Was the concept of flipping the pyramid as a treatment strategy explained to you when you were started on a DMT?
For several years I have been arguing for adopting the concept of flipping the pyramid as a treatment strategy for MS. This is a treatment strategy developed by rheumatologists for treating rheumatoid arthritis with great success. In short, flipping the pyramid is using very high efficacy treatments first line. The other treatment strategies are watchful waiting, slow escalation or rapid escalation.
I kid you not that watchful waiting is still alive and kicking, but is less common now than it was a decade or so ago. The message is finally getting through that ‘active MS’ is a modifiable disease and should be treated. Please note my emphasis on ‘active MS’, we are unable to offer people with inactive MS DMTs nor should we, therefore, watchful waiting is entirely appropriate in this situation. The debate, however, is about how to define inactive MS and how hard should we interrogate patients to exclude smouldering MS?
The slow escalation strategy uses clinical monitoring to make a decision to change treatments or not and is probably still the norm in the UK. The main reason is a lack of resources, i.e. staff and MRI scanners to implement annual MRI monitoring. Rapid escalation is probably the most common option chosen by patients and neurologists in other high-income countries, however, frequent MRI monitoring which is costly remains a barrier in many parts of the world.
By maintenance-escalation, we mean starting low and escalating up a treatment ladder using MRI monitoring to assist decision making. We know from several real-life data sets and clinical trials that on average you do better if you start on either natalizumab, fingolimod, alemtuzumab, daclizumab or more recently ocrelizumab, compared to the lower efficacy platform therapies.
It is very reassuring to see the latest real-life data set from Wales showing how much better pwMS do when they have started an ‘early intensive therapy’ compared to a ‘moderate efficacy maintenance-escalation’ approach. The evidence is now overwhelmingly in favour of the former treatment approach.
The question is whether or not neurologists and HCPs will at least register these observations and start to offer their patients a choice between these two treatment approaches?
When we designed our treat-2-target NEDA trial to compare these two approaches, several years ago, these concepts were quite new. When the trials finally got funded we at Barts-MS declined to participate because we don’t think there is clinical equipoise anymore; in other words, we don’t think it is ethical to randomise patients to a maintenance-escalation arm of a study given the emerging evidence-base.
At Barts-MS we feel strongly that our patients are educated about the above issues and actively participate in the decisions about which treatments they are started on or switched to. This does not mean that we the neurologists are not involved. In some situations, we make the decisions for our patients or limit the choices available because of extenuating factors. We also offer patients the choice of allowing us to choose or recommend a specific treatment for them. Interestingly, with the rising complexity of treatment options many more patients are opting for the latter.
Paternalistic medicine, i.e when the doctor makes the decisions, is making a comeback but only this time as an informed choice
Many of the relevant issues I discuss above were covered in my ‘Hot Topics’ talk at ECTRIMS. I am going to suggest I do a Hangout on this topic to go through these in more detail and to allow you to ask questions. In particular, I need you to understand about the cognitive bias I refer to as the Gambler’s dilemma and how you need to try and overcome it when making decisions about your treatment.
For those of you reading this post and have been started on DMTs in the last 5 years was the concept of flipping the pyramid ever explained to you and the potential consequences, to you and your brain, if you chose the slower maintenance-escalation approach?
Harding et al. Clinical Outcomes of Escalation vs Early Intensive Disease-Modifying Therapy in Patients With Multiple Sclerosis. JAMA Neurol. 2019 Feb 18. doi: 10.1001/jamaneurol.2018.4905.
IMPORTANCE: Uncertainty remains about how aggressively to treat early multiple sclerosis. High-efficacy disease-modifying therapies (DMTs) are often reserved for individuals expressing poor prognostic features at baseline.
OBJECTIVE: To analyze long-term outcomes in a population-based cohort according to initial treatment strategy.
DESIGN, SETTING AND PARTICIPANTS: In this cohort study, data were derived from January 1998 to December 2016, and analysis was performed in January 2017. From a total of 720 patients prescribed a DMT, 592 (82%) were included in the analysis. Reasons for exclusion were first treated elsewhere or privately (n = 39), clinical trial participant (n = 25), and insufficient clinical data (n = 45).
EXPOSURES: Patients were classified according to first-line treatment strategy: high-efficacy (early intensive treatment [EIT]) or moderate-efficacy DMT (escalation [ESC]).
