Natalizumab to fingolimod washout in patients at risk of PML: When good intentions yield bad outcomes.

Jokubaitis et al. Fingolimod after natalizumab and the risk of short-term relapse. Neurology. 2014 Mar. [Epub ahead of print]

OBJECTIVE: To determine early risk of relapse after switch from natalizumab to fingolimod; to compare the switch experience to that in patients switching from interferon-β/glatiramer acetate (IFN-β/GA) and those previously treatment naive; and to determine predictors of time to first relapse on fingolimod.

METHODS: Data were obtained from the MSBase Registry. Relapse rates (RRs) for each patient group were compared using adjusted negative binomial regression. Survival analyses coupled with adjusted Cox regression were used to model predictors of time to first relapse on fingolimod.

RESULTS: A total of 536 patients (natalizumab-fingolimod [n = 89]; IFN-β/GA-fingolimod [n = 350]; naive-fingolimod [n = 97]) were followed up for a median 10 months. In the natalizumab-fingolimod group, there was a small increase in RR on fingolimod (annualized RR [ARR] 0.38) relative to natalizumab (ARR 0.26; p = 0.002). RRs were generally low across all patient groups in the first 9 months on fingolimod (RR 0.001-0.13). However, 30% of patients with disease activity on natalizumab relapsed within the first 6 months on fingolimod. Independent predictors of time to first relapse on fingolimod were the number of relapses in the prior 6 months (hazard ratio [HR] 1.59 per relapse; p = 0.002) and a gap in treatment of 2-4 months compared to no gap (HR 2.10; p = 0.041).

CONCLUSIONS: RRs after switch to fingolimod were low in all patient groups. The strongest predictor of relapse on fingolimod was prior relapse activity. Based on our data, we recommend a maximum 2-month treatment gap for switches to fingolimod to decrease the hazard of relapse.

With more choices for multiple sclerosis (MS) disease-modifying therapies, data are urgently required to support clinical decisions regarding safe transitioning and sequencing of therapies. With over 7 years of clinical experience, natalizumab has been confirmed as highly effective in reducing MS disease activity. However, natalizumab carries a risk of progressive multifocal leukoencephalopathy (PML). The optimal length of natalizumab washout became the subject of intense consternation and debate. This study suggests a maximum of  of 8 weeks but on this subject ProfG has recently posted

MSBase and several smaller studies, which show that if you have a wash-out period when switching from natalizumab you are more likely to have a relapse than if you don’t have a washout. Why? Natalizumab has a circulating half-life close to 2 weeks; the half-life describes the period of time it takes for the levels to drop by 50%. It therefore takes about 10-12 weeks (5-6 half lives) for natalizumab levels to drop to low enough levels to allow lymphocytes to start trafficking back into the brain and spinal cord. If these cells are autoimmune cells they will set-up an local inflammatory response and trigger a relapse. This process takes several weeks. This is why we see rebound disease activity (relapses or MRI activity) about 3-4 months after stopping natalizumab. Therefore it is not a good idea to stop natalizumab without starting another DMT to prevent this rebound. Unfortunately, interferon beta and GA have not proven to be very effective post-natalizumab. What about oral drugs? We don’t have data yet on teriflunomide (Aubagio) or BG12 (Tecfidera). However, fingolimod has been studied and provided it is started with 8 weeks of stopping natalizumab it can prevent most of the rebound. The sooner you start it the better. At the Royal London Hospital we have adopted this practice for sometime now. If the switch is in a JCV positive MSers we do an MRI for new white matter lesions and lumbar puncture to analyse the spinal fluid for JCV DNA. If these test are clear the likelihood of asymptomatic PML is low and we start fingolimod. This typically occurs at around week 3 or 4 after the last infusion of natalizumab. As it takes about 6 weeks for fingolimod to take an effect by the time natalizumab is out of your system fingolimod is working.”

“If you are being switched from natalizumab to fingolimod and your neurologist wants to do a prolonged washout ask him/her why?”

“What is most intriguing about stopping natalizumab is the rebound activity that is often very severe and greater than that what was seen prior to starting natalizumab. Why? I suggest you read my post from last year on this topic; it generated a lot of discussion about MS and its potential cause.”

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  • How does rebound fit in with your theory that MS is caused by the EBV? Likewise, how does Tysabri fit into your theory that MS is cause by the EBV? If MS is caused by EBV, it will continue even if immune cells hampered from getting into the CNS which Tysabri does. Clearly this is not the case.

