Is it time to slay the Gambler’s dilemma?

At a teaching session last week I presented several slides showing that at a population level rapid escalation (vertical switching) or flipping the pyramid (high-efficacy first-line) are really the only two treatment options we should be using to maximise life-long brain health of people with MS (pwMS). I also have little doubt that flipping the pyramid will also prove to be better than rapid escalation; there is some early data to support this and at least two clinical trials ongoing to address this.

The study below shows vertical switching  (low/moderate to high efficacy switching) is superior to horizontal switching (between low/moderate efficacy DMTs). 

The issue we debated on the teaching course is that as neurologists we don’t treat populations, but individuals with MS and hence patient choice should always trump data like this. I explained to the audience that they must be careful not to share their patient’s biases, i.e. the gambler’s dilemma.  A gambler never goes into a casino to lose money. However, the gambler knows that on average he/she will lose money. The cognitive bias here is that they will be the lucky one that will win. Someone with MS is never going to have bad MS, they are always going to be the one that ends up with no problems in the future, therefore, they don’t need more effective treatments. This is wrong. Given sufficient time MS causes disability in the majority of people with MS. Time is brain and brain lost is never regained. Therefore the practices of watchful waiting (a British medical tradition) and slow stepwise escalation comes at a cost to individuals and populations of individuals with MS. 

Can I suggest to counteract these cognitive biases you play a little game and imagine how you would treat yourself if you had MS? 

The treatment targets in MS have evolved from simply reducing the frequency of relapses (NEDA-0), to becoming relapse-free (NEDA-1) to having no measurable disease activity (NEDA-3), to preventing end-organ damage (NEDA4 and NEDA-5) to finally maximising brain health to allow our patients with MS so that they can age normally. In the future, we will want to cure our patients with MS before any meaningful damage is done to their brains and spinal cords, and we will want to prevent MS in people at risk of getting MS. To achieve these latter targets we need a much more proactive treatment approach and we also need to manage MS holistically, which includes actively managing comorbidities and focusing on wellness and lifestyle factors.

Is it time to slay the Gambler’s dilemma? 

You can download these slides via the new ProfG’s SlideShare site that I now control myself. Please feel free to use the slides. 

Chalmer et al. Treatment escalation leads to fewer relapses compared with switching to another moderately effective therapy. J Neurol. 2018 Dec 4. doi: 10.1007/s00415-018-9126-y.

BACKGROUND: Patients with multiple sclerosis who experience disease breakthrough often switch disease-modifying therapy (DMT).

OBJECTIVE: To compare treatment effectiveness of switch to highly effective DMT (heDMT) with switch to moderately effective DMT (meDMT) for patients who switch due to disease breakthrough defined as at least one relapse within 12 months of their treatment switch.

METHODS: We retrieved data from The Danish Multiple Sclerosis Registry on all relapsing-remitting MS patients with expanded disability status scale (EDSS) less than 6 who experienced disease breakthrough. We used propensity score matching to compare annualized relapse rates (ARRs), time to first confirmed relapse, time to first confirmed EDSS worsening and time to first confirmed EDSS improvement.

RESULTS: Each matched group comprised 404 patients. Median follow-up time was 3.2 years [interquartile range (IQR) 1.7-5.8]. ARRs were 0.22 (0.19-0.27) with heDMT and 0.32 (IQR 0.28-0.37) with meDMT; relapse rate ratio was 0.70 (95% CI 0.56-0.86; p = 0.001). Escalation to heDMT reduced the hazard of reaching a first relapse (HR 0.65; 95% CI 0.53-0.80; p < 0.001). We found no evidence of delayed disability worsening (HR 0.83; 95% CI 0.62-1.10; p = 0.20) and weak evidence of disability improvement (HR 1.33; 95% CI 1.00-1.76; p = 0.05) with heDMT.

CONCLUSION: Switching to heDMT is associated with reduced ARR and delay of first relapse compared with switching to meDMT. Patients on DMT who experience relapses should escalate therapy to heDMT.

CoI: multiple

36 thoughts on “Is it time to slay the Gambler’s dilemma?”

