Saturday, 1 December 2012

Rebound on withdrawal of natalizumab and fingolimod

#MSBlog: MSers on more active maintenance treatments are at risk of rebound in disease activity when the drugs are withdrawn and the barbarians attack!

"The potential rebound in MS disease activity that is commonly seen after withdrawal of natalizumab, and now fingolimod, reminds me of the book 'Waiting for the Barbarians' by JM Coetzee, which I read as a teenager. In the book the locals, and imperialist forces, wait for the barbarians to attack, but they never do. Instead the imperialist forces go out and make a pre-emptive strike against the natives or barbarians, based on the ideology or false belief that they are malicious peoples." 

"Both natalizumab and fingolimod are drugs that work by keeping auto-reactive immune cells, or the barbarians, from gaining access to the brain and spinal cord. Natalizumab blocks lymphocyte migration across the blood-brain-barrier (barricades) and fingolimod traps them inside lymph nodes (concentration camps). When you remove the block these lymphocytes pour back into the brain and exacerbate MS; the so called rebound activity. The relapses and MRI lesions that occur as part of this rebound can be fatal and cause severe disability, which is why we are now reconsidering our policy of a defined wash-out period before switching from natalizumab to fingolimod. The idea of the wash-out period was to allow lymphocytes back into the brain to detect any early or subclinical PML and allow the immune system to flush it out. PML clearly has an asymptomatic or pre-clinical period of a few months before it manifests. Our current proposal is to now do an MRI, to look for any new lesions that looks suspicious of PML, and a lumbar puncture to make sure there is no JC virus in the spinal fluid. If these two tests are negative to then start fingolimod immediately after stopping natalizumab. By doing this you will hopefully trap the autoreactive lymphocytes or barbarians in the lymph nodes before the natalizumab wears off. The obvious danger of this approach is if your MRI and spinal fluid analysis are falsely negative and you then go onto develop PML, whilst on fingolimod. The only treatment we have for PML is to let the immune system do its job and allow the T-cells back into the brain to fight the infection. If you are on fingolimod, when you develop PML, it takes weeks for the drug to wash-out of your system. In the time it takes for fingolimod washout and the lymphocytes to recirculate, PML can cause a lot of damage. So this strategy is clearly a balancing act between keeping the barbarians at bay and making sure  there are no traitors (JCV)  within the central nervous system to cause problems. Who said treating MS was simple?" 

"One eminent neurologist, who will remain unnamed, referred to natalizumab and fingolimod as sticky plaster; i.e. a temporary fix. You remover the sticky plaster and the disease comes back with a vengeance  The advantage of induction therapies, such as alemtuzumab, cladribine, rituximab and ocrelizumab, is that we think they work by rebooting components of the immune system. These treatments don't stop working suddenly; i.e. they kill, or wipe-out, or severely deplete the barbarians. This is why I personally find the philosophy of an induction therapy so appealing. They are also the only therapies that offer a potential cure; that is assuming MS is an autoimmune disease. However, on the down side induction therapies cannot be reversed; once you reboot your immune system you can't unreboot it."

"'Waiting for the Barbarians' is actually a book about apartheid in South Africa. History has shown that the threat that the barbarians were meant to pose never materialised. Apartheid eventually failed and South Africa went on to adopt one of the World's most liberal constitutions. Maybe the barbarians in MS won't materialise either? MS may yet prove to be due to an infection, and not an autoimmune disease. This is one of the reasons why it is so important for us to push ahead with The Charcot Project." 

"'You may be interested to know that 'Waiting for the Barbarians' was chosen by Penguin for its series 'Great Books of the 20th Century' and won both the 'James Tait Black Memorial Prize' and the 'Geoffrey Faber Memorial Prize' for fiction. JM Coetzee went on to great things winning many awards including the Booker Prize, twice, and the Nobel Prize for literature in 2003. He is an extraordinary writer."   

Jander et al. Emerging tumefactive multiple sclerosis after switching therapy from natalizumab to fingolimod. Mult Scler. 2012 Nov;18(11):1650-2. doi: 10.1177/1352458512463768. This report describes an MSer who developed a relapse with MRI features of tumefactive demyelination after switching therapy from natalizumab to fingolimod.