    • Tysabri is keeping cells that want to cause damage at bay, take that away and the damaging cells get in and rebound occurs. Are they targeting EBV in the CNS to cause disease or does the EBV trigger the development of autoimmunity then the presence of EBV may not matter. There are so many ways that MS could trigger MS.
      Maybe I'll let ProfG answer this one but it depends on how you view EBV fitting in the jigsaw to some it is the trigger of autoimmunity, then there is the latency and re-activation could this drive relapse could it cause oligodendrocytes to get stressed

    • No, this goes back to the black swan posts as well as all the posts about how much emphasis is being placed on autoimmunity. The assertion was that EBV causes direct damage in MS. It would function like the JC virus causes damage to the CNS. So, if Tysabri hampers immune cells from getting into the CNS then MS should continue to do its damage because the immune system is not involved. It would be just like PML, the JC virus is responsible for the damage. Otherwise you have to admit something is wrong with msers immune system and surrender that ms is an autoimmune disease.

  • "What is most intriguing about stopping natalizumab is the rebound activity that is often very severe and greater than that what was seen prior to starting natalizumab, this has implications about MS and its potential cause". If the autoreactive T-cells are responding to the damage inside the BBB not causing the damage then "inside out" theory is possible. In PML the cause is immune response to JCV causing massive inflammation and demyelination. If relapse occurs in the absence of an infectious agent what is simmering inside the BBB that flares when the adaptive immune response is restored? Latent EBV in lesions driving innate immune response in the CNS? EBVers say yes, autoimmuners no.

    • "Latent EBV in lesions driving innate immune response in the CNS?"

      The innate immune system is non-specific and only acts on viruses when it encounters them outside of cells. The adaptive immune system is responsible for killing cells that are infected with a virus. So, if Tysabri restricts adaptive cells from crossing the blood brain barrier, the attack on virus infected cells by the immune system is not going to happen.

      Another problem is that EBV infects b-cell, not white matter. So, unlike JVC, EBV does not cause damage to meylin directly. I guess this is why ms is considered an autoimmune disease by the vast, vast, vast majority of scientists working in this field. Unfortunately we only get one person's biased views on the subject. It would be great if a guest blogger/scientist could be invited to explain the mainstream view.

  • On what aspect do you want? You know there are other world views…… you want the inside out the outside in the outside inside in. The vast vast vast vast majoriy thinkTh1 good, Th2 bad. But then comes along Th17.
    How about Th1 bad Th2 bad this abetter fit

    • All I'm asking for is a basis for the assertion that EBV is the direct cause of ms. Clearly EBV is involved in MS, but there has been zero evidence provided that it is responsible for the damage produced in ms.

      Why don't you explain why what I have described about EBV, the innate immune system and Tysabri is wrong instead of changing the subject about other factors in ms?

      Portraying yourselves as mavericks outside of the science of MS just confuses people, especially patients. This is how phenomena like CCSVI get started. Yes new discoveries are being made all the time in ms and you would think scientist would be eager to keep up on what these are so they can better understand this disease. Instead, it seems you take it as "oh, a new discovery about Th 17 cells, great, now what am I suppose to believe".

      Fortunately, there are more places on the net that can discuss what's going on with ms research. Although the researchers who run these sites don't spend 95% of there time on the blog, the information is of better quality. I guess they have more important things to do.

    • I am not going to defend this position because.this is profG ideal not necessarily min the easiest way is to see it as a trigger in autoimmunity what triggers relapse could be a multitude of different things..

      As we have always said it is one world view there are others so who are you thinking for a guest post ……yourself.

      I am sure post tysabri relapses are imprtant in understanding of relapses.

      If there is no content there is noy blog.

    • "As we have always said it is one world view there are others so who are you thinking for a guest post ……yourself."

      I think Stephen Miller would be a great guest blogger and be a logical person who could challenge the Gioavoni's on the assertion EBV directly is the cause of ms. He probably would not accept due to all of the bashing you have gave him, but he is one a the true hero's in ms research. The US ms society thinks ms so also.

      "Stephen Miller, PhD and his colleagues at Northwestern University are investigating the idea that perhaps it’s not a virus itself that causes MS, but some immune response triggered by viruses."

      I would pay good money to see a debate against the best you got and him.

    • Obligative epitope spread.

      ProfG loves debates maybe he can get a guess post.

      However these are not debates but opinions.

  • Lets hope his studies work we have followed in some of his footsteps and he in ours believe it or not.

    On some things we will agree on others not.

    • Yes epitope spreading is a real phenomenon, who does not accept that it occurs, not me. It
      is not however obligate. Maybe this is your world view, many would agree with this view, I do however not buy it. Popper would prevail in this instance, test the hypothesis and it fails in most peoples hands.

