Be careful when switching from Fingolimod to Siponimod


Barts-MS rose-tinted-odometer: zero-★s (purple Sunday)

The following case suggests a horizontal switch from fingolimod to siponimod may not be the wisest thing to do. This patient developed severe fingolimod rebound despite switching to siponimod without a washout. As you know fingolimod works on 4 out of 5 of S1P receptors (S1P1, 3, 4, and 5). In comparison, siponimod works on S1P1 and S1P5 only. Is this telling us that some of the modes of action of the S1P modulators are via S1P3 and S1P4? I suspect Yes. S1P4 may be important for antigen presentation and germinal centre (GC) function in lymph nodes and other secondary lymphoid organs, which explains why COVID-19 vaccine responses are so flat in pwMS on fingolimod. If this is correct then we may see better vaccine response in patients on the other S1P modulators that don’t impact GC biology to the same extent.  

I predict that there will be many more patients like this. The important thing is to ask why and to explore exactly what the differences are between fingolimod and siponimod on immune function in MS. Who knows what it is telling us about the cause and immunology of MS. 

Senzaki et al. Disease reactivation in a patient with secondary progressive multiple sclerosis after switching treatment from fingolimod to siponimod. eNeurologicalSci. 2021 May 15;23:100346. doi: 10.1016/j.ensci.2021.100346.

Excerpt: …… A 42-year-old woman with RRMS was started on fingolimod due to high disease activity; three relapses in the previous year and the presence of gadolinium-enhancing brain lesions before fingolimod. During the first two years after initiation of fingolimod, she experienced several relapses with incomplete recovery and progressive increase in brain magnetic resonance imaging (MRI) lesion load, and her EDSS deteriorated from 3.5 to 5.5. In the next five years, she was relapse-free without MRI activity; however, her disability gradually worsened to EDSS score of 7.0 and she was diagnosed with SPMS. Fingolimod was switched to siponimod without a wash-out period. Peripheral lymphocyte count at initiation of siponimod (day 1) was 376/μL, and 433/μL at day 7. She developed double vision at day 11.  Neurological examination revealed no new additional findings except for right internuclear ophthalmoplegia. Brain MRI showed multiple hyperintense infra- and supra-tentorial lesions on fluid-attenuated inversion-recovery images, some of which were enhanced with gadolinium (Fig. 1).

Conflicts of Interest

Preventive Neurology




General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • The switching from siponimod to fingolimod is a bit of a distraction to the real nub of this case:

    “In the next five years, she was relapse-free without MRI activity; however, her disability gradually worsened to EDSS score of 7.0 [from 5.5] and she was diagnosed with SPMS.”

    The medical profession (neurology) is prescribing incredibly expensive drugs which, for many patient, are not tackling accumulating disability / progressive MS. Patients are lured into a false sense of security that no relapses, a clean MRI and a pat on the head at their annual neuro appointment means things are all okay. 3,5,7,10 years later accruing damage shunts them up the EDSS and has profound personal, social and economic implications. Do any other MSers not feel we are being let down? Living with MS is hard enough, but knowing that the real MS is not being tackled leaves a bad taste in the mouth (as pharma pulls in £ billions per year from drugs which don’t address the real disease). Prof G can’t be the only MSologist to see that anti-relapse drugs don’t dent the real MS. Surely the next ECTRIMS conference should be addressing this! I admire all your efforts and honesty Prof G, but we need to move on from posts to pills (a drug to tackle smouldering MS).

    • “Prof G can’t be the only MSologist to see that anti-relapse drugs don’t dent the real MS.”

      Don’t think he is…But a more interesting question is do any neurologists even care
      enough about their patients to ask why someone is worsening on a drug that costs
      $100,000 a year..Or is ms just one more neurology disease where they watch patients
      decline endlessly. Like ALS..and PSP…etc. The above patient should have been diagnosed
      spms at edss 2 or 3….and with so much lesion activity been given hsct.

      Pender has had his EBV theory for 20 years and his trial is just now going in phase 2.
      Google Pender EBV CD8+…to read his papers on the real ms

    • Re: “a bit of a distraction to the real nub of this case”

      Yes, this is a case of smouldering MS, i.e. NEDA-2 with worsening. She needs an anti-inflammatory by add-on treatments to stop the ongoing neurodegeneration.

      • Prof G,

        When are we likely to see such “add-on treatments to stop the ongoing neurodegeneration”? Are there any promising trials which this patient should be considering joining eg simvastatin, Octopus, remyelination trials (eg at Cambridge)?

        Enjoy the sunny Bank Holiday

        • These Add-on treatments get mentioned here for the last 5 or is it 10…or 15 years….Don’t expect anything in next 5 years.

  • Really interesting letter (open access).
    Despite mode of action of S1Ps always being put down to S1P1 lymph node egress, there’s so much more going on. Especially in the CNS.

    • I suspect what is going on in the periphery in terms of the immunology of MS is as important as what is going on centrally in terms of the pathobiology (abnormal biology) of MS.

  • What would be a “good” replacement of Gilenya? Specially with current Covid Risk. I am having very low Lymphocyte (0.3) and planning to shift to another medicine. But I am looking for something which will not increase severe COVID risk.

    • Prof G would be in favor of IRTs like Alemtuzumab and Cladribine. However it has been reported Gilenya may make IRT’s ineffective as cells may still hide in lymphglands if IRTs are conducted too early, and the other side of the story is rebound risk if IRTs are followed too late.

      If reversible S1P modulators are still posing rebound risk then personally I think CD20 therapies would be the safest way to get off S1Ps (two infusions one immediately and one a month later). And then one can consider other therapies.

      I wounder what’s Prof G’s strategy for his patients considering swithcing from Fingolimod.

      • Under the NHS England’s guidelines or algorithm this patient would have had to stop fingolimod and once rebound occurred would become eligible for siponimod. I don’t agree with this and would look for activity using other means, for example, a lumbar puncture to detect raised neurofilament levels. If there were signs of ongoing inflammatory activity then this patient could be considered for off-label subcutaneous cladribine. Tragically the only DMT we have licensed in the NHS for active SPMS is siponimod. Another option would be off-label rituximab or recruitment and randomisation into a clinical trial, for example, the MS-STAT2 trial of high-dose simvastatin 80mg per day versus placebo.

        • “however, her disability gradually worsened to EDSS score of 7.0 [from 5.5]”

          “or recruitment and randomisation into a clinical trial, for example, the MS-STAT2 trial of high-dose simvastatin 80mg per day”

          Really…Do you honestly believe Simvastatin could help this

  • Please note that once you label someone as having SPMS according to the Lublin criteria it is a one-way street, i.e. you can’t undo that diagnosis. This is why MS is like having two diseases and not one. As you know I don’t agree with this; #MS_is_1_not_2_or_3_diseases!

  • Is there really such a big difference between fingolimod and siponimod or for that matter the other newer S1P1 modulators?

    • A friend of mine switched from fingolimod to siponimod last week, no washout. He had significantly elevated ALT AST levels for liver enzyme while on Fingolimod, and persistent for a year, Fingolimod was making him sicker and sicker (He had to quit his job last year). And just yesterday he told me his ALT AST levels are now within the normal range.

      So I have warned him about a rebound risk and asked him to take actions, thanks again Prof G and TheMS Blog.

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