Barts-MS rose-tinted-odometer: zero-★s
I saw her in the clinic last year for a second opinion. She has secondary progressive MS and had been on fingolimod for just shy of 4 years with an EDSS of at least 5.5. She was using a walking stick intermittently, particularly when mobilising outdoors and her EDSS was probably 6.0 or even 6.5 because on her own admission she was unable to walk 100m. She was told by her treating neurologist that according to NHS England guidelines he was going to have to stop her fingolimod because she had secondary progressive MS. He told her she must not worry because in 12 months time she could be eligible for the high-dose simvastatin or STAT-2 trial. Despite being anxious she stopped her fingolimod and two months later she had a rebound relapse with a brainstem syndrome. Repeat MRI after the relapse showed she had at least 8 new lesions. When I saw her she had an EDSS 7.0, which was during the recovery phase of her relapse. We restarted her on fingolimod. She has managed to claw back some function and her EDSS is between 6.5 and 7.0.
This case is not unique. Several times a year one of my colleagues will discuss a patient who has advanced MS (wheelchair-user) who after stopping their DMT have recurrent inflammatory activity and relapse. Please note that we have to stop DMTs when patients become wheelchair users or reach an EDSS of 7.0; this is what the NHS England’s stopping criteria mandate (black and white?).
NHS England Stopping Criteria 2019
The current DMT should be stopped if any of the following criteria are met:
1. No reduction in frequency or severity of relapses compared with the pre-treatment phase following adequate exposure to the DMTs (which varies for each DMT, but should be a minimum of 6 months)
2. Intolerable adverse effects of the drug
3. Development of inability to walk (EDSS 7.0), persistent for more than 6 months due to MS
4. Confirmed secondary progressive disease with an observable increase in disability for more than a 12 month period, in the absence of relapse activity. Secondary progressive disease would usually only be diagnosed in patients with an EDSS of 6.0 or greater. (Except for the rare phenotype of “relapsing-progressive multiple sclerosis” detailed in section 13).
Criteria 1 and 2 might lead to switching to alternative DMTs.
Criteria 3 and 4 will lead to stopping all DMTs.
Past criteria have included pregnancy, breastfeeding or attempting conception, but increasing evidence shows that some DMTs may be considered safe in these situations.
Stopping DMTs should lead to continued care within the MS team or transfer of care to services which can provide appropriate support, such as neuro-rehabilitation. If a drug is stopped for a reason other than intolerance or lack of efficacy, then it may be restarted at a later date, even though the patient may not have “requalified” through new lesions. This may apply, for instance, to people who come off a drug during pregnancy or to take an experimental drug in a trial.
Rebound MS disease activity is particularly problematic with anti-trafficking therapies such as natalizumab, fingolimod and potentially with the other newer-generation S1P modulators (siponimod, ozanimod, ponesimod). This is why I feel so uncomfortable about applying the NHS England’s stopping criteria to patients on these therapies. Another thing to remember is that the NHS England treatment guidelines are only based on evidence in terms of starting DMTs. In comparison the stopping criteria are not evidence-based, which is why I proposed we do a national trial to see how appropriate they are.
I suggested a few years ago that we, the MS community, do a randomised controlled trial to assess the efficacy of generic cladribine in patients with advanced MS. Patients having to stop their existing DMT because they have developed SPMS or reached EDSS 7.0 are randomised to treatment with generic cladribine or placebo with the primary outcome being NEDA or disease progression as defined using upper limb function. The trial will be an event driven study and if someone reaches study end-point they can be unblinded and offered a course of cladribine if they were previously treated with placebo or a further course of treatment or another off-label salvage therapy if they had been randomised to cladribine.
The SALVAGE-MS study would become part of our suite of #ThinkHand trials; i.e. to salvage upper limb function in people with more advanced MS. The real question is do we have equipoise to do this study?
Please note that in a small French study below, of stopping DMTs in pwSPMS, 35% of the cohort had relapses, or MRI activity, in the follow-up period (~5 years). Similarly, in the MS-BASE study below, of 485 DMT-stoppers vs. 854 DMT-stayers followed for at least 3-years, time to confirmed disability progression was significantly shorter among DMT stoppers than stayers. The data from these two studies would indicate that we should really question NHS England’s stopping criteria. Do you agree?
Another practice that is emerging is the stopping of DMTs in patients with so-called ‘inactive SPMS’ in the hope they become active and hence are eligible for siponimod treatment. Please note this practice puts patients like the one above at risk of rebound disease activity, which may come at a cost to the individual.
FRENCH STUDY
Bonenfant et al. Can we stop immunomodulatory treatments in secondary progressive multiple sclerosis? Eur J Neurol. 2016. doi: 10.1111/ene.13181
BACKGROUND AND PURPOSE: The benefits of immunomodulatory treatments in secondary progressive multiple sclerosis (SPMS) are unclear, calling into question their continuation. In the present observational study, we investigated the effect of treatment withdrawal on the clinical course of SPMS.
