Wednesday, 4 May 2016

ClinicSpeak: rebound post-fingolimod

Rebound post-fingolimod is not just an observation; it is food for thought! #ClinicSpeak #MSResearch #MSBlog

"The danger of stopping drugs that target trafficking of lymphocytes into the CNS (natalizumab) and/or sequester lymphocytes in lymph nodes (fingolimod and other emerging S1P modulators) are well known. The study below is just more evidence to support the phenomenon of rebound that occurs on stopping fingolimod. I find it fascinating that when you remove the brakes on the immune system and allow the so called 'auto-reactive lymphocytes' the opportunity to recirculate, they enter the CNS and cause disease activity that can be way and beyond what you would have expected, based on baseline levels of disease activity documented before patients started on these therapies. In the case of fingolimod we have even seen rebound in patients with PPMS who had to stop fingolimod after the negative phase 3 INFORMS trial results. Isn't it interesting that a DMT, such as fingolimod or for that matter natalizumab, can convert a non-relapsing phenotype into a relapsing phenotype? This is just further evidence that the MS disease classification based on clinical course is flawed."

"Why we get rebound needs to be studied further. I have proposed the concept of the field hypothesis in the past. Whatever is causing MS is allowed to proliferate and spread in the brain and spinal cord when the immune system is stopped from doing what it is supposed to do; survey the CNS. When the brakes of the immune system are then removed and immune surveillance recommences the cells find the cause of MS and set-up multi-focal inflammatory lesions, i.e. rebound. If I was a betting man I suspect the best brains to study to find the virus that causes MS are brains collected from people dying of MS on natalizumab or fingolimod who have not had immune reconstitution. The question that is often asked is why then do people on long-term fingolimod and natalizumab don't develop any problems from the proliferation of whatever is causing MS? I don't know, but may be they do we just haven't looked for it. Or we an live happily with the viral cause of MS in our brains provided we don't mount an immune response to it."



"The bottom line is if you have MS that is well controlled on fingolimod you may want consider any decision to simply stop taking it more carefully. I suspect it will be safer to transition onto another DMTs long before the action of fingolimod wears off (~3-4 weeks). The latter is really important for women on fingolimod who are planning to fall pregnant. This may be the place to use a PIRT (pulsatile immune reconstitution therapy), formerly known as induction therapies. They get the disease under control and are out of the system when the woman wants to fall pregnant. In the long-term the PIRTs will be the big disruptor in the MS DMT space. Let's hope oral cladribine gets its licence; I suspect it will be the drug of choice post-fingolimod for women wanting to fall pregnant."

Hatcher et al. Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment. JAMA Neurol. 2016 May 2. doi: 10.1001/jamaneurol.2016.0826.

IMPORTANCE: The appropriate sequencing of agents with strong immune system effects has become increasingly important. Transitions require careful balance between safety and protection against relapse. The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods (4 weeks) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies, such as rituximab.


OBJECTIVE: To describe rebound syndrome in patients with multiple sclerosis (MS) after cessation of fingolimod treatment.

DESIGN, SETTING, AND PARTICIPANTS: Clinical and demographic data were extracted from electronic medical records from the University of California, San Francisco, Multiple Sclerosis Center from January 2014 to December 2015. Magnetic resonance images were reviewed by MS neurologists (J.S.G., E.W., B.N., and E.C.H.). Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, with the development of multiple new or enhancing lesions exceeding baseline activity. We reviewed the PubMed database from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation. Participants were included if they stopped receiving fingolimod between January 2014 and December 2015. Five patients were identified who experienced rebound after ceasing fingolimod treatment.

EXPOSURES: Each patient received treatment with oral fingolimod for various durations.

MAIN OUTCOMES AND MEASURES: Occurrence of rebound after ceasing fingolimod treatment.

RESULTS: The mean (SD) age of the 5 female patients presented in this case series was 35.2 (6.4) years. Of the 46 patients that stopped fingolimod treatment within the 2-year period, 5 (10.9%) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment. Despite varying prior severity of relapsing-remitting course, all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidenced by a median (range) increase of 9 (0->30) new gadolinium-enhancing lesions and a median (range) of 9 (0->30) new T2 lesions. New lesion development persisted for 3 to 6 months despite treatment with corticosteroids (n = 3) and initiation of B-cell depleting therapy (n = 2). In addition, 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases.

CONCLUSIONS AND RELEVANCE: These cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.