MAIN OUTCOMES AND MEASURES: Primary outcome was 5-year change in Expanded Disability Status Scale score. Secondary outcome was time to sustained accumulation of disability (SAD). Models were adjusted for sex, age at treatment, year of starting DMT, and escalation to high-efficacy treatment in the ESC group.
RESULTS: Mean (SD) age of 592 patients at symptom onset was 27.0 (9.4) years. Mean (SD) 5-year change in Expanded Disability Status Scale score was lower in the EIT group than the ESC group (0.3 [1.5] vs 1.2 [1.5]); this remained significant after adjustment for relevant covariates (β = -0.85; 95% CI, -1.38 to -0.32; P = .002). Median (95% CI) time to SAD was 6.0 (3.17-9.16) years for EIT and 3.14 (2.77-4.00) years for ESC (P = .05). For those within the ESC group who escalated to high-efficacy DMT as second-line treatment, median (95% CI) time to SAD was 3.3 years (1.8-5.6; compared with EIT group log-rank test P = .08). After adjustment for relevant covariates, there was no difference in hazard of SAD between the groups. However, 60% of those who escalated to high-efficacy DMTs were observed to develop SAD while still receiving initial moderate-efficacy treatment before escalation.
CONCLUSIONS AND RELEVANCE: In a real-life setting, long-term outcomes were more favorable following early intensive therapy vs first-line moderate-efficacy DMT. Contemporary surveillance strategies and escalation protocols may be insufficiently responsive. This finding is particularly relevant as patients in real-world practice are typically selected for an EIT approach to therapy on the basis of clinical and radiological features predictive of a poor outcome. These data support the need for a prospective randomized clinical trial.
CoI: multiple
I was diagnosed in 2017 after ‘collapsing’ in just about every sense of the word and being hospitalised unable to do much at all for 2 months. I then had to wait three months to be put on a choice of anything but a high efficacy drug. 2 (‘bad’) MRIs later and still feeling ill I was allowed to move to a 2nd line drug which could have been Fingolimod, Tysabri or Lemtrada. Never was the idea of flipping the pyramid explained and noone would give any advice on which drug to choose, first or second line. When pushed it seemed the hospital/team preferred one of the two former drugs. No real reason given.
Hi so what drug do you now take? Is it effective? I’m still waiting 16 months on and have been given those options. I do u decided and all I have is a leaflet.
What happened to the BVL hangout promissed weeks ago?
How things have changed. 26y ago I came to the consult (UK) where the news of RRMS was delivered. V matter of fact.
An apparently respected professor at St Mary’s.
I was understandably surprised, asked for advice and about drug treatments.
Replies (I kid you not):
Eat less red meat.
High dose steroids
End of discussion.
The red meat advice is definitely not evidence-based; the whole anti-red-meat campaign is all based on association studies. However, it is widely accepted that the way we produce red meat and at the scale we are doing it at present is bad for the planet.
Quite. 26y ago I’m not sure that rationale underpinned the advice given.
The co2 input required per kg of red meat is startlingly high. If you have a spare 5 min to horrify your self look at the drone footage of the enormous feed lots in the US!
Anonymous 8 35 here. They have not changed that much everywhere in the UK – as shown by my recent experience and the approach of the hospital/centre I attended. London is another country …
I hate to be in agreememt with you.
It shouldn’t be
Anonymous 8 35 here. They have not changed that much everywhere in the UK – as shown by my recent experience and the approach of the hospital/centre I attended. London is another country …
Your passion, persistence, and persuasive summaries of the research, or lack thereof is helping my family make better choices. Thank you for all you do!
For those who want a quick explanation of the above study – Aaron Boster on YouTube.
2015
4 years ago
” if you try and design a horse by committee you get a Camel”
“If normalising atrophy is so important….given that it’s one of the biggest correlates with disability…..why would you issue guidelines that a) don’t even mention it and b) seemingly recommends first line treatments, for a majority of patients, which have close to zero impact on atrophy? Feels like these guidelines are going to lead to many patients committing to a path which leads to SPMS (for which you have no treatments), when there are drugs which can apparently delay (or maybe even prevent) SPMS when given early…….Really, in 2015, knowing what we know, why would a neurologist give anyone interferon beta, the lowest efficacy drug which bears almost no prospect of long term normalisation of atrophy, prevention/delay of SPMS, etc……………neurologist/the field in general needs a good kick up the arse and a reality check for being too conservative… And then you go and deliver a paper like this!
https://multiple-sclerosis-research.org/2015/06/neurologists-are-too-blue-abn-2015-guidlelines/
I’m not sure why you think that the inverted pyramid is commonplace. I’m sorry but you have been misled on this.
