Rebound on fingolimod, let’s move away from the hive mind


Mult Scler Relat Disord. 2017 Jan;11:1-3. doi: 10.1016/j.msard.2016.11.003. Epub 2016 Nov 11.

Severe rebound after withdrawal of fingolimod treatment in patients with multiple sclerosis.

Gündüz T, Kürtüncü M, Eraksoy M.

Ther Adv Neurol Disord. 2015 Sep;8(5):233-8. doi: 10.1177/1756285615594575.

Tumefactive multiple sclerosis lesions in two patients after cessation of fingolimod treatment.

Faissner S, Hoepner R, Lukas C, Chan A, Gold R, Ellrichmann G.



Fingolimod (FTY) is the first oral medication approved for multiple sclerosis therapy. Until now, little has been known about the effects of FTY withdrawal regarding disease activity and development of tumefactive demyelinating lesions (TDLs), as already described in patients who discontinue natalizumab.


In this study we present the clinical and radiological findings of two patients who had a severe rebound after FTY withdrawal and compare these with patients identified by a PubMed data bank analysis using the search term ‘fingolimod rebound’. In total, 10 patients, of whom three developed TDLs, are presented.


Patients suffering from TDLs were free of clinical and radiological signs of disease activity under FTY therapy (100% versus 57%, compared with patients without TDLs) and had rebounds after a mean of 14.6 weeks (standard deviation 11.5) [patients without TDLs 11.7 (standard deviation 3.4)].


We propose that a good therapeutic response to FTY might be predisposing for a severe rebound after withdrawal. Consequently, therapy switches should be planned carefully with a short therapy free interval.

Figure 1: From Gunduz et al. Note the relapses after cessation of fingolimod treatment.

In a rush to get therapies licensed, the collective ‘we’ have overlooked potentially devastating side effects of treatments, assimilating resistance by repetitive preeching. Can we ever get this right?

In this case, rebound of MS disease activity on treatment withdrawal, and in some cases the end result is worse than the original disease. Not only this, you are also then committed to buying into possibly life-long immunosuppression in order to avoid the possibility of rebound (and one with a “short therapy free interval”). En face, rebound doesn’t sound as serious as say PML, but it can still result in great disability, even if your disability score states that you have progressive MS and may not benefit immunomodulatory treatment (see Figure 1)!

I’ve been pondering this for a while…

Both natalizumab and fingolimod are gating mechanisms; one holding back the immune system from entering the brain (natalizumab), the other sequestering them in lymph nodes (fingolimod). In the same way that there is flooding during extreme river flows, the release in the tight hold on the immune system leads to rebound. With fingolimod, animal data suggests that there is a rapid increase in the receptor number (sphingosine 1 phosphate) that is blocked by fingolimod on T cells after stopping treatment. This is then followed by an immediate efflux of self-reactive T cells from the lymph nodes that quickly enter the brain.

It may therefore not be wise to cycle from natalizumab to fingolimod, or to be on fingolimod for too long. The key may be to cycle through treatments over short periods, i.e. keep the immune system guessing. As far as I’m aware this has not been suggested before, and as such have no evidence to support this statement. But, we may in the future, start writing treatment plans for the next five years for PwMS if this is demonstrated to work!

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  • The Natalizumab gate is downstream of the Fingolimod gate; but the 'water' behind the Natalizumab gate but below the Fingolimod gate is destructive?

  • why on earth would pharma develop drugs designed not to be taken forever, when they can develop drugs designed to be taken forever.

    kinda like anti depressants… ever tried to get off one?

  • The auto reactive immune subsets remain and may even multiply further as antigens are presented again and again…

  • Does Fingolimod/Gilenya really sequester immune cells in lymph nodes? If so, why don't Gilenya treated subjects show enlarged lymph nodes?
    There's quite a lot of evidence (that has seemed to have been ignored) that the mechanism of action is via apoptosis of cells with T cells being more susceptible than B cells.
    Seems to me a meme has taken hold.

    • Doesn't cause lymphadenopathy as the circulating load of lymphocytes is only 2% which is what the body naturally tries to maintain. Fingo preferentially impairs recirculating cells expressing lymph node homing receptors, naive T cells (not previously activated) and memory cells.

    • Yep We don't all think the same.

      We (MDs) have been having this very debate because ProfG wants us to do some work.The experiment should be a slam dunk but it isnt. We think we may be working in an alternative reality

      There is pharma spin land which creates nice digestible mechanisms and is reinforced at meetings like ectrims where you get to see some beautiful video and it is crystal clear in black and white.

      The myth is spun by the KOL.

      Then there is literature land which is fifty shades of grey where you get tied up trying to figure the real world

    • If you look at the cases of lymphoma linked to fingolimod there is a mechanism of reduced immune surveillance by CD4+ Tcells which generally become activated in draining lymph nodes to Th1phenotype – so it can't all be here say.

    • i'm confused. i thought all the treatments work differently and take a few weeks to months to work… if that's the case, and even accounting for the ongoing effect of a previous dmt, wouldn't it mean that people would remain exposed in between the treatment switches?

    • MD, that would probably vary depending on antigens, affinity of the antibodies, circumstances (f.ex. steroids) and individual variations ( young and healthy individuals versus older and with chronic disease). In the clinic we assume 2 weeks is a safer bet than 6-7 days, but the vaccines are generally given at least 4 weeks before immunosuppressive drugs if this can be planned ahead. (Genzyme says at least 6 weeks before alemtuzumab).

    • Ta. 6-7 days would be the start in the beasties and the antibody response would grow with time and boosts when making monocloncal antibodies is every 2-4 weeks. I was interested in how quick it could be in a human, you'll understand why I asked the question soon.

    • i'm confused. i thought all the treatments work differently and take a few weeks to months to work…

      You weren't reading my posts last week:-(

      I think that activity that is set in motion by the time you start taking the new meds are going to happen regard less. This may because the cells are in the CNS and as most drugs dont get in or act in the CNS they can't act.

    • Interesting. But then things improve rapidly after high dose steroids i.v.,so the scene for new MS attack is set but some things can still stop the Frankenstein party in the CNS?



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