I am surprised at is that it seems like they are not taking blood from Tysabri patients and looking at the cells to see which have "Tysabri" attached to their alpha-4 integrin. Maybe this is harder than it sounds and more than just a microscope problem. It's hard to tell what's not possible yet or what the drug companies just aren't doing for some unknown reason. Maybe they do know, they're just not telling us. Or maybe the information would just not be useful.

    I'm not trying to be paranoid, I'm just curious as to why so little continued scientific information about Tysabri is released. It's been many years since Tysabri was created, there should be a ton of new data. Maybe unlike you guys, many companies think we don't care, but we do. Of course, my only way of getting information is this blog, so it's extremely likely I just don't have the information. I wish the researchers for Biogen also blogged.

    This is one of those comments where I'm pretty sure I'm in over my head. I'm going to post it anyway as an example of someone who's trying to understand the drugs he's taking, putting in an honest effort, but obviously not going back to medical school. I think there might be others like me.

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  5. Dear Matt
    I have done a post for tuesday about how gilenya works, which I hope will clarify things more.

    It is not quite the same but similar Gilenya stops cells getting into the blood so they can not get into the brain.

    Tysabri works by stopping the cells in the blood from going into the brain.

    We can be sure which cells have alpha-4 integrin this is quite easy and takes less than an hour to do.

    Yes there are may different cells T cells, B cells and monocyte, macrophages. Some cells have more than others and this can change as cells mature etc. It is apparently also on some stem cells (at least in mice) so it could stop them migrating into the brain. There is no published evidence in humans that I am aware of.

    The Dogma (see prof G post) is that it is the T cells that are the problem in MS so the marketing indicates that tysabri is blocking T cells.

    If dogma changed and it was B cells then the story would change.

    However when you look for hard evidence for T cells causing the problem in MS, it is not that strong, could it work by blocking B cells or monocytes/macrophages.

    It could be argued that it works by affecting monocytes. In cell cultures blockade of the alpha 4 integrin and the counter receptor VCAM-1 (vascular cellular adhesion molecule) perhaps works better on monocytes than it does on T cells in some system.

    But is it because it inhibits migration of both cell types that is why it works. You can show in a test tube how and on which cells it works but in MS it is not easily provable. Especially as there are no anti-monocyte/macrophage agents available yet.

    So rather than presenting an unclear picture it is easier to stick with Dogma.

    However there is alot of work going on about tysabri, alot it is probably in the vaults of Biogen. But why tell your competitors how it works, let them do their own work as they will want to make a competing drug

    There is no conspiracy by Biogen and who knows there could be a Biogen reader out there that will add to the post.

    The tysabri antibody does not cross react with say rodent cells so that makes it more difficult to ask and answer questions?

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  6. Also I will post video on mechanisms of action of Tysabri.

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  7. Re: "...there are no anti-monocyte/macrophage agents available yet."

    Is this something that's being worked on? Will we see treatments for this in the pipeline?

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  8. Even we have data on this, and am sure that we are not alone. However the problem is likely going to be the side effects if used in humans

    Insects can happily live without lymphocytes, but they have macrophage-like cells as do most simple organisms to remove them and their may be problems. However there are thought to be macrophage subsets that can be good and bad and I have no doubt that work in ongoing in this direction

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  9. I thought laquinomod acted on monocytes- although not very effectively according to the data produced on MS and laquinomod.

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  10. Yes there was some experimental evidence about effect of laquinimod on monocytes but there is evidence that it works by other mechanisms alos but the clinical effect in MS was idsappointing and it did worse than beta interferon on relapses.

    However there was a question about whehter it may effect progression
    this is yet to be proven. We may never know if it does not get developed as seems likely

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  11. Hi - I've developed a very low WBC and neutropenia after being on fingolomod (500ug daily) for 12 mths- having had 2 relapses - my first 18 mths ago.
    My neurologist is considering halving my dose by taking it every second day.
    I don't want to stop it as I havn't had any relapses since starting on it.
    Could you please comment on my situation. I have late-onset MS (60yr old)
    Thanks

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  12. I have recently come off Gilenya due to my immune system being too severely and dangerously suppressed. I am now having the most severe relapse I have ever had which currently leaves me very disabled - I am functioning so badly that I have had to call my mum to help me get around, cook and help me in the shower - she is typing this as I am unable to type very well at the moment.

    My previous experiences on Betaferon and Copaxone were almost equally horrific.

    I am reluctant to take further medication as the side effects of the drugs I have taken have been awful

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