When it comes to holding a strategic conversation about treatment options, forget it. Try asking people with MS about that ! Almost without exception, every person with MS who I know has had to fight with their neuro every step of the way. Mine spent a good 10 minutes patronising me by repeatedly telling me that there is a difference between DMDs and symptomatic treatment. No s**t Sherlock! All because I asked for more effective treatment than he was offering. He was bullying and unwilling to discuss my treatment. It was his way or no way.
You’ll find that around 75% of patients leave the consult where they are told of their diagnosis with not so much as a leaflet. A friend of mine recently died in her sleep aged 38. She was diagnosed in October 2015 and at the time of her death 2 weeks ago, had yet to receive any DMDs. I was offered Tec or nothing despite asking to hit it hard and fast immediately. Anecdotally I hear almost daily pwMS being given a list of drugs to choose from. They are routinely asking advice in social media groups about which they should choose. Clearly their MS specialists are just not doing their job properly.
As for not treating “inactive” disease, this is shocking. Show me one person who can say with absolute certainty that MS is inactive in any patient. It’s always “inactive” or “benign” or “mild” right up until the time it’s not. Watchful waiting is never, absolutely never, ever, appropriate. I bet you wouldn’t take that approach for yourself. You’d want to hit it hard without delay.
I can’t think of any illness where it would be recommended to see how bad it gets before bothering to offer the best possible treatment.
My apologies if I sound angry, but it’s because I am. Angry and frustrated. Genuinely, what makes MS so different that it’s not treated until it’s too late ? We are effectively consigning 5,000 people to the scrap heap every year. That’s 1 person in every 600.
5,000 lives, 5,000 families, every year that doctors are playing God with, by failing to offer the most effective treatment at the time of diagnosis.
I can not comprehend the logic that sees value in a study that states the obvious. Let’s runaway similar study for cancer. One group gets chemo, the other paracetamol. Let’s see which group has a better long term prognosis.
The way DMDs are prescribed, or not, seems woeful. When finally allowed to get a higher efficacy drug – by getting more and more sick – I was told to go away and research them and choose one. I am not a scientist or a doctor. What other illnesses lead to the patient being told to choose a drug by doing their own research?! I did my best using pubMed (via university access I have due to being educated in a completely different discipline) and was told at a later appointment I was over thinking things and being too anxious when asking questions. Then when I finally chose a drug I was given the strong ‘hint’ that I should ‘choose’ another one which …. the hospital administers more often, apparently. Sorry to be a ‘moan’ as well but I just don’t get what drives the treatment approach (other than at Barts which I read about wistfully). Can’t there be a nationwide treatment protocol which is evidence based to be in the patients’ best interest? Stress isn’t good for MS!
“It was his way or no way”
Of course its not IS BRAIN
Obrigado
Yes! Everything you said!
Re: “As for not treating “inactive” disease, this is shocking.”
NHS England guidelines are quite clear on who we can and cannot treat. We also don’t have evidence of DMTs working in so-called ‘inactive MS’, because all the trials only recruit subjects with active disease.
What sort of input is being made by the research/lobbying/patient groups to have the issue of ‘inactive MS’ addressed so that early DMT intervention is a therapeutic option?
Caould it be being done better or differently?
Invert the pyramid? I don’t think many Neurologists know about the pyramid to start with, let alone the need to invert it.
Almost 3,000 members in my UK Forum all wanting to get their MS into remission. Across the board, I hear daily stories of no medication, no MRIs, no Neuro appointments, no compassion. Brits only realise that one MRI in 11 years and no drugs is NOT the norm, once they find our Forum. Literally hundreds of them, have had to not just flip the triangle, but also flip their Neurologist!
I am constantly embarrassed when dealing with the a International MS community, at how dreadfully MS patients are treated in the UK. Let’s start telling cancer patients to go away and get worse before we help them. That should work, eh? To me MS is a cancer of the immune system; so let’s start taking MS seriously.
