Please note that I am so conflicted when it comes to giving advice about DMTs that you need to take what I say and think with a ‘pinch of salt’; including the contents of this post.
Meaning: To take something with a “grain of salt” or “pinch of salt” is an English language idiom that means to view something with scepticism or not to interpret something literally.
The endless churn or cycling of DMTs is creating problems for MSologists and their patients alike. I am increasingly seeing patients who have been on six or more DMTs. Why? Many switching decisions are related to tolerance issues, unacceptable adverse events, family planning and breakthrough disease activity. However, some churn sadly is due to unrealistic expectations, over- or under-stretched healthcare systems or simply fashion.
Let’s deal with unrealistic expectations. If you are on DMT x and you are NEDA 1&2, i.e. no relapses or new focal MRI activity, but are still getting worse many patients are being switched in the hope that a different DMT will get on top of smouldering MS. The reality is that we have no data on the efficacy of DMTs in this situation; in fact, we have data from more advanced MS trials that anti-inflammatory DMTs don’t actually make much difference to the pathology driving this stage of the disease. This is why we are pushing so hard for combination therapy trials and the oncologising of MS to create the infrastructure to run multiple, parallel, add-on trials to address smouldering MS.
Overstretched healthcare systems are incentivising their HCPs to switch patients onto treatments that are less of a burden to the healthcare system, i.e. less monitoring and less hassle for the neurologists and nurse specialists. I have seen this with many patients who are relatively low risk of PML on natalizumab who have been switched off natalizumab to another DMT without having the relative risks, nor the strategies we can use to lower the risk of PML explained to them. In addition, some of the switch therapies, in particular anti-CD20 therapies, come with undefined long-term risks of their own. One of the patients I saw in this situation wants to go back onto natalizumab as she does not feel ‘as well’ on an anti-CD20 as she did on natalizumab. She is complaining that her brain fog has returned. If she had had things explained to her I suspect she would not have switched-off natalizumab.
Switching as a result of under-stretched healthcare systems is the switching of patients onto treatments to increase clinical activity and hence profits. This is more common in fee-for-service healthcare systems but also occurs in the NHS. In short, if you want to maximise your income it is better to have patients on treatments that you can charge extra for, i.e. infusions, monitoring visits, etc. Neurologists are no different from other people; if you create a perverse incentive for doing something we neurologists respond to it, it is human nature.
Fashion refers to the trend that patients often want to be on the newest and coolest DMT. The trend for the latest, brightest and most expensive DMT is often driven by social media influencers; pwMS who promote officially or unofficially DMTs. Switching therapies based on these criteria is not ideal, but some neurologists give-in to their patient’s demands and switch treatments for no apparent treatment benefit. If you are doing well on one treatment moving to another DMT is no guarantee that you are necessarily going to do better on the new drug. In fact, the new treatment may be associated with adverse events and long-term complications that have yet to emerge (known-unknowns on unknown-unknowns).
When I push the early-diagnosis, early-treatment, high-efficacy-first-line, flipping-the-pyramid philosophy of treating MS, I know that some patients will be harmed for the benefit of the overall population of pwMS. The counter-argument is to maximise the safety of the individual by using a slower-escalation strategy. This strategy, however, comes at a cost for the overall population; i.e. a less favourable group outcome. The path between these two extremes is a narrow one and full of obstacles or cognitive biases that in my opinion get in the way of doing what is best for pwMS. What we can do as neurologists, regardless of what treatment philosophy we subscribe to, is to avoid unnecessary DMT churn.
Marangi et al. Changing therapeutic strategies and persistence to disease-modifying treatments in a population of multiple sclerosis patients from Veneto region, Italy. Mult Scler Relat Disord. 2020 Feb 10;41:102004.
BACKGROUND: The availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy.
METHODS: Demographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence.
RESULTS: Of 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among second-line DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation.
CONCLUSION: The use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors.
CoI: multiple
Does the low-churn strategy apply to Siponimod as well?
I am still trying to understand when the latter is prescribed….
Siponimod is a difficult one. Whilst the MS community keeping pushing MS as 3 or 4 diseases and siponimod is only licensed from SPMS it is the dead-end or cul-de-sac DMT.
I have written on this before https://multiple-sclerosis-research.org/2019/12/is-siponimod-the-first-cul-de-sac-dmt/
Do you think masitinib is answer to stop smouldering MS? I know MD did a article but without full release of data the jury is still out. What’s your personal opnion? And if it is effective then surly it is the ideal addon treatment?
yes, it may be one of the answers to smouldering MS and needs to be trialled as an add-on therapy.
Excellent post. Thank you.
Long time listener, first time caller.
Some great points here Gavin. In the “under-stretched healthcare system” section I would include the group of NEDA2 patients with SPMS on a therapy who visit a private neurologist who recommends switching to a therapy they are clearly not eligible (or appropriate) for through the NHS, presumably because of the pressures of a fee-for-service model.
re add-ons
are you talking about current treatments?
What would you think should be added to Mavenclad or Tecfidera etc?
In the case of cladribine (Mavenclad), it would be a sequential treatment strategy, i.e. induction-maintenance. After cladribine, I would use teriflunomide or a BTK inhibitor or an antiviral. You then have the potential option of adding onto the maintenance treatment.
For DMF (Tecfiera) there are many add-on options at the moment we are pushing for a pioglitazone add-on study because of the synergy in the MOA between the two drugs.