      Private industry accepting something is no guarantee of success or reality, otherwise intravenous MBP would have worked in progressive MS and proved the autoimmune hypothesis? Maybe other data will.

    • Wow, if you think the autoimmune hypothesis is somehow related to progressive disease, the blizzard Institute is in worse shape than I thought.

      You may want to get Bruce Trapp from the Cleveland Clinic on here to explain a few things.

      it's too bad Dr. Miller and Dr. Trapp don't have blogs of their own. But it is good enough for me they are at the leading edge of ms research and much too busy for this type of activity.

    • I suggest yoi take your head out from the hoke it ia in. Do some reading amd keep an open mind you are souding like a ccsvi evangelist.

      As to linking autoimmunity to progressive disease in my mind this is indeed possible.

      What is progression. It would seem that not all pathologists agree

      I s aw Bruce on friday i will tell himhe has a fan club wanting a blog

    • Seriously, do you guys have any hypothesis on what causes MS or do you just run from one ludicrous proposal to the next? At first prof G was postulating that EBV was the direct cause of MS, in another post he claims EBV is the trigger. Sounds like there is a problem with attention deficit disorder. No surprise though. Isn't your PHD in zoology? There are some high standards at the Blizzard Institute.

    • So, you are equating Bruce Trapp with Zamboni now are you? I think you have an over estimation of your prestige in MS research circles. What were you doing when you saw Dr. Trapp? My guess is you are moonlighting as a valet car parker.

  • MS rebound after discontinuation of Natalizumab…. does this provide a glimpse into the genesis of MS immunopathology? As the trafficking of lymphocytes into the CNS begins what are the HLA profiles of patients who relapse? The cytokine profile? HIV patients that develop IRIS are categorized with TB-IRIS, Cryptoccal-IRIS, etc. depending on the underlying infectious agent response by the reconstituted immune system. Dr. Gold mentioned that he observed an HIV patient with MS and the disease was ameliorated with induction of HAART. Some HIV patients display an increase in the frequency or exacerbations of autoimmune diseases (sarcoidosis, RA,SLE) following HAART. Why not MS? Hopefully the phenomenon of MS rebound will shed light on the pathogenesis.

    • Ancedote is no antidote for reality. These are observational studies. It can all crash and burn.

      They (ProfGs) have created a hypothesis and they are attempting to disprove it. If the agents are not particularly effective they may have problems. however, maybe it is a wrong idea..that's the nature of science.

      However, we should not have a monoculture of science otherwise we can all go down a dead end

      …. I agree MS rebound after treatment must tell us something about genesis of pathology..Whether the

  • Yeah we have a new nemesis

    . To you i apologise for not posting all your comments but i need to read the links and cant be bothered to do it by phone… I am on a parking toiur…valet indeed. I am part of the fan club of the nemesis and i get demoted tolicking shoes. I suggest you get a name rather than anon and please dont take Carl Pilkingtonits taken :-()

    • OK, thanks for the username suggestion.

      Also, when cleaning Dr. Miller and Dr. Traps shoes you should polish them to a mirror-like finish.

    • I suggest you get a name too so you can get a fan club…. maybe Warwick
      4fa72896-c3bf-11e3-aea0-000bcdcb8a73 as a name sounds abit tedious :=)

    • I went through the trouble of setting up an AOL account and my user name was set as new.nemeis. But all that came out was gibberish. Probably an issue on your end.

    • When posting, choose the option for Name/URL. You can choose whatever name you want.

      BTW, a "nemesis" is usually considered to be someone on a similar intellectual level. So far, your arguments consist of quoting someone else, and name calling/weak insults. To be MD's true nemesis, you should try coming up with arguments a little more on his level. You are going to have to step up your game.

    • Fortunately, I am not a scientist working in the field of MS, so I leave it to other experts in the field who have hypothesis about what causes MS. So, no I am not his equal in that respect. But if you were paying attention, all I am asking for is an explanation on how EBV causes MS if the vast majority of humans have this virus. How does the fact that Tysabri prohibits immune cells from crossing the BBB which subsequently reduces MS activity support the EBV is a direct cause of MS proposal? I don't think it does.

      The fact that prof. G first made the statement that he thinks EBV is the direct cause of MS, stated he disagreed with Dr. Pender that it is a catalyst and now comes up with the "field theory" which suggests EBV is a trigger is quite schizophrenic.

      As stated, I do not work in MS research but I'm beginning to understand why we are where we are with finding the cause of this disease.