  1. Good post Prof G.I was treated with Alemtuzumab 10 years and 9 years ago and have seen excellent results (I did get a thyroid issue which is treatable). I have a bias from (i) my excellent results and (ii) the experiences of others whom I met during my treatment.I think a highly effective drug (such as Alemtuzumab) from the start is the way to go to maximise long term health, but I have the following observations (mainly from my bias for Alemtuzumab):(i) this blog shoots itself in the foot by keep posting grim looking side effects from Alemtuzumab. I'm not suggesting a cover-up and am all for transparency, but the side effects need to be put into context i.e. percentage of recipients who experience the side effect and whether the side effect is treatable (my thyroid side effect was picked up through regular monitoring and treated effectively). We shouldn't be scaring off potential recipients given the outcomes which many experience. (ii) I still attend my annual clinic appointment / have my annual MRI so that I am part of the long term follow-up study. My neuro told me that many who have had Alemtuzumab and are 10 years out with good results often fall off the radar i.e. they are doing so well that they end up not attending annual clinic visits. So the overall long-term outcomes for the Alemtuzumab population may be under-stated.(iii) The key decider for me regarding going for Alemtuzumab was sitting in the neuro's waiting room a month after diagnosis and seeing the number of MSers in wheelchairs and in very poor health. My neuro told me that many of these patients had been diagnosed in the 80s and had not had the option of a disease modifying drug. My GP is amazed how well I am doing 11 years after diagnosis. My GP told me that she visits a care home in the area every week and there are half a dozen women in their late 30s to mid-40s (I'm a 42 year old woman) who are wheelchair bound or bed bound. MS can be a dreadful disease, but the MS websites often portray a different picture i.e. too rosy. MS neuros need to share real life experiences of patients with their newly diagnosed patients i.e. experiences of other MSers who have either not taken dmts or who chose low efficacy dmts i.e. how are they actually doing 10, 15 years later. A friend who was diagnosed a few years before me read that on average an MSer needs a wheelchair 15-20 years after diagnosis. She has taken the view that she will start a dmt 12-13 years after diagnosis to avoid the need for a wheelchair. She doesn't seem to understand that damage builds up from the start and and is irreversible. She also thinks that she will have a benign version of MS – even though I can see that she is accumulating deficits. Her neuro seems to be too keen to let the patient decide rather that give some hard truths and a strong steer.Many thanks for all your work.

    1. A very important comment highlighting the perspective of someone with MS. Over half the patients we treat with alemtuzumab at Barts-MS are out of area patients coming for second opinions. Why? Because their local neurologist has not offered them alemtuzumab, or is not prepared to take on the monitoring burden and to deal with the adverse events when they occur. This is unacceptable.

    2. Anon, you practically took the words out of my mouth,I have long been of the opinion that MS is just not treated seriously enough by the MS websites. I was on the MS Society website looking at counselling, and even the photos there showed everyone having a jolly old laugh, and they are so coy regarding symptoms and ridiculously positive – everything in the garden will be rosy.Well, I have PPMS, and suspect, with the benefit of hindsight, that I have had MS for at least 25 years – and up to about 6 years ago, not only would you not have known there was anything wrong with me, I didn't. So I wasn't offered DMTS, as I was past the point they would be effective when dx'd.So if I can go from apparently fit and healthy to EDSS 6.5 in six years (and I'm rapidly heading for EDSS 7 if I'm honest), what is building for people who have enough symptoms to be dx'd at the same age I was when I was living in my fool's paradise?And whilst I appreciate that the MS websites are trying not to frighten the newbies – they are overcompensating by being way too rosy – the newly dx'd need to be properly informed, as otherwise, they won't take on the perceived risks of effective treatment – thereby ensuring that if their MS does take a bad course, they will have a bad outcome.We aren't children, we are adults, we need information to make properly informed choices, not the endless optimism being pushed by the MS websites.

    3. The point about the therapeutic lag is that it should never be too late to start DMT, but it will take years to show benefit.

  2. Fatigue resolution should be included at NEDA. It is a debilitating symptom, maybe more than others. As another patient here had said, fatigue can work like the canary in the mine, you can see how well a treatment works.

    1. Fatigue is a very complex symptom and is not necessarily modifiable by DMTs. I will do a detailed post on this topic for you.

    1. Re: "Is there really a place for watchful waiting in the modern management of MS?"Yes, not all patients have active MS and would not be eligible for DMTs under NHS England Guidelines. Rather than discharge these patients they need to be followed and monitored. The latter can be called watchful waiting.

  3. Many of us are not blessed to have a neurologist who will do the necessary monitoring post Alemtuzunab. I feel this is critical when taking the higher efficy DMT’s. Switching doctors here in the US can be limited by ones insurance. I wish I had known all this 10 years ago when I was first diagnosed and could have been a better advocate for myself. Thank you for your interest and hard work.

    1. We recently discovered that NICE guidance is legally binding, i.e. if NICE has approved a therapy for MS and you are eligible your neurologist has to tell you that and make it available to you. The latter is subject to interpretation, however. It is only a matter of time before the law steps in and there is a medico-legal case around this issue. Maybe this is the nudge the we need to actively manage MS.