CoI: multiple

9 comments:

  1. ProfG,
    Any evidence of rebound post-DMF (Tecfidera)?

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  2. Goes to show that these drugs are just a sticking plaster. Prof G is blinded by Big Pharma propaganda ... oh shoot, they'll probably censor my comment because it dares to disagree with their agenda.

    You are cowards, Barts. The least you can do is debate back rather than cower and cry because someone questions your stance. I can't believe you are now deleting our comments because they question you or disagree. This blog is a joke run by jokers.

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    Replies
    1. If you have specific questions, we'll try to answer but your posts seem to be just abusive anger venting, which isn't conducive to dialogue.

      Delete
    2. One of the things we have REALLY noticed about some folks is assaulting based on little and at times even considered knowledge.

      Here's the thing... People have MS. It can manifest in countless ways which you are all well aware. One of my dearest friends w/o MS is Bi-Polar and looses it one any driver that does the least wrong thing even if that least wrong thing really wasnt wrong at all cept' to her. Not road rage but just words flyin'.

      With MS lots of issues out there needing lots of tissues.

      There is both truth in Pharma matters and complete misinformation as is the case in essentially any sized business or for that matter just about any other meaningful subject matter.

      With MS between misinformation, damage to the CNS, life with MS and all that might be due to that and a considerable "other" laundry list that could be just about anything people have all forms of emotion.

      They lash out. Many do not realize they may well be acting inappropriately.

      There was a person on social media who constantly rips the NMSS about funds. My fiance' directed him to their public facing records as an NPO. He even broke it down for him. So this character goes off on my fiance' with "Ah hah! Now I have someone who works for them and on and on..." Conspiracy theories. Atop this, Guy lives in Canada and thus the US NMSS nothing to do with him. But, he clearly has a psychosis.

      Yet another went at me one day saying, "MS is an unproven disease based solely on symptoms". I explained my circumstances and pointed him towards facts. Ooops. He went into this TyranoMSaSaurus mode. Calmed that all down... Then he wants to meet me and says I am like no other women he'd ever met (yet never met) and is like, "Lets have puppies".

      Like, "Oh yes thats exactly what I want at 52 with MS. Been looking all my life for someone just like this!"

      Delete
    3. At this point I have to say I actually wouldn't blame them for censoring comments. It's actually getting a bit tedious and irritating to read the hate and negativity. The rude comments are the worst part of the blog. 99% of the people who comment are very fair and intelligent, but there are a few people who seem to be vindictive and nasty towards MS researchers. I have to stop myself posting replies like these because I will end up looking like a shill for Barts! I'm frustrated by MS too, but it hasn't stolen my manners from me yet. I haven't given up the fight yet but nor do I want to spend my days accusing researchers of conspiring to hide a cure from me. Life really is too short.

      Delete
    4. Anon at 11.41pm
      I couldn't agree more. Sad that there is a bunch of misfits out there who feel a need to get their jollies by just posting vitriolic garbage. Wouldn't be so bad if they posted constructive arguments or discussion, but No, they just have to go down the path of schoolyard bullying and posturing - they clearly don't have any constructive comments to offer.......

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  3. I find this very realistic field hypothesis. Because we live with a multitude of viruses and bacterias without them they express when our bodies can "balance" this coexistence.
    But when there is an imbalance, or those pathogens find some loophole they can proliferate, and like it or not, trigger the action of the immune system. I do a comparison with the Zika virus. N amaior infected people it is completely asymptomatic, but in some people it finds loophole to cause ADEM and Guillain-Barré ...

    I know a doctor who has MS here in Brazil (has the disease for 06 years) and became triathlete after illness.
    Everything was fine when there 02 years, she said, she decided to stop treatment with Rebif 44a (which I think is a mistake, because it has no way to predict when MS will appear, and you may not be able to recover from the outbreak).
    He was right then made the decision to stop treatment. But in February she had a strong outbreak, was able to fully recover from it, but made it clear to her that whatever is causing the disease is a virus or an immune specific genetic alteration riding autoimmune response against myelin, it is still there, and present it in full swing...

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  4. It is interesting, am on Nataizumab now for 18 months, in Dec I had an embolism so I get blood work done regularly. My auto diff total lymphocytes is always outside the 22 to 40 range at 42 (we know that 42 is the answer but what is the question :)) been at that level for months. I was thinking that it is all in the blood and the DMT is preventing it from crossing the BBB.

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  5. Being on Gilenya myself with quite a lot infections lately I was wondering how the 39 other patients managed?

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