ResearchSpeak: predicting transition to progressive MS
Isn’t it time we removed the EDSS blinkers? #MSResearch #MSBlog #ResearchSpeak
“The study below demonstrates how poor a predictor relapses are when it come to predicting the onset of the clinically-apparent secondary progressive stage of the disease. Are you surprised? I am not.”
“I personally don’t think relapses are the disease (MS). Relapses are simply a response of the immune system to what is causing MS. This is why in natural history studies, and the placebo-arms of clinical trials, relapses (and focal MRI activity) are such a poor predictors of disability outcomes. Relapses and focal MRI activity are only predictive of disability outcomes when you are on a DMT. Why? I suspect focal inflammatory MS lesions, the pathological substrate for relapses and MRI activity, are the immune system’s response to the the underlying cause of MS and are not MS; i.e. they are not a surrogate of the disease, if they were a surrogate they will be predictive of outcome on and off treatment. This is why MSers who do are doing well on natalizumab develop rebound activity when the drug is washed out; i.e. the immune system finds something in the brain and spinal cord and attacks it. What is interesting is whatever is causing MS does little harm in the absence of an immune response; the one proviso is this statement refers to short and the intermediate term outcomes (< 10 years). We can only answer the long-term question once we seen what happens to MSers who have been on natalizumab for more than 10 years. Anyone prepared to predict?”
“The other mistake the researchers below make is to define SPMS clinically. All the accumulating evidence points towards progressive MS beginning long before it becomes clinically apparent. This is why we need a biological definition of progressive MS that can be applied before MSers become disabled. Only by doing this will be able to prevent, or at least successfully, treat SP and PPMS. There is no point waiting for the horse to bolt. It is about time we, the MS research community, removed our EDSS-blinkers. Hopefully, research funded via the International Progressive MS Alliance will allow this to happen.”
BACKGROUND: Prediction of the course of multiple sclerosis (MS) was traditionally based on features close to onset.
OBJECTIVE: To evaluate predictors of the individual risk of secondary progression (SP) identified at any time during relapsing-remitting MS.
METHODS: We analysed a database comprising an untreated MS incidence cohort (n=306) with five decades of follow-up. Data regarding predictors of all attacks (n=749) and demographics from patients (n=157) with at least one distinct second attack were included as covariates in a Poisson regression analysis with SP as outcome.
RESULTS: The average hazard function of transition to SPMS was 0.046 events per patient year, showing a maximum at age 33. Three covariates were significant predictors: age, a descriptor of the most recent relapse, and the interaction between the descriptor and time since the relapse. A hazard function termed “prediction score” estimated the risk of SP as number of transition events per patient year (range <0.01 to >0.15).
CONCLUSIONS: The insights gained from this study are that the risk of transition to SP varies over time in individual patients, that the risk of SP is linked to previous relapses, that predictors in the later stages of the course are more effective than the traditional onset predictors, and that the number of potential predictors can be reduced to a few (three in this study) essential items. This advanced simplification facilitates adaption of the “prediction score” to other (more recent, benign or treated) materials, and allows for compact web-based applications (http://msprediction.com).
36 thoughts on “ResearchSpeak: predicting transition to progressive MS”
Yes, I am back from holiday!
Does this not tell us that MS is an autoimmue disease?
Re: "Does this not tell us that MS is an autoimmune disease?"Probably, but what is the immune system reacting to? Is it an autoantigen, an altered self-antigen that has been modified, a trojan horse antigen, or an exogenous antigen? Until we identify the inciting antigen the autoimmune hypothesis remains a hypothesis.
What's a Trojan horse antigen? Are you any closer to figuring out what the antigen might be? Is this what oligoclonal bands bind to?
"Probably, but what is the immune system reacting to?"Can the difference between MS and not MS not just be an overreaction to a commonly available trigger? The data of HSCT/Alemtuzumab (EDSS scores) would suggest that since the triggers after those therapies are most likely still available…
For all I've read here on the blog and other sources I have also thought about it: it could be MS caused by something that is hidden in the brain and cerebrospinal fluid? …Only then I ask again: if so, why is it so hard to find this causative agent for tissue analysis of the brain and the CFS itself?
