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Case study: smouldering MS - to switch or not to switch to siponimod
This patient is NEDA-2 (no relapses or MRI activity), but is getting worse on DMF (Tecfidera). She has smouldering MS. Do I label her as having SPMS and switch her to siponimod (Mayzent), or not?
I am a 40-year old woman with MS who is NEDA-2 (no evident disease activity) on DMF (Tecfidera). I have had no relapses in the last 4 years and my annual MRI scans show no new or enlarging MS lesions. I have been told that my MRI looks like swiss cheese with a large number of black holes. Despite being told my MS is inactive I am clearly getting worse. I have increasing bladder problems and progressive stiffness and weakness in my legs. I have been told that my EDSS has moved from 4.0 to 5.5 in the last three years. I am sure I have secondary progressive MS and want to switch to siponimod. Would you recommend this?
Prof G’s opinion
Unfortunately, according to the current NICE approval and NHSE guidelines, this patient is ineligible for siponimod because she has inactive MS (NEDA-2).
Siponimod is licensed for the “treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity” (see Siponimod SmPc). Based on this strict definition this patient is unfortunately not eligible for siponimod.
To prescribe siponimod we will have to (1) label this patient as having secondary progressive MS and (2) provide evidence that the patient has active disease. The latter would be relapses and/or evidence of MRI activity (new or enlarging T2 lesions or Gd-enhancing lesions). The latest NICE guidance, which is trying to standardise the definition states that MRI activity is “1 T1 gadolinium-enhancing lesion at baseline MRI or a significant increase in T2-lesion load compared with a previous MRI”. Although we haven’t been given a specific time period it is likely to refer to the last 24-36 months. We need some wiggle room because not all patients with SPMS are getting routine annual MRI scans, particularly in the last 18 months many non-urgent MRI scans have been cancelled or postponed due to COVID-19 induced changes to NHS services.
Some questions. If the relapses and MRI activity occurred prior to the diagnosis of SPMS can they still be counted? Or does the diagnosis of SPMS rebaseline patients? I think the answer should be somewhere in between these two extremes. As the diagnosis of SPMS is retrospective the baseline or clock for assessing disease activity should be set when the first objective evidence of worsening was documented. In reality, this is typically 6 or 12 months in the past depending on the frequency of follow-up appointments. The definition of SPMS requires at least 6 months of worsening disability independent of relapse activity. The problem here is that to have active SPMS you also need to have had a relapse and/or MRI activity in this period as well. So it becomes very difficult to untangle worsening disability from relapses from worsening independent of relapses. Clearly, these definitions are a mess!
In an ideal world, all the above may make sense, but this does not take into account the reluctance of neurologists and HCPs to document or label their patients as having SPMS. In some countries, a label of SPMS means the current DMTs may need to be stopped. Also the label SPMS has other negative connotations; it is often interpreted as having a second disease, importantly a disease that is not modifiable. I know this happens a lot. When we tried to recruit study subjects for our PROXIMUS study (add-on neuroprotection with oxcarbazepine) my colleagues were reluctant to refer their patients for the trial as it required them to diagnose early SPMS and nobody wanted to do that.
Another issue that arises is that once someone is labelled as having SPMS can you unlabel them and refer to them as having relapsing MS? Common wisdom says no. In other words, once you have transitioned (and I hate this term) to becoming SPMS you can’t go backwards. This has major implications for patients with active SPMS; once you are on siponimod it may close the door to the other DMTs as they are not licensed, at least in Europe, for SPMS. At present this is one of the biggest hurdles for the widespread adoption of siponimod for active SPMS in the UK. In other words, siponimod has become the cul-de-sac or dead-end DMT until another DMT is licensed for SPMS. I can already see NHS England making it impossible to switch someone who is failing on siponimod, can’t tolerate it, or develops adverse events that require stopping siponimod, onto another high-cost DMT that is licensed for RRMS. They will do this via their blueteq database, which will not allow registered patients to go onto another DMT once they have been on siponimod.
I think we as an MS community need to make the argument that you can flip-flop between MS subtypes. We have evidence buried in the trial data that a subset of patients labelled as having SPMS behave as having RRMS, i.e. their EDSS scores improve despite superimposed relapses. Similarly, there is a subgroup of patients with ‘inactive’ or ‘smouldering’ SPMS who have not had a relapse for years suddenly become active. The same thing happens with PPMS; approximately 25% of pwPPMS will go onto have superimposed relapses. Surely these people have relapsing MS rather than PPMS? Calling them progressive-relapsing MS does not deal with the biology of the disease in these patients nor their treatment. Leaving them as having a form of PPMS means that are only eligible for ocrelizumab, whereas relabeling them as having RMS opens up many more treatment options for these patients.
These arguments are more than just semantics they have real-life implications for individuals with MS and how we treat their disease.
At the end of the day, we can avoid all these arguments by defining MS as one disease and not two or three diseases (#MS_is_1_not_2_or_3_diseases).
Back to the questions do I recommend, this patient stops her DMF so that her MS can reactivate, which will then make her eligible for siponimod? Most MSologists would say yes, mainly because the development of SPMS is one of NHS England’s stopping criteria. The problem I have is we, the patient and I, have no idea how active her MS will become if and when her MS reactivates. For example, she could have a catastrophic spinal relapse that leaves her doubly incontinent and quadriplegic or it may be on the other side of the spectrum, i.e. one or two new asymptomatic MRI lesions on her annual MRI follow-up. If you were in her position would you stop your treatment to develop active MS?
If we had no obstacles to prescribing I would allow this patient to switch to siponimod. The reason is we have not data on DMF in this population, but we do have data showing siponimod slows worsening progression, reduces the rate of brain and grey volume loss and also slows down cognitive worsening in SPMS.
One complication is COVID-19 and vaccinations. As S1P modulators blunt vaccine responses I would make sure this patient is double-vaccinated and potentially has their booster dose before starting siponimod.
Provided this patient does not have DMF-induced lymphopaenia and all the necessary baseline checks are done I can’t think of any reason why this patient couldn’t be switched directly from DMF to siponimod without any washout.
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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.