Saturday, 30 August 2014

ClinicSpeak: life-threatening exacerbation on stopping natalizumab

Do we have enough evidence to stop MSers walking the natalizumab-rebound gauntlet? #ClinicSpeak #MSBlog #MSResearch

"The tragic case report below highlights what we know already that when you stop natalizumab MS comes back with a vengeance. This poor lady had massive rebound and when they decided to restart natalizumab her conditioned go much worse. I assume they were worried about her having PML, or a tumour, so that did a brain biopsy that showed acute demyelination with a large number of B cells present. This case highlights that whatever is driving MS must reside within the central nervous system, and that if keep the immune system out nothing happens. If you remove the sticky plaster, or natalizumab, the immune cells pour back in find what they are meant to find and cause severe inflammation and in this case a life-threatening and devastating relapse."
"I have been proposing for a few years now that we need to use natalizumab rebound as a model of MS relapse to study the disease. If MS is due to a virus the best tissue to use to search for this virus must be tissue from natalizumab treated patients."

"I am so sensitised to natalizumab-rebound after seeing it several of my own patients that I don't allow people to stop natalizumab treatment without starting some other form of alternative treatment. I am using fingolimod at the moment, but we really need evidence for teriflunomide and DMF in this situation. The data on using interferon-beta, glatiramer acetate and steroids in this situation is not good; rebound occurs with all of these agents. I have highlighted my concerns about using alemtuzumab in this situation; in this post and have proposed that the safest option is the bridging option (see figure below). The biggest problem we have are woman wanting to come off natalizumab to fall pregnant. I have one patient who had been stable on natalizumab for over 8 years, having previously had only 2 relapses, who stopped natalizumab to start a family. Four months later she came in with a devastating spinal cord relapse and an MRI that lit up like a Christmas tree with 60-80 gadolinium-enhancing lesions. Needless to say she went back onto natalizumab and has decided against starting a family. I am aware that some neurologists are instructing their patients to fall pregnant on natalizumab before stopping it and then restarting it just before, or shortly after, delivery. Other neurologists are telling patients to stay on natalizumab throughout pregnancy. All this advice is not evidence-based; we simply don't have enough data to say whether or not natalizumab is safe during pregnancy. Natalizumab is a so called IgG4 antibody and will cross the placenta. In a small series of babies born to mothers on natalizumab there were transient minor changes to their blood counts. Although small this series is reassuring in that these babies had not long lasting effects of natalizumab on their bone marrow function. This is where alemtuzumab, an induction therapy, has the advantage over natalizumab and other maintenance therapies." 


"The authors below hypothesise that restarting natalizumab during rebound made things worse as it affected the population of cells in the brain of this patient. I am not sure I buy this at present as all the cases that I have been involved in have not had worsening of lesions when restarting natalizumab. I think we need to be vigilant and watch out for this in this situation in the future."

"I can't help but feel very sorry for this lady; it shows you had bad MS can be despite having been treated with a transformational drug."

Beume et al. Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumab. J Clin Neurosci. 2014 Aug 20.

We present a 46-year-old woman with a relapse of multiple sclerosis (MS) that began 3 months after withdrawal from long-term treatment with natalizumab. Shortly after restart of a single dose of natalizumab she developed a fulminant MS rebound with stupor and tetraparesis. Cerebral MRI showed massive progression in the number of lesions and tumefactive lesions with ring gadolinium-enhancement. Stereotactic brain biopsy revealed acute demyelination and B-cell dominated inflammation. The patient improved during therapeutic plasma exchange. We speculate that early restart of natalizumab in the case of a relapse may worsen disease evolution possibly by modifying regulatory immune effector processes during an inflammatory rebound phase. A restart of natalizumab in MS patients suffering from a recent relapse or with signs of active inflammation should be considered with caution.

CoI: multiple

18 comments:

  1. As someone with RRMS, I find the idea of natalizumab quite scary. I'm fortunate in that Copaxone is effective for me at the moment. No relapse in just over two years. Should this research make us more cautious about considering starting natalizumab in the first place? Would the lady mentioned have been better off if she'd never had that particular treatment to start with?

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    1. Re: "Would the lady mentioned have been better off if she'd never had that particular treatment to start with?"

      Impossible to tell; she may simply have had very active MS and natalizumab kept the beast at bay.

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  2. Is anyone doing research using tysabri treated brain tissue? Have there been any reports?

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    1. Re: "Is anyone doing research using tysabri treated brain tissue? Have there been any reports?"

      All the reports are on patients with PML. We need to study tissue without inflammation. In other words the MSer would have had to die from other causes whilst on natalizumab and then donate their brain for research.