METHODS: We included 100 consecutive patients with SPMS who regularly attended our multiple sclerosis clinic. Inclusion criteria were (i) secondary progressive phenotype for at least 2 years, (ii) immunomodulatory treatment for at least 6 months and (iii) treatment stopped with no plans to switch to another. Clinical and magnetic resonance imaging (MRI) data before and after treatment discontinuation were assessed. Factors associated with relapses and/or MRI activity were identified.
RESULTS: Mean treatment duration was 60.4 ± 39.3 months, and mean follow-up duration after treatment withdrawal was 62.4 ± 38.4 months. The annualized relapse rate remained stable at 1 and 3 years after treatment withdrawal [0.09, 95% confidence interval (CI), 0.05-0.17 and 0.07, 95% CI, 0.05-0.11, respectively], relative to the 3 years prior to treatment withdrawal (0.12, 95% CI, 0.09-0.16). Sixteen patients experienced a relapse and 19 had a gadolinium-positive MRI scan without relapse during follow-up. A gadolinium-positive MRI scan within the previous 3 years before treatment withdrawal and Expanded Disability Status Scale score of <6 were positively associated with relapse and/or MRI activity after discontinuation (P = 0.0004 and P = 0.03, respectively).
CONCLUSION: In this retrospective study, including a limited number of patients with SPMS, the annualized relapse rate remained stable after treatment withdrawal, relative to before treatment withdrawal. Further prospective studies are needed to confirm this result and provide evidence-based guidelines for daily practice.
MS-BASE STUDY
Kister et al. Discontinuing disease-modifying therapy in MS after a prolonged relapse-free period: a propensity score-matched study. J Neurol Neurosurg Psychiatry. 2016 Oct;87(10):1133-7.
BACKGROUND: Discontinuation of injectable disease-modifying therapy (DMT) for multiple sclerosis (MS) after a long period of relapse freedom is frequently considered, but data on post-cessation disease course are lacking.
OBJECTIVES: (1) To compare time to first relapse and disability progression among ‘DMT stoppers’ and propensity-score matched ‘DMT stayers’ in the MSBase Registry; (2) To identify predictors of time to first relapse and disability progression in DMT stoppers.
METHODS: Inclusion criteria for DMT stoppers were: age ≥18 years; no relapses for ≥5 years at DMT discontinuation; follow-up for ≥3 years after stopping DMT; not restarting DMT for ≥3 months after discontinuation. DMT stayers were required to have no relapses for ≥5 years at baseline, and were propensity-score matched to stoppers for age, sex, disability (Expanded Disability Status Score), disease duration and time on treatment. Relapse and disability progression events in matched stoppers and stayers were compared using a marginal Cox model. Predictors of first relapse and disability progression among DMT stoppers were investigated using a Cox proportional hazards model.
RESULTS: Time to first relapse among 485 DMT stoppers and 854 stayers was similar (adjusted HR, aHR=1.07, 95% CI 0.84 to 1.37; p=0.584), while time to confirmed disability progression was significantly shorter among DMT stoppers than stayers (aHR=1.47, 95% CI 1.18 to 1.84, p=0.001). The difference in hazards of progression was due mainly to patients who had not experienced disability progression in the prebaseline treatment period.
CONCLUSIONS: Patients with MS who discontinued injectable DMT after a long period of relapse freedom had a similar relapse rate as propensity score-matched patients who continued on DMT, but higher hazard for disability progression.
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.
Is Prof G seeing red again? What happened to your rose-tinted glasses?
Yes, I am tired and in a bad mood.
We are still dealing with the fall-out of a major complaint about the blog and how it sometimes leads to patients questioning how they are being managed by their neurologists.
“I didn’t study all those years and work so hard just to become accountable to my PATIENTS!!!”
ProfG – we love you, and your crew, please keep doing what you do. MS makes our lives so dark and your work and particularly this blog, shine such a bright light on the condition and on our lives.
It has influenced me to make massive changes in my life which I am benefiting from hugely and I would be most upset if it’s taken offline. Withdrawing information availability is a terrible thing to do to patients.
Ask them to explain how exactly is patients questioning the management of their disease by their neurologist a bad thing. Who is it bad for? The patient or the neurologist? Who suffers the most? And since it is the only language that some understand… In the long term which costs the most?
It’s a rare PwMS whose only source of information about treatment options is a neurologist. MS material is publicly available on thousands of websites run by health authorities, drug companies, charities, foundations, advocacy groups, universities, medical schools, professional associations, research publishers, news aggregators, physician networks, private clinics, insurers, health management organizations, and individual bloggers. Anyone with university or college privileges, which are often given to alumni, has access to the vast research literature. Hundreds of thousands – possibly millions – of PwMS exchange information on Facebook. Personal experiences shared in private MS groups there include detailed accounts of interaction with clinics, hospitals and providers of care, including neurologists. Word travels quickly about the duds, but most mentions I’ve seen on Facebook or ratings sites are favourable. Some neurologists are highly praised for their clinical acumen and willingness to discuss options with patients.