    • I think Prof. G is simply being provocative and putting forward a hypothesis. The fact that the data suggests that best protection against getting MS is not to get infected with EBV is quite compelling don't you think? I am worried by the observation that a large number of people with MS on Tysabri are entering the secondary progressive phase of the illness and some are showing progressive brain atrophy suggest that what is causing MS may still turnout to be the brain of people with MS. Prof G may yet be proved right.

    • Yes, I agree that if you could eradicate EBV from humans it may prevent people from getting ms in the first place. But is this even possible? EBV can lie dormant and become reactivated, so it seems like it may be impossible to eliminate it from humans.

      But this comes back to the fact that most humans have the EBV and yet a small fraction get ms. To me, this seems like an issue where people with ms may have an immune system that reacts inappropriately to EBV. This goes back to theory such as molecular mimicry, epitope spreading and the immune hypotheisis. There is strong evidence for the autoimmune hypothesis because those that undergo HSCT and Lemtrada treatment have their disease halted if they are still in the relapsing phase of the disease. Many of these people have their disease halted for more than 10 years. If they try these therapies in progressive forms, they don't work quite as well. Why? It is suspected that when your nerves are chronically demeylinated, they begin to die ushering in progressive disease (Dr. Trapp).

      I don't have a problem with trying to eradicate EBV, but first is this even possible? The second issue I have is that Prof. G seems to bash the autoimmune hypothesis (Dr. Pender), yet turns around and agrees with it with his new "Field Theory".

      It would be great if we could cure ms by preventing people from getting EBV, but my view is the fundamental problem is MSers have problems with their immune systems. So, my question is how likely is it that EBV can be eradicated from humans to prevent those susceptible from getting ms?

    • Listen ere shoeshine. ..Has a nice ring .Prof g has answered your question, so time to move threads. Bring it on.

    • "I went through the trouble of setting up an AOL account and all that came out was gibberish".

      Em..gibberish. Anyway my advice is either use Name/URL or you can set up gmail account
      and it links

    • I don't known what you mean by popper. I think I need a British English to American English translation dictionary.

      But I've been thinking my new users name can be "m&m". This will complement Dr. Dre and also keep rap in the spotlight.

    • Dear Slim Shady
      I would suggest another name besides m&ampm it looks a bit crap, but not quite as bad as 4fa72896-c3bf-11e3-aea0-000bcdcb8a73

      Blogger is rather unforgiving when you use ampersand ("and" in British and American Engrish I guess).

      However, we already have a DoctorMandM so you would either be a disgruntled member of TeamG ( who would not need to ask questions or you are an impersonator/imposter

      Impersonating what…a scientist?…. surely not as one would know about Karl Popper and testing a hypothesis

      So Dictionary No…..Just some Homework.

      Maybe if you had seen the front page of the blog today you may have got some clue about Popper there's a picture

      Maybe stay away from rappin, as the "popper" does not mean a chemical class called alkyl nitrites that are inhaled for recreational purposes.

      Unfortunately too much rap starts with a "c" 🙂

  • OK, Dr. cat tongue, I will try Slim Shady instead if m&m to see if that works. I see your point about popper and testing hypothesis. I guess it doesn't matter if the hypothesis makes any sense or not just so long as you test it. Maybe this is how you came up with the idea of testing caniboids for ms? One day you were sitting around taking a big drag off your bong and whala! Marijuana could be the cure for MS. I've got to start to experimenting with my mice!

    Anyway guys, keep up the good work!

    • I would suggest something like Billy the Kid as you seem to like to Shoot from the hip.

      When you want to insult remember there is a trollometer and spam and we have been advised to avoid personal spats. My wrist have been slapped or the rogue weekend. Be warned.

      Popper theory suggests doing experiments to disprove the hypothesis, but to repeat if you read you can enlighten yourself.

      As to the idea of cannabinoids, this was from the UK MS Society. They organised a meeting in Scotland where I talked on the same programme as Roger Pertwee a cannabinoid pharmacologist. The MS Society said can you investigate this. Because of doing other experiments we had a mouse with a tremor called Kate Moss (Long story). The impact of cannabinoids was dramatic, we then contacted ProfG who was working in another Institute fom us and he found us a human movement expert who came to see the animals.He then invented and made the equipment to measure the limb stiffness.

      If you care to read some of our papers you will see they have someone from MS Society as co-author.

      However the point to note is that this idea translated from EAE into humans unlike many of the two thousand or so drugs that treat EAE. If you read the work we are not talking of cure when we talk about symptomatic treatments.

      The CUPID trial for control of progression was a bit of a disappointment to us, but even there in the people with EDSS less than 5.5 there was a significant beneficial effect. There is solid biology and its involvement with T cell biology is not important.

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