Rinaldi et al. Switching therapy from natalizumab to fingolimod in relapsing-remitting multiple sclerosis: clinical and magnetic resonance imaging findings. Mult Scler. 2012 Nov;18(11):1640-3. doi: 10.1177/1352458512464282. In this study 22 RRMSers  were switched from natalizumab to fingolimod after a 3-month washout period. Disease reactivation was observed in 11/22 (50%) MSers: clinical relapses in 6 MSers (four MSers within the first month of therapy) and MRI activity in a further 5 MSers (3 MSers within the first month of therapy).

Laroni et al. Early switch to fingolimod may decrease the risk of disease recurrence after natalizumab interruption. Mult Scler. 2012 Nov 26.  This is an descriptive report comparing MSers who switched from natalizumab to fingolimod or other immunomodulatory drugs (interferon-beta or glatiramer acetate); the number of relapses was lower in the fingolimod switchers. These group included a washout period of ~18 weeks before starting the fingolimod. 

Havla et al. Rebound of disease activity after withdrawal of fingolimod (FTY720) treatment. Arch Neurol. 2012 Feb;69(2):262-4. This report describes an MSer who discontinued fingolimod treatment after a local malignant melanoma was diagnosed. Three months after cessation, he had a striking rebound of multiple sclerosis activity.

Ghezzi et al. Disease reactivation after fingolimod discontinuation in two multiple sclerosis patients. J Neurol. 2012 Nov 16. In this letter this group describe two MSers with massive rebound after withdrawal of fingolimod.


Gheuens et al.  Simultaneous PML-IRIS after discontinuation of natalizumab in a patient with MS. Neurology. 2012 May 1;78(18):1390-3. This is a report of an MSer who had widespread PML and severe IRIS after withdrawal of natalizumab. New Gd-enhancing white matter lesions, occurring after discontinuation of natalizumab, can be the manifestation of PML-IRIS rather than an MS exacerbation. 

19 comments:

  1. Worryingly Prof G there seems ro be a lot of guess work in the above post,

    "is that we think they work by rebooting components of the immune system"

    I would like to think you would know how these new set of drugs work before prescribing.

    Without wishing to be rude it wouldn't be unfair would it not, if you heard the football chant "You don't know what you're doing"

    Regards as always.

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    1. We have a hypothesis and we are testing it! I have outlined the holes in the current dogma, which is why we are working on a new paradigm. I am not yet confident enough to discard the old one, but would do so at the drop of a hat when, and only when, the science supported it.

      Science is seldom black and white, but shades of grey.

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  2. Yes you would like to know the mechanism.

    How does beta interferon work?

    How does copaxone work...the mechanism of action has changed with every dogma over the past twnty years and I have not bought into any of them

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  3. Why do you say the downside is that you can't unreboot the immune system? Is this because the immune system for some time is in a weaker state than it was? Presumably you wouldn't get IRIS if you switched from natalizumab to alemtuzumab as there are different methods of action. I agree that MSers should be offered an induction therapy if they so wished- in an ideal world.

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    1. No! When you deplete your immune system you kill cells that can't be replaced. When it reboots a lot of new cells are born that need to be educated and in the case of alemtuzumab become mis-educated and cause autoimmunity themselves, i.e. thyroid disease and ITP. These processes can't be undone. In the case of natalizumab and fingolimod these cells are not killed but kept alive so that when you remove the drug they go to work with a vengeance.

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  4. South Africa is the greatest nation on Earth. We have been written off many times but look how we bounce back. The weather, the beauty, the light... oh, this nation is heaven on Earth. Now if only we can reduce our crime then I am sure the world will realise that this is where everyone will want to live. Come visit and see for yourselves.

    If ever a cure for MS is found it will be dicovered by a South African. In Prof G we trust. Do not let us down, son.

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    1. As a Yorkshireman I need to disagree:-)

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    2. It is a great pity that you (Jacob) and your cronies are destroying SA. It is now the country with the greatest disparity between rich and poor. Not to mention the corruption. You are right to imply that your best export is your people, but what does that do for your country in the long-term?