Far from complaining, your fellow specialists ought to be recommending the Barts blog as a premium source of information and insight. I hope you’re rid of this annoyance soon and look forward to many more posts from you and your colleagues. You don’t have to do this but you do, and it’s deeply appreciated.
“Far from complaining, your fellow specialists ought to be recommending the Barts blog as a premium source of information and insight.”
Shortly followed by a fly-by from the aerial porcine squadron 🙂
I second this. I’m a human being with a brain that can think, despite my MS. I read a lot too. I want a doctor that will listen and work collaboratively, and I certainly don’t want to be written off because I get confused when too much is coming at me or because I use a mobility aid.
“Far from complaining, your fellow specialists ought to be recommending the Barts blog as a premium source of information and insight.”
And couldn’t these specialists who don’t like their patients doing their own reading and having their own opinions not publish their own blog? It’s a free world. Instead of getting all hot under the collar about others providing evidence-based information and expert opinions why not do the same themselves? Then they can direct their patients who, strangely, can read and think, to another source of material sanctioned by themselves.
🙂
Surely we want patients to ask questions?
Long gone are the days when ‘doctor knows best’. The best kind of medical relationship for long term conditions is a collaborative approach.
To facilitate this we need patients to be informed and empowered. Then for doctors to recognise what they know about MS from books/papers they have read in the past, clinical experience of so many hours a week since specialising, and many other sources. However one thing the majority do not have knowledge or experience of is LIVING WITH MULTIPLE SCLEROSIS FOR YEARS! – With once a year reviews if you’re lucky per patient (for half an hour?) that isn’t comparable.
Patients bring their own expertise that a wise doctor engages with.
This blog is vitally important to inform patients and encourages them to think for themselves and empowers them. It is more up to date with current evidence and studies than many other sources. Yes it gives opinions too but most of the time these opinions become mainstream after several years. It is the difference between instant news on the Internet or the slow printed paper delivered next Sunday – guess which one is in the process of dying. We as MS patients can’t afford to wait that long!
My own personal example was 2 years ago thinking about switching DMT and this blog referencing a study which directly affected me specifically. At my consultant appointment I was told that wasn’t true. I almost cried. The next year the consultant opened up with an apology that I was in fact correct and did have the latest information. I think they learned a valuable lesson that day., and so did I –
Doctors are extremely busy and will eventually find out the truth, but patients can get latest specific info quicker. We can be more informed than our consultant and I think that threatens some traditional doctor roles/egos.
Don’t get me wrong, I value consultant experience, wisdom and judgement. We just need to value a patient informing themselves and being an expert too.
Nobody has all the answers, we’re all muddling through as best we can, doctors and patients. Let’s work together for goodness sake, there is wisdom in the phrase ‘Two heads are better than one’
Why would a secure professional not like being asked questions about their practice? Surely they would like the fact that someone was reading up on their subject and taking an interest in it? Hmm … think the clue is in the word ‘secure’. And no wonder you are angry. But it only goes to show that the blog and the generous way you share information through it are badly needed.
I have a proposal, let’s reverse the onus of proof here. Rather than having to explain yourselves, why don’t the people who are complaining about patients questioning them explain themselves?
If they’ve got convincing arguments as to why pwMS shouldn’t have access to this information I’m sure they will be comfortable sharing them with us. If they’re not willing to have this conversation with us then I think they need to question themselves and if they are really putting the interests of pwMS first.
So please offer them a chance to post and explain themselves (perhaps anonymously?). I’d love to see it.
My objection to the ‘shut up and take the drug’ brand of doctor was not borne out of reading this blog.
I would be interested to hear what their objections to educated patients are but very much doubt they would want to say, and again my thoughts on that are not borne out of reading this blog.
🙂
Don’t you think stopping fingolimod in patients with SPMS to make them eligible for the simvastatin trial is unethical based on this patient’s experience?
Yes and no. It depends on who you talk to. Clearly, if you follow NHS England’s guidelines it is fine. However, if you think of the biology of MS and how DMTs work then you could argue that it not ethical. Why should DMTs suddenly stop working when someone moves from EDSS 6.5 to 7.0?
“Why should DMTs suddenly stop working when someone moves from EDSS 6.5 to 7.0?”