    2. I sincerely hope so ProfG I have it in writing that the neuro didn't think I met the criteria for highly active MS, following 2 relapses in 4 months and a new lesion apparent in MRI 3 months later. It's also in same letter, neuro thought I'd be fine on Tecfidera!The Blog is literally life-changing. I pursued further online info following things I read on this site, realised I met criteria for highly active disease, put pressure on said neuro who referred me into London. No evidence there of a neuro applying the guidelines of his own professional body or the NICE guidance!In Feb this year you had a whole heap of replies to the post about the meta analysis showing that DMTs post age 53, do nothing for preventing disability progression. You highlighted therapeutic lag and the cases you've seen of older PwMS responding to DMTs.I'm 55 years old, and a year on from receiving Alemtuzumab I'm NEDA ( MRI back in June)I agree with Anon, Sunday 16th – put side effects into perspective when choosing DMT and don't allow age to be a barrier!Oh, and follow ProfG advise on comorbidities and lifestyle. Going to be very unBrtish and praise myself to back this up. I am a healthy weight, don't smoke, drink very little, eat a reasonably healthy diet, exercise, use a degree of intermittent fasting and take supplements such as alpha lipoic acid. I saw my neuro physiotherapist last Wednesday for the first time in 9 months. She told me that I'm now at no more risk of falling than a normal person🙂Right here, right now, that's a perfect Xmas present and is worth all the effort of daily balance exercises and the risks associated with having had a DMT such as Alemtuzumab Wish everyone with MS knew of the Blog and could benefit from it as I have, to date.

  4. Thank you ProgG, this has really distilled my thoughts regarding what I want to do as a Prof Scientist wMS ( probably had first relapse 14 years ago, undiagnosed, but little obvious activity since, until 12 months ago, now with multiple lesions, so probably many silent relapses, but still NEDA), fortunate enough to have a fantastic neurologist, who listens and recognises that I understand risk/benefit and evidence based medicine, and to currently live in Australia where choice of treatment is not dictated by NHS. Your posts have confirmed my decision.Thank you again.

  5. "To achieve these latter targets we need a much more proactive treatment approach and we also need to manage MS holistically"Apparently, finding the cause of MS is not a prerequisite for curing or preventing the disease. There is a widespread fallacy in this blog that meaningful advances are possible without grasping in detail the pathology of MS. But you have to know your enemy, or else you are just shooting darts in the fog.

    1. Re: "… finding the cause of MS …"Don't you realise that we think we may have found the cause of MS (EBV) and that we are testing the hypothesis at the moment. The cure experiment is intrinsically linked to the EBV and the B-cell hypothesis. The problem is that the experiment is a 15-20 year experiment.

    2. Re: "But you have to know your enemy, or else you are just shooting darts in the fog."Not sure we don't know our enemy and that we are shooting darts in the fog. How do you think alemtuzumab, HSCT, anti-CD20 and cladribine work?

    3. For that matter how do you think natalizumab and fingolimod work? These therapies are based on a hypothesis that seems to tell a story, But you take these therapies away and you get rebound and you then have to develop another narrative. Its is the congruency of the narratives that is important.

    4. "we THINK we MAY have found".All you have is statistic data, no clear pathology. You can't explain anything about MS: How and why a lesion is formed, why lesions have an MS specific topology, why they stop growing (remission after relapse), why there is such an heterogeneity in MS types. Can you provide mechanisms for the above that utilize EBV?No. Instead of answering these questions first, you organize drug trials. Sorry, but no trial can have the scientific validity of old fashioned laboratory proof. You only waste valuable time.

    5. "How do you think alemtuzumab, HSCT, anti-CD20 and cladribine work?"How do you know they work? You don't know the exact pathology, so you can't measure it before and after the use of these drugs. You only measure the visible signs of normal immune response to CNS trauma. The damage goes on. The drugs don't stop the disease pathology, but the immune counteraction. They may be helpful in reducing the perceived burden of MS through swelling reduction, but they don't touch the real cause.

    6. "For that matter how do you think natalizumab and fingolimod work?"They prohibit the invasion of immune system cells and thus reduce swelling within the compartmentalized CNS. They prevent the full blown natural edema which is the result of a prior CNS damage. That way, less lesions are visible and less pressure is applied on damaged axons (perceived effectiveness). The damaging cause is not affected at all, so more and more damaged axons are gathered, upon which no natural immune action has been applied. Therefore, when the drugs are stopped, immune cells enter CNS and find countless damaged cells and go furious (rebound). Prove me wrong.

    7. VV you need to read the long-term follow-up data on the natalizumab treated pwMS. They do extraordinary well. Not sure they would if they had ongoing damage.

    8. Not all of them, so you can't be sure whether the extraordinary course of some is the result of natalizumab or just their MS. After all, most natalizumab treated patients were early in their disease, so many years must pass before they spent their neuronal reserve. Natalizumab just reduced their relapses, which in early stages leave little or no long term disability, apart from the short-term burden.

