#ClinicSpeak: what’s in a name?

Why have we turned MS into two diseases instead of one? #ClinicSpeak #MSBlog

I was a meeting this weekend and presented a talk in which I discussed MS being a length-dependent axonopathy. I made the case why progressive MS is modifiable and presented the positive results of the oral low dose methotrexate and ASCEND (natalizumab) trials and said that we had thrown the baby out with the bathwater. If we had interpreted the results of the oral low-dose methotrexate progressive trial from over 20 years ago correctly we would have had licensed therapies for progressive MS decades ago. 

I was then told by one of the participants at the meeting that the parcelling up of MS into relapsing and non-relapsing forms, and of chronic progressive MS into primary and secondary progressive MS, was driven by money. When the interferon trials started it was important to make MS an orphan disease, i.e. to having fewer than 200,000 patients classified as having the disease. Being an orphan disease allowed Pharma to access the market with one pivotal trial, gave them market exclusivity and allowed them to charge much more for their drugs. The consequences of this is that we have divided MS into being many diseases, which is to the detriment of people with MS. The consequences of this are not trivial. Being diagnosed as having MS is bad enough, but then being diagnosed as having secondary progressive disease is worse. The latter is interpreted by most people that their disease is not modifiable and that they are not eligible for DMTs. This is incorrect; remember #ThinkHand. In England we are meant to stop DMTs in the SPMS phase. There are also many other reasons to avoid the diagnosis of SPMS. 

An analogy to the RRMS vs. SPMS dichotomy is being diagnosed with a low-grade tumour, that on average is quite indolent and slow growing, however, after time the tumour mutates to become highly-malignant and terminal. Just as people fear their tumour mutating, and becoming ‘terminal’, people with relapsing MS live in fear of developing progressive MS. 

Two diseases-in-one.

Our PROXIMUS trial, which is now over a year behind in recruitment, has been a victim of MS being two and not one disease. We made the mistake of calling it a secondary progressive trial. Very few of my colleagues have referred patients for this trial simply because it means diagnosing their patients as having early SPMS. Almost every neurologist I know avoids making a diagnosis of SPMS as long as possible because of the repercussions it has for their patients. 

I think we need to turn the clock back and get rid of arbitrary, non-science, based definitions of MS. They don’t help us clinically. I recently wrote a short commentary for MSARDs arguing the MS begins long before the first clinical attack, I plan to write a piece on the observations that progressive MS is present from the start of the disease. There is simply no magic point in time when you become SPMS. Dividing MS into relapsing and progressive phases may have helped Pharma get interferons licensed under the orphan-drug act, made them lots of money, but it has done the field of MS a major disservice

26 thoughts on “#ClinicSpeak: what’s in a name?”

    1. In SMART the criteria of the people entering the study were different because in SMART people had been labelled SPMS. In Proximus people have to be on DMT so they think they are RRMS

  1. Prof G this is your best post of the year by far and why I love this blog. The implications of what you are saying are staggering and suggests that we should have been treating people with progressive MS with DMTs years ago. Is that correct?

    1. However NICE would put a spanner in the works on cost-effective issues because people may still be progressing..but at a slower rate.However have a low cost alternative and this is not so much of an issue.

  2. I second that comment. As I age that is my biggest fear: converting to SPMS. Bravo for your commitment and courage to stand proud as a clinician. We are a society who likes labels and assigning them. Think Attention Deficit Disorder and Hyperactivityl

  3. Well said Prof G. All of us with any degree of MS have been, and will continue to be, disadvantqaged and let down by the non-scientific and profit-motivated categorisations of this disease.

  4. Do other diseases get played around with as much as MS? I was told by my neuro that I had the best type of MS – RRMS, but that by ten years it was likely to become SPMS. Now it would appear that the disease isn't really like that – we are all progressive from the start. Has it really taken 25 years to work this out? It was sad to hear that your PROXIMUS trial is already running behind schedule. With 100k MSers in the country there is a fundamental flaw somewhere.