Surely this answers the question. If someone with progressive MS on a DMT continues to progress (up the EDSS) then the DMT isn’t working. I wonder if the effort / resources for this study (Salvage-MS) would be better spent on trials of agents that provide neuro-protection or address smouldering MS. Keeping progressive patients on expensive DMTs which only marginally slow down the speed of disability accumulation doesn’t seem a good use of NHS money. Would you really be happy to be told by a neuro that “you’ll still get progressively more disabled by continuing on the DMT, but it will take a teeny bit longer before you need a cane, wheelchair..”. MS patients deserve so much better than this!
How does the proposed trial fit in with MS Society’s Stop MS campaign (£100m campaign) with the aim of:
“By 2025, we want to be in the final stages of testing treatments for everyone with MS. Treatments that slow or stop disability progression.”?
Sid, you know the theoretical underpinnings of smouldering MS. You can still get worse and the treatment is working. Remove the DMT and the inflammatory activity returns and you progress much quicker. This is why we need a sandwich, with an anti-inflammatory at the base with add-on treatments to target the processes driving smouldering MS.
Doing studies tackling smouldering MS without an anti-inflammatory at the base are likely to fail. MS-SMART for example was not so smart in my opinion. Let’s hope the OCTOPUS trial design will be different. These concepts are critical for MS-STAT-2; if simvastatin has anti-inflammatory effects the trial is likely to be positive, if not, the study is likely to be negative.
I don’t want a wheelchair either, but that image in your post… It’s not really called for.
From my experience being on a wheelchair isn’t that bad but being unable to get in and out of it or loosing arm is bad
Photo is desolating
I don’t agree.
Let’s face it, none of us want to end up in a wheelchair.
And also let’s face it, with other serious PROGRESSIVE illnesses, there isn’t the “wait and see what happens” rubbish that we with MS get told is there?
MS needs to be treated fast and effectively, ASAP after diagnosis, and it’s about time some of the lazy neuroligists woke up and smelt the coffee.
And if a pic like the wheelchair scares the heck out of someone galvanizes someone into pressing their neuro to pull their finger out and treat effectively, I’m all for that
I agree with you to some extent, but I think we should remember that there are a lot of people in wheelchairs, for all sorts of reasons, some since childhood. I think the image is to some extent disrespectful to these people. It also depends on what context the image is used of course. But at the end of the day, the wheelchair is not the issue, the disability from MS is. (And not all MS disability is so clearly evident as to be appropriately signified by an image of a wheelchair.) A wheelchair is but a tool, a mobility aid, which helps many live their lives. Prof G himself has addressed the issue of wheelchair stigma on this very blog. And yet he posts this image.
Please note the wheelchair is empty, which is symbolic.
This post raises all sorts of questions, for example, what proportion of patients with SPMS should on a DMT and how many off a DMT? When do the risks of DMTs in people with SPMS outweigh the potential benefits of treatment?
Can’t be bothered to read this post. Where’s the EBV stuff.
Discontinuation of Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS) (DISCOMS)
https://clinicaltrials.gov/ct2/show/study/NCT03073603
One more thought: I wish there were a better term than salvage. I’m EDSS 7.5 on a good day but still seaworthy. Like bulk carriers, cruise ships and yachts, this MS-SCOW wants to stay afloat!
Salvage is really a criticism of the wider MS community and NHS England etc. who seem to think once you are EDSS 7.0 you are too far gone for trials, DMTs, etc. We are trying to change that attitude. Sometimes you have to be cruel to be kind. However, I am up for a more palatable name. Any ideas? But it needs to capture what we are trying to do.
Reclaim?
Very good. Not sure I can Trump that one 😉
Thank you so much for your blog and for all the time you give to help those of us with multiple sclerosis. Hope you are feeling more optimistic today and have the chance to get some proper rest over the weekend. I felt particularly low yesterday but was SO inspired by the beautiful music played by the brilliant semi- finalists of the BBC Young Musician of the Year last night. I believe the final is on Sunday on BBC Four and Radio Three – highly recommend for anyone needing a boost. Best wishes to all at Barts.
ta
That’s why the inductions could be better.
It’s not just neurologists and MS. I’m a person that had highly active MS at a very young age. No DMTs and no disability discrimination act. The relapses stopped and I didn’t become SPMS until 30 years later after serious unrelated illness. When I was visiting hospital in my business clothes, I was treated totally different to how I am now that I’ve retired and use walking aids or a wheelchair. I look around and it’s not just MS, it’’s that some doctors forget that their patients had careers and contributed to society. Luckily, those specialists are in the minority, but when you are seriously ill it’s frightening. As for stopping DMTs, I don’t know I’ve never had one.
The research misses the pwMS that don’t have a neurologist or DMTs.
Yes, I identify with this problem, which is why our motto for the ‘Raising the Bar’ initiative is ‘no patient left behind’. What can MS services do to find and look after everyone in their patch who has MS. In addition, there is a lot more that can be done to manage MS over and above DMTs. This is why I spend an extraordinary amount of my time pushing the message behind the holistic management of MS.