Now I’m confused. I was NEDA-2 on Copaxone for 5 years. But as an avid reader of this blog, became convinced that I was probably undergoing unnecessary brain atrophy using a drug considered barely better than placebo!
So when my neuro offered Ocrelizumab, I jumped at the chance.
But are you now saying that neither drug offers better protection against atrophy?
The data for ocrelizumab on brain atrophy could be better and there should be a study looking at ocrelizumab given after diagnosis. I predict the atrophy data will look better at that point
The problem is that all the evidence in trials has been in ‘active MS’ and not smouldering MS. What I mean by this is that to get into clinical trials, including the ocrelizumab relapsing-MS trials, trial subjects had to have had relapses and/or MRI activity in the last few years. So we don’t know how effective ocrelizumab would be in patients with ‘stable-inactive’ MS or ‘smouldering’ MS. This is why we need clinical trials.
I can’t tell you how much I appreciate your posts and your honesty.
Thanks I am sure profG appreciates your kind words
Unfortunately the 40 watters are in power and as they line up to stop any real change to the status quo, it looks like a string of fairy lights
Thanks. Don’t forget that I am conflicted and I am likely to have many conscious and unconscious biases. For example, I am biased in favour of high-efficacy DMTs first-line. I think this is based on my personal experience of managing patients with active MS; they seem to do so well compared to patients who start on lower efficacy therapies. I often refer to the history of MS to the era before (BN) and after natalizumab (AN).
Prof G,
“I am biased in favour of high-efficacy DMTs first-line. I think this is based on my personal experience of managing patients with active MS; they seem to do so well compared to patients who start on lower efficacy therapies.”
I think this is a really key point. I have no idea how many patients with MS would fall under a neuro – 50/100/150. In specialist centres it will probably run into the hundreds – many of these patients will have RRMS and will be on a DMT. The neuro must start seeing patterns of how well patients are doing on a particular DMT. While some patients may be doing okay on the lower efficacy DMTs it must be obvious that patients on the higher efficacy treatments do better (lower relapse rate, better on MRI scans, better when asked about QoL issues etc. Surely a neuro should be using this real life experience to steer patients to higher efficacy DMTs? I can’t believe this issue would occur in oncology ie you have cancer X and I’d like to start you on an old low efficacy treatment! What about rheumatology? I think you have said before that using highly effective treatments have led to far fewer operations (to replace hip joints etc.). Are neuros who start patients on low efficacy DMTs risk averse, lazy (less monitoring), not aware of the benefits of treating hard and early? NICE need to review the efficacy of the older DMTs (which are still very expensive) and start removing them from the approved list.
Bingo! During the ECTRIM’s ‘Burning Debate‘ Gisela Kobelt argued from a population perspective for neurologists to stop using injectable 1st-line DMTs and to use the more cost-effective higher efficacy DMTs. She lost the debate to Magd Zakaria (Professor of Neurology, Cairo, Egypt) who said we should continue using injectables. Gisela was so horrified with the audience response that she has sadly stopped working in the field of MS. I suggest you watch the debate; it is still online:
https://onlinelibrary.ectrims-congress.eu/ectrims/2019/stockholm/281809/gisela.kobelt.for.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D6%2Amedia%3D1%2Ace_id%3D1603%2Aces_id%3D24911
In the ongoing maelstrom that is the world of MS research, diagnosis and treatment this can be said to be one weeny something, but I have found the loss of Gisela truly sad. It does seem as if the flipping the pyramid model of treatment is constantly crushed underneath the feet of the dinosaurs.
This post has made me realise that I’m unsure what, if any DMT, I should pursue receiving if I am,at some point, post third dose of Alemtuzumab, either with evidence of active or smouldering MS. It would be awfully helped ProfG if you could provide one of your ‘route maps’ as to patient options regarding DMTs throughout.
Post third dose means about 75-80% of people will go NEDAfor a long time….if you need a forth dose you need to be asking are you making an anti-drug response.
What ever happens the biology is clear and that is inhibit what you can as best as you can and hope that too much shouldering has not started.
Do you know any ‘influencers’, i.e. patients who are being sponsored to promote certain DMTs?
https://platform.twitter.com/widgets.js
Yes, I meet these influencers all the time at meetings and advisory boards. They are not necessarily hired to do blatant posts, but they are conflicted to a similar extent as so-called KoLs (key opinion leaders) and so when they post on Instagram, Facebook, shift.ms, twitter and/or other platforms they have an impact. The article above acknowledges this.
Selma Blair has promoteda type of steroids in the US, if you look through her Instagram you’ll see it.
There is no one size fits alland what may be good for Selma may not be good for others
Yeah, it’s pretty untoward… legal over there I’m sure.
God bless America!!
https://www.instagram.com/p/B40CumVHnMy/?igshid=1kz1ju7hbqxao
acthar gel.
Prof G if you were currently driving a 20-year old VW Golf wouldn’t you want the opportunity to trade-in your car for a Ferrari?
Speed kills and I am not the kind of person who likes flash cars 😉
I’ve been on daily Copaxone, now generic Glatopa. Stable on this for 13 years. Sometimes I get the drift I’m on an old fashioned drug. But why switch now? I will not.
Isn’t that common sense?
For newly diagnosed, So many choices. A friend’s daughter couldn’t handle shots. I’m fine with shots, especially when they sting-feels medicinal 🤦♀️
I do know you must take one of them and adjust if it’s not effective judged by periodic neurological exams by MS specialist Doctor.