Personally I will keep fighting for UK MS patients until my dying breath. Which luckily, due to completely ignoring all UK based ‘MS advice’, and having HSCT in Moscow in 2015, should at least be another couple of decades! The campaign for proper UK treatment for MS is only just starting. All the rubbish Neurologists need to be afraid, in fact any of them not as knowledgable as Bart’s team, need to be very afraid! 😊
Can I suggest a soft approach rather than an adversarial approach? The way to win minds is by diplomacy.
I tried the ‘soft approach’ for many years and got nowhere… ☹️
“an escalation approach to DMT may be inadequate to prevent unfavorable long-term outcomes.”
The way DMDs are prescribed, or not, seems woeful. When finally allowed to get a higher efficacy drug – by getting more and more sick – I was told to go away and research them and choose one. I am not a scientist or a doctor. What other illnesses lead to the patient being told to choose a drug by doing their own research?! I did my best using pubMed (via university access I have due to being educated in a completely different discipline) and was told at a later appointment I was over thinking things and being too anxious when asking questions. Then when I finally chose a drug I was given the strong ‘hint’ that I should ‘choose’ another one which …. the hospital administers more often, apparently. Sorry to be a ‘moan’ as well but I just don’t get what drives the treatment approach (other than at Barts which I read about wistfully). Can’t there be a nationwide treatment protocol which is evidence based to be in the patients’ best interest? Stress isn’t good for MS!
Everything phoenix2507 said. I am in the us and agree here too we treat ms worse than cancer patients. We wait until there’s irreversible damage before we hit it harder. Even though all the evidence we have says your best chance is hitting it as hard as you can the first few years. I went on Ocrevus a year after dx after failing copaxone. I pray i hit it hard early enough. That year on copaxone caused relapses I’ll never get over. I’m still mad I don’t get the choice for hsct. I would take it in a second. No one wants to sit there and watch themselves deteriorate whilst medical professionals that are supposed to help us just wait and see. We know what happens when you wait and see. Lives get smaller and smaller and it’s too late.
You need to put the things in context. Neurologists by way of their nature tend to be conservative in comparison to oncologists. The way to influence neurologists is to show them the evidence, i.e. data.
So it’s up to us patients to show our doctors the data? What data do we show (at least in the US) regarding hsct which isn’t fda approved yet with not yet completed trials? I love your point about flipping the pyramid (even if we’re not talking hsct)?and will do everything I can as a patient in the us to help. IMO except for very informed patients who insist (it is their choice!) the use of CRAB drugs for first line needs to stop!
Another side of the coin, which is rarely discussed on this blog, is the large group of pwMS who don’t want to be treated, i.e. the so-called DMT-denialists. They tend to believe in a conspiracy theory that neurologists are just pharma-puppets peddling dangerous drugs so Pharma can make money. How do we manage them?
It’s the same situation as in cancer, albeit not so extreme, but this is to be expected – in MS, it takes years and years to deteriorate, in cancer, it’s much quicker.
How to deal with this? By treating pwMS as early as possible. And then others will see that they are doing better than those without drugs.,
I think it’s very important not to be too judgemental of PwMS who have such ideas. I think it comes down to a patient’s lack of trust in their neurologist, which is often understandable. I’ve seen several, and they were mostly wooden, dismissive, distant etc. The only one I really trusted most importantly had a sense of humour… MS is a scary disease, and fear generates mistrust.
The ‘MS world’ is very tribal. There are those who quite aggressively promote this or that treatment to all and sundry too.
I think too though that there’s no smoke without fire, and a certain eminent neurologist has said, when it comes to prescribing, you always follow the money…
Re: “I think it comes down to a patient’s lack of trust in their neurologist…”
I agree with you 100% on this. The question is why have we become so aloof and have lost the trust of our patients? How do we regain their trust?
“The question is why have we become so aloof and have lost the trust of our patients? How do we regain their trust?”
I can only speak personally when I say that I’ve experienced mistrust of a neurologist in that having slow PPMS, he offered me nothing. That wasn’t the problem though – I think DMTs would do nothing much for my MS – it was his manner. He came across as arrogant, uncaring, almost defensive. I dealt with it by just asking the question – is this a budget decision? He softened up a bit then.