Yes good question.If MS is autoimmune the answer is simple…the target is in the oligodendrocyte such as a myelin protein, a heat shock protein, an ion channel etc. and it is waiting there to be attacked.If MS is not autoimmune the answer should also be simple….the target is in the oligodendrocyte as this seems to be the target cell disappearing in MS.ProfG argues it is a virus….so the virus must be present and detectable in the target.Some people think it is a HERV. These are these endogenous viruses are in genome of every cell in the body, but when MS re-activates why is it only the brain only that reactivates?EBV, why is is so hard to find and why the brain?. JC virus?Maybe we are not looking in the right way…there was the Monkey colony in Oregon with demyelination their first attempts to find a virus failed.Maybe we need to deep sequence and see if there is anything lurking.
Since everyone has autoreactive immune cells in their body, including healthy people you would thin after the years and years of searching you would come to a conclusion. The same goes with looking for the elusive MS virus But as Einstein said "Insanity: doing the same thing over and over again and expecting different results."It is clear that the nervous system has control over the immune system and this is where the problem exists. Why would your immune system function autonomously while every other system in your body is governed by the nervous system?
Is it possible to have an oligodendrocyte transplant?
MD on Oregon monkeys with a similar condition to the MS I have read that researchers have isolated a previously unknown virus from a tissue sample taken damaged spinal nerve from an animal.If it is to bet on a viral trigger I bet the Herpes family of viruses … Correct me if I'm wrong but also found traces of Epstein Barr virus in the lesions in brain tissue of deceased people who had MS, or not?
oligodendrocyte translpant this is stem cells but it is not going to eliminate the esisting oligos.Yes there have been EBV found in brains of people with MS
I began as a child prone to bronchitis with every cold virus infection; this abated before puberty. In my family, there are some occurences of eczema and a lot of dairy allergy, and possibly thyroditis in a sibling. I developed dairy allergy as an adult and unfortunately an "allergy" to myelin as well??? I would say MS needs consideration within the context of a lot of other autoimmune disorders. And allergies. But I know that many with more knowledge than I will laugh at that; I'm certainly no expert, just another person with PPMS frustrated about MS's apparently endless smoke and mirrors.
I totally agree. I think human endogenous retroviruses or JC virus become active through interaction with other factors, such as Epstein-Barr virus or JC virus, more genetic predisposition factor and low solar radiation (VITD). The immune system does not know how to fight this endogenous retroviruses or JC virus then uses a mega arsenal damaging everything in place. It is the medicine worse than the disease? Maybe at first. Then with age, old age, the immune system ceases war and HERV or JC can grow up in peace and disability begins.
Prof G,Am I right in my understanding of what you are saying? There is something in the brain which causes no harm, however an event occurs and the immune system gets involved. The immune system is a combo of outside (which causes relapses) and inside (which causes progression i.e nerve degeneration). With Alem and Tysabri, the outside immune response can be quelled. Why don't we see lots of SPMS cases for those on these treatments? Is this where genes come in ie the extent to which the immune response is from the inside or outside?
Re: "With Alem and Tysabri, the outside immune response can be quelled. Why don't we see lots of SPMS cases for those on these treatments?"I am not sure we can answer this question yet. We need to see what happens to MSers who have been treated with Natalizumab or Alemtuzumab 15+ years ago. If the majority still progress, i.e. enter the clinically-apparent SP stage, then MS is unlikely to be an autoimmune disease. This experiment is currently running.
Dr. Giovannoni,At the moment, what percentage of patients treated with Alemmtuzumab would you say have progressed to the "clinically apparent SP stage" within 10 years of their first dose? How is the "experiment" currently looking?
It is a question that has some answers from the Cambridge data. There were 2-4 of about 80 but you have to ask when did they start. According to ProfColes these converters had the most aggressive disease and the most courses of drug i.e the poor responders. Start too late and the frequency increases.How long is the therapeutic window because this would focus the decision making.
Re: "[We] need a biological definition of progressive MS that can be applied before MSers become disabled."Huh? What's taking you? PPMSers become disabled from the get-go, long before they can benefit from clinical intervention, although even then they still can't benefit.What can be done to aid progressive MSers?
I place great hope in research into neuroprotectives. And I have faith that I and others with PPMS whose mobility is already affected will not be excluded from such new therapies and effectively sent to the knackers yard.
It's probably crazy to ask, but could there be any connection between MS and acne? Like some kind of diffuse inflammation? I was still having pimples even at 30. However lemtrada or the associated medication seems to have cleared it up remarkably. People talk about steroids making them break out, seems to have had the opposite effect on me.