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  5. Would you also then avoid a wash-out period if someone was moving from Natalizumab onto Alemtuzumab, Cladribine etc ?

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    1. Re: "Would you also then avoid a wash-out period if someone was moving from Natalizumab onto Alemtuzumab, Cladribine etc ?"

      This is a more difficult question. In principle yes, but if you get it wrong the MSer will probably die. PML in someone who has had an irreversible immunosuppressant is a bad idea. I would discuss this with the MSer and explain the risks and if they were prepared to take the risks, which by the way are low, I would treat them without a washout.

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  6. Might the reboundeffect after Fingolimod be avoided by not stopping it apruptly but going down in dose more slowly (e.g. using it every other day, twice a week, once a week and so on) like one does with drugs like Gabapentin?

    Why is it that I don't seem to be able anymore to make any comments using my computer (safari), no matter if I try to post as anonymous, openID or google account, the comment just vanishes as soon as I press the publish or preview-button. There used to be an extra window opening, this does not happen anymore. I didn't make any changes on my computer, did you change anything? It is quite unnerving to write on a smartphone...

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    1. The extra window was removed by Prof G as he likes the reply feature.

      As to the rest I do not know it is probably a google thing. So maybe down load another browser for use with the the blog, I bet chrome will work.

      My smart phone no longer allows me to comment as I can't get to show an ID so obviously some things have changed as I used to be able to do this.

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    2. Re: "Might the reboundeffect after Fingolimod be avoided by not stopping it apruptly but going down in dose more slowly (e.g. using it every other day, twice a week, once a week and so on) like one does with drugs like Gabapentin?"

      No the rebound effect is due to cells trafficking back into the brain and spinal cord. This can't be prevented by a slow withdrawal.

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    3. On your i-app, go to "settings" , "safari" and change private browsing from on to off. This should do it.

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  7. JM Coetzee is a great writer but I haven't got over the shock of seeing The Fountainhead in your favourite books. I read Ayn Rand in my teens, loved her books then, and outgrew them soon after.

    Altruism is bad and selfishness is good?

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    1. Ayn Rand was and remains a fascist. Her work is venerated by the American establishment, the one percent that brought about the biggest economic downfall in living memory. I bet Big Pharma adores Rand’s canon – her autocratic and totalitarian stance must make them weep in adulation.

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    2. Glad to hear you found her books though provoking. May be that was her intention?

      The wikipedia entry on her philosophy is very different to your take:

      "In 1957, she published her best-known work, the novel Atlas Shrugged. Afterward she turned to nonfiction to promote her philosophy, publishing her own magazines and releasing several collections of essays until her death in 1982. Rand advocated reason as the only means of acquiring knowledge and rejected all forms of faith and religion. She supported rational and ethical egoism, and rejected ethical altruism. In politics, she condemned the initiation of force as immoral and opposed all forms of collectivism and statism, instead supporting laissez-faire capitalism, which she believed was the only social system that protected individual rights. She promoted romantic realism in art. She was sharply critical of the philosophers and philosophical traditions known to her, except Aristotle."

      http://en.wikipedia.org/wiki/Ayn_Rand

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  8. The title of Coetzee's book is taken from a famous poem by C.P.Cavafy:

    http://www.cavafy.com/poems/content.asp?id=119&cat=1

    The poem is about a declining society that awaits external intervention and salvation (Barbarians), only to find out that it will never come.

    Neurology has long depended on modulating/downregulating/depleting the immune system regarding MS, either accusing it directly (autoimmune theory), or indirectly (viral theory). A huge pharma industry thrives out of the malfunctioning (barbarian) immune system. The same with university departments, academic careers, research teams, MS societies. A complex network of people and their families have lived their life in prosperity thanks to the autoimmune barbarians. Now, it is said they may not exist at all, so new barbarians are needed, the viral ones. When we are done with them, the gene barbarians will take their place, then the environmental, then the VitD, etc.

    The current establishment can not live without the ghost of an "enemy, and.this is beyond any personal motivation.

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    1. Lfe and its inventions are all about incentives! It is a pretty simple philosophy, but it explains almost everything. Sometimes it is difficult to spot the incentive. For example, what are VV's? What if he is wrong?

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