My best ever neurologist came across as caring about me as a person with a life to live, not as yet another patient with a defect. He talked to me, not at me. His advice was the same, but I never felt any trust issue with him.
But this is no doubt a complex, multifaceted issue. Worthy of a blog post?
I think, sadly, it’s a significant degree of the opposite: as with many others I had complete faith! It was some 6-9months post diagnosis that I was the more informed patient. By which point I was blown away by the baloney that I’d been given, by not one but two neuros. Trust and faith was replaced by distrust and anger.
If asked, I would now feel compelled to advise anyone newly diagnosed to become as informed as possible and to be prepared for a potential battle.
Reckon I can safely claim to have met, under the NHS Treatment Algorithm for MS DMTs, the definition for Rapidly Evolving RRMS as I had two disabling relapses within a six month period and enhancing lesions. Or the definition of Highly Active disease, except for being treatment naive. At the point of seeing the second neuro I was requesting Fingolimod. I didn’t know at the time I was eligible for Alemtuzumab and only asked for Fingolimod because Neuro No1 had mentioned it as the next appropriate option after my second relapse. Yet neuro no2 in his letter to my GP stated that ‘I would not describe her as having highly active MS, according to NHS England guidelines and she should be offered one of the first line DMTs i.e. the injectables or oral treatment.’
Said before – perverse luck: in fighting neuro no2 he decided to refer me into London and the referral wasn’t sent, so that there was a delay of 5 months until I wasn’t seen in the Capital. During that time I was desperately trying to go from ignorant to more knowledgeable and stumbled across a vid of you ProfG on YouTube talking about: you guessed it: Alemtuzumab!
Neuro no3 presented with two sides of A4 spelling out clearly: knew I could have it and why I wanted it!
If only everyone were so lucky!
If I had my choice everyone would see a Bart’s trained neuro!
Im sure the Barts trained Neuros are grateful for your kind words, but as you say knowledge is key.
I know it can still be a frustrating journey navigating the NHS and know it from my own personal experience of what a pain some people can be, but likewise I have experienced the amazing care and too. If we can help train the new generation of neuros it will help protect us from the dinosaurs. It was a pleasure at a recent London wide training day that we got some great feedback. The dya was organised by ProfG and most of the speakers were from Barts singing from a coherent hymn sheet:-).
Prof G the difference in tone between your comment excusing conservative neurologists and your comment regarding pwms described as ‘DMT-denialists’ is stark.
What are the numbers involved in the ‘large group of pwms who don’t want to be treated’? Of those how many pwms do want to be treated just not with currently available DMT’s? How many pwms are untreated simply because they don’t know which way to turn or what to think, not surprising given cognition issues? How many pwms not on a DMT are denialists? How many pwms not on a DMT are influenced by past experiences? How many pwms is it that ‘tend to believe in a conspiracy theory’, are pwms influenced by other conspiracy theories that you haven’t mentioned and what is being done to address those theories, if that is what they are? Neurologists also make money in the process not just pharma, where does that fit in? Perhaps the data that informed your comment could help you with your disdainful query, ‘How do we deal with them?’
Thanks MD.
You’re correct of course!
I’m surprised I let my bitterness claim me again to that extent, such that I didn’t add Neuro no3 has been fab and worked in unison with me concerning treatment and living with MS.
Being as knowledgeable and as assertive a PwMS as someone is capable of being is beneficial to engaging effectively with clinicians in more of a partnership of care.
I should have been clearer in stating that what I think would be ideal is if it were compulsory for all trainee neuros to attend training with Bart’s so that fewer and fewer PwMS are prescribed CRABS. Furthermore, that flipping the pyramid becomes the norm asap!
As always access to the Blog makes a world of difference to those of us who are aware of it 😊
May I just say this dialogue here in the comments section is one of the best examples of doctor patient dialogues I have ever seen. Keep up this work prof g you are creating more educated and empowered patients, more motivated and empathetic physicians and significantly elevating the discourse around this nasty disease
Please could you put a figure around this?
“Another side of the coin, which is rarely discussed on this blog, is the large group of pwMS who don’t want to be treated, i.e. the so-called DMT-denialists.”
Thank you.
Low, but not that low. I would guess in the order of 5% based on my experience. There are facebook groups dedicated to alternative therapies in MS. Common to them all is not to use licensed DMTs.
She love you ❤️😘. cutie 😍