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    2. Will analysis of CSF be equally revealing? Spinal taps after tysabri discontinuation sound a lot easier than post-mortem brain tissue analysis.

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  3. All this goes to show no-one really knows what to do about MS. The disease is neurologically degenerative, not immunological. Yet we keep pushing the later as a target.

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    1. Re: "All this goes to show no-one really knows what to do about MS. The disease is neurologically degenerative, not immunological. Yet we keep pushing the later as a target."

      Not sure about this interpretation. MSers do very well on natalizumab in the short and intermediate term. It is only when natalizumab is stopped to we get problems. If MS was not immunologically driven you would expect MSers on natalizumab to get worse and to have progressive brain atrophy. The latter does not appear to occur. I am keeping an open mind about things. I do think the evidence supports inflammation playing a major role in MS. The real question is what is driving that inflammation; autoimmunity or a virus? I think it is a virus.

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    2. And I think you are right Prof G - keep hangin' on there!

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    3. A virus can possibly be a cause of inflammation but if autoimmunity is the cause what is the cause of the autoimmunity response? It seems logical to find and treat the root cause of the condition instead of just treating symptoms!

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  4. I feel very sad at this woman's suffering. There's not enough information about this case to make a useful comment. However, years ago I had a relapse unable to work. after a few weeks at home I went to my GP, he gave me a vitamin B12 injection and was given the okay to go back to work. I went home on the bus Within two hours I was becoming more and more paralysed down one side. I was rushed to the National and told the doctors I was willing to take anything. This was before DMTs and my point is the unpredictability of this disease makes it so frustrating. Without well kept records of incidents like this lady we will never know. Is everybody frightened of being sued?

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    1. Re: "Is everybody frightened of being sued?"

      I don't think so; most of us are trying to make the most of what we have got to improve the lives of MSers. The decision to start a particular DMT is shared decision, at least in my practice, hence we both share the responsibility if anything goes wrong. In my experience most MSers know that there are risks and there are benefits; if you have enough MSers on a particular treatment you will get a few major life threatening adverse events and some MSers may even die. However, the overall population will benefit from the treatment. This lady unfortunately had severe rebound that we can now control and largely prevent; knowing how to prevent rebound has taken research and a clinical trial.

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  5. What does B cell dominated inflammation in the patient resuming natalizumab therapy tell us about the pathology of MS? Are these B cells involved in surveillance, reactive towards EBV or an HERV? If a virus is implicated can this scenario be replicated in an animal model of MS using TMEV?

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  6. This is the single biggest reason I've stayed away from natalizumab. I currently have very little disability and seem to be progressing slowly, but I'm also a big believer in the preventative NEDA-targeting approach to MS. However, there is a fairly high risk I would need to come off natalizumab at some point due to PML risk or antibodies, and the risk of side a massive relapse erasing a lot of the benefits of the drug (along with its inherent risks) make me stay away unless I see signs my MS is progressing rapidly.

    I'm glad there is so much work going on to minimize PML risk and solve this rebound problem because, if we can sort them out, natalizumab really is an amazing drug.

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    1. Re: "I'm glad there is so much work going on to minimize PML risk and solve this rebound problem because, if we can sort them out, natalizumab really is an amazing drug"

      I think the PML problem has been de-risked, particularly now that we have alternative highly-active drugs to use in place of natalizumab. What we still need is a drug to treat PML or even better a drug to clear the virus from the body. This is not science fiction and has been done with other chronic viral infections, for example hepatitis C.

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    2. I think someone should start working on a drug for PML since there is a slight risk of developing PML after taking DMF - we don't know yet if people on Tecfidera will develop it but it would be good to have a drug for PML just in case.

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  7. How long was this lady off the Tysabri before the relapse kicked in? I found your post very scary!
    I have been taking Tysabri since April 2012 and have had no problems or exacerbations during that time. I was JC negative the last time I was tested. I have had to delay my 32nd infusion for a couple of weeks due to an infection - am I at higher risk of relapsing now?

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    1. Re: "How long was this lady off the Tysabri before the relapse kicked in?"

      The case report states 3 months. Three to 4 months is the time when the natalizumab levels drop low enough to allow cells to start re trafficking back into the CNS. Therefore a short break or a delay in your natalizumab infusions of less than 2 months should not cause too much of a problem. Please note that the level of saturation of VLA-4 the antigen on lymphocytes varies from MSer to MSer so the exact timing of re trafficking can be predicted with certainty.

      In our centre we do not delay natalizumab infusions if someone has an infection, unless it is a brain infection or they are have a very contagious infection and we don't want them to infect their fellow MSers, or staff, in the infusion unit.

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    2. Thanks very much for your answer, keep up the excellent blog!

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