    9. "They do extraordinary well."+"Not very convincing"You should know and share with us the percentage of natalizumab recipients that have NOT switched to other drugs. It could help your readers decide whose arguments are more convincing. You should also update us with the total PML fatalities that are escalating to scandalous levels.

    10. The PML figures go up every month. About 60% switch to derisk PML It is scandalous but that is the perverse incentives to make money out of infusions.

    11. "Don't you realise that we think we may have found the cause of MS (EBV) and that we are testing the hypothesis at the moment. The cure experiment is intrinsically linked to the EBV and the B-cell hypothesis"CSF B-cells in relapsing multiple sclerosis are driven towards a similar,inflamatory fateObjective: To leverage a comprehensive, multidimensional RNA-sequencing pipeline to test the relative merits of three hypotheses regarding the role of B-cells in multiple sclerosis (MS) pathophysiology.Background: Three prominent hypotheses for the role that B-cells play in MS are 1) clonally expanded B-cells in the central nervous system (CNS) target unidentified autoantigens resulting in pathogenic antibody secretion and/or antigen presentation to pathogenic T cells, 2) CNS B-cells display a pro-inflammatory phenotype or cause tissue injury through secreted factors other than pathogenic autoantibodies, and 3) virally-infected B-cells trigger CNS demyelination.Results:We identified memory and plasmablast clonal connections (including identical clones) between patients across the CSF and periphery, dominated by IgA, IgG and IgM immunoglobulin subclasses. We identified pro-inflammatory profiles of CSF plasmablast B-cells that distinguish them from their peripheral counterparts and other CSF B-cell subsets. Finally, we detected no viral transcripts, including Epstein-Barr virus, in the B-cells (n=70 B-cell subsets).Conclusion: We describe a multi-pronged bioinformatics protocol that mines a unified transcriptomic B-cell dataset to answer questions regarding clonal connections, B-cell phenotypes and infectious triggers of MS. Our findings support the hypothesis that B-cells originating in the periphery undergo clonal expansion and sustain a pro-inflammatory shift in the CSF in MS, without detectable viral infection.Sorry no virus found:(

    12. "Don't you realise that we think we may have found the cause of MS" This is HUGECan i tell my neuro doc?Or wait a sec….?Obrigado

  6. Welcome back to the blog prof gMouse has been doing a good job but it's always good to have more inputIs Klaus on his way back more often?Everybody regardless of how good or bad their disease is should access this blog I know when I was diagnosed 13 years ago having probably had Ms for 20 plus years this blog would have helped steer me in the right direction

    1. Thanks for asking, DrK been very busy keeping the horses happy pulling #ChariotMS – more soon…

  7. In favor of the black swan :)"These results suggest selective migration of EBV-specific CD8+ T cells in the MS brain. Together with neuropathological evidence that EBV infection is dysregulated in the MS brain, these data support the concept that a CD8+ T cell-mediated immunopathological response toward EBV might sustain chronic neuroinflammation in MS."*search=Serafini*listing=3*browseby=8Obrigado

  8. InconclusivePrevious studies attempting to demonstrate EBV in the MSbrain observed the presence of EBV-infected B cells inlymphoid-like B-cell follicles.3 These initial studies werechallenged by the inability of different groups to consistentlyidentify EBV-infected B cells in cortical structures such asmeningeal follicles with germinal centers. We were also unableto identify any lymphoid-like structures in the tissue weexamined, leaving open the question of whether such structuresexist and whether meningeal B-cell follicles represent animportant site for accumulation of EBV-infected B cells in theMS brain.Molecular signature of Epstein-Barr virusinfection in MS brain lesionsdoi:10.1212/NXI.0000000000000466

  9. In favor of the swanIn conclusion, this study supports a role for EBV infection in MS, as both EBER-ISH andPCR revealed preferential, but scattered and low level of EBV infection in the brain of mostMS cases. Thus, without meticulous and thorough examination, low level of EBV positivitycould be easily missed, leading to underestimation of EBV positivity in MS. Our data also suggeststhat EBV may infect more than one cell type in MS, including microglia and astrocytes.However these findings need to be verified and the possible link between the presence of EBV,neuroinflammation, and neurodegeneration remains to be investigEpstein-Barr virus is present in the brain ofmost cases of multiple sclerosis and mayengage more than just B cells

  10. InconclusiveIt further highlights that unequivocalproof of Epstein–Barr virus infection in multiple sclerosis lesions is still lacking, due to issues related to the sensitivity andspecificity of the detection methods.Epstein–Barr virus in the multiple sclerosis brain: acontroversial issue—report on a focused workshopheld in the Centre for Brain Research of theMedical University of Vienna, AustriaBrain 2011: 134; 2772–2786 | 2772

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