Interesting point – I too find I flare up with pimples with immune system being over active. Also steroids and antibiotics do it too. I think our hormone regulators are all quite quirky and unique, but there could be patterns to explore.
I really like the summary on the tisch ms site, it appears to makes sense:www.tischms.org/finding-cause-msAm sure this link has been shared before. How accurate is the immune system? Does it react to something that looks like myelin and then get confused?
I read in the Tisch MS site on the X protein derived from an environmental agent, so far not associated with MS or any other disease … But I just saw on the site as recent news therapies with stem cells promoted by researchers group of the Tisch … So at what stage is the research with X protein?
Cinara,I understand that they are still working on it, there was no end date given.
Prof G – Does this mean you no longer believe induction therapies are likely to offer a cure? Your stance in the past has generally been that you believe by stopping immune attacks/relapses and treating early, you can prevent SPMS/end organ damage occuring. Like the rheumatism example you provide, where preventing inflammation early prevents the secondary degenerative condition developing.What you seem to be saying here is that the immune attacks/relapses are a smokescreen, and there is something else happening to cause the neurodegeneration. So stopping those relapses won't fix the problem.That's quite a big departure.If this is the case, then Alemtuzumab and the other induction therapies don't look likely to be long term solutions, as the immune system makes a near-complete recovery within a few years.Can you clarify what your current thinking is please?
There is essentially no evidence presented in this post. I wouldn't be too worried about Prof G's opinion on the matter until there is a coherent theory backed up by evidence.
Is post-natalizumab rebound the main evidence for this hypothesis? I'm sorry to beat a dead horse, but where's the evidence that post-natalizumab rebound is a real phenomenon? I've posted this question on two consecutive threads (now three) about rebounding, as the published evidence for this seems quite weak. Why base your theory around such a fragile phenomenon?
Re: "Why base your theory around such a fragile phenomenon?"I am not sure it is a fragile phenomenon; we also see rebound post-fingolimod. I am not aware of any my MSology colleagues who have a lot of experience with natalizumab stating that it does not occur. I personally have seen several cases of bad rebound.
Re: "Is post-natalizumab rebound the main evidence for this hypothesis?"No I have done several presentations on this topic in the last 2 years. http://www.slideshare.net/gavingiovannoni/why-i-think-ms-is-an-infectious-disease-for-the-blog
Thanks for your response. Below is the comment that I've posted on previous threads. The concern is that the rebound "phenomenon" is a statistical artifact. Where is the evidence that it's not?I've been confused about claims in the literature to have identified a rebound effect. Most papers that report a rebound effect have found it in no more than 20% of patients. Isn't rebound activity, as currently defined, expected in many patients just by chance? The pre-natalizumab baseline is a noisy estimate of how much disease activity these patients are naturally prone to. Some of these patients will be prone to disease activity which is higher than this estimate, and some will be prone to disease activity which is lower. So the observed rebound effect may just be these patients returning to their natural disease course. Not only that, but the patients being put on natalizumab are those with a poor prognosis and severe disease. Won't some proportion of these people be expected to have catastrophic relapses (as have been observed post-natalizumab) by chance? What was the base rate of such relapses in the population before any DMTs became available?
Prof G: Two comments on your slides:-Slide 6 presents data showing that enhancing lesions are preceded by other pathological changes in white matter. This is supposed to suggest that the inflammatory response is a reaction to some prior change in the white matter, e.g. a viral infection. This inference doesn't seem very convincing, since Reich has a 2014 paper (http://www.ncbi.nlm.nih.gov/pubmed/25088017) showing that white matter in marmoset EAE shows pathological changes prior to enhancement. This shows that pre-enhancement damage is expected even under the autoimmune model, and cannot be used to infer an inflammatory response to a pathogen.-Why would EBV infection of B cells trigger post-natalizumab rebound? Is the suggestion that there are infected B cells which lie dormant in the CNS during natalizumab treatment, and are then targeted after withdrawal?
Multiple sclerosis is primarily a neurodegenerative disease.http://www.ncbi.nlm.nih.gov/pubmed/23982272
This one opinion there are others
Re: "Multiple sclerosis is primarily a neurodegenerative disease."The long-term HSCT and alemtuzumab follow-up will either prove or disprove this hypothesis. The question is are you prepared to wait for the answer before choosing one of the induction therapies as a treatment option?
I will wait for the answer taking vitamin D.