    1. One was over estimating the willingness of people to have lumbar punctures…wish there were Swedish sites who do not appear to shy aware from lumbar punctures

  5. It's a mixed up (insert f-word if desired) world. We love pharma, we hate pharma. We love the NHS, we hate NICE. We don't want to be Spms even though we are all progressive. MSers of the world unite, you have nothing to lose but your canes. Team G has another campaign!

    1. Re: "…we are all progressive."No correct you all have MS and if we treat you early and effectively we will hopefully prevent your from developing more advanced MS that is associated with disability, etc… The aim is to get you to old age with enough reserve to fight the ravages of ageing, or not! Ageing is a fact of life.

  6. That's why I love this blog! All posts are true classes, teaching, and many times it seems that you report what we often, patients think of truth about EM and we face with it. Yesterday I read the sad news that a 24-year-old had their diagnosis changed to SPMS.It's as if a bomb had been left in his lap and he didn't know what to do with it. He said his treatment is likely to change radically. He's in Natalizumab, after passing the Fingolimod without success. Then I asked myself "what makes this guy already has SPMS so young, and I don't, at the moment? When will I go to the SPMS, or already am I progressive, even without sequelae, since MS is one?" …

  7. How do you explain cases of MSers who are doing well 20 plus years after diagnosis and others being very quickly devastatingly disabling if all MS is progressive?

    1. Mouse Doc – good point but then one more question: how do you explain this variability – with DNA? OR could it be – as I have read somewhere – that MS is T-cell driven in some people and more B-cell driven in others? That could explain the different levels of disability and also the varied efficacy of drugs.

    2. Lots of reasons for variability in progression.Off the top of my head.Location of lesions.Number of lesions.Age.Gender.Some will be able to handle the insult better than others.Some will repair damage better than others.Time between diagnosis and effective treatment.Lifestyle.And many more.

    3. could someone comment of this statement which surprised me when I first encountered it:MS is T-cell disease in some people and B-cell disease in others?

    4. I second MD2 comments 11.55MS is a T cell disease in some and B cell in others…I don't think there are two diseases. The manifestations I currently believe are part of the same condition, whether T cells play a part at some point and B cells at another point is a possibility but it they are involved they are both involved. Does one play a more prominant role.The evidence that MS is a T cell disease is circumstantial.Remember the CD4 depletion trial failed….or did it? There was some reduction in disease activity but it wasn't startling. Was the deletion enough, I suspect not. However we will never know if the depletion used was enough as they are not going to do the trial againDo B cells play a role. We know they do because there are pathogenic antibodies made but are these secondary to the cause more than likely.B cell depletion works…is it because they activate T cells maybe, is it because T cells express CD20 (I doubt it).However where could we get this idea from T cells cause blood brain barrier break down and cause relapses, B cell follicles in the brain cause grey matter lesions and progressive MS. Is this idea true or rubbish….we need more work

  8. I don't know, I agree with the statement that splitting MS into parts has been bad for patients. I do think we blame the profit motive a little too often on this blog; if we brought drugs to the market after one trial we saved many people; right? The question is, given where the pieces are on the board what do we do now? I think that people with MS, or whatever the PC term is, can spend too much time focused on the past and that can lead to depressive thinking and on to depression.

    1. You are right. Without relapsing-MS being defined as an orphan disease we may not have gotten the first licensed DMT for MS and the creation of the market that has subsequently driven innovation and has gotten us to this point today. Interestingly, about 5 years ago we went to the EMA to get PPMS defined as an orphan disease and they were having none of it. We could't convince the European regulators that PPMS was a separate disease. We can't have our cake and eat it.

    2. I disagree. I think it has been bad for patients. Who says no DMTs would have been developed if you didn't have the phenotypes? As a scientist, can you not have phenotypes but understand the limitations? – understand that you are grouping people for the purpose of powering trial results, instead of grouping them on the basis of what you can see (which, when these phenotpyes were developed, wasn't much at all). I feel like neuros have made a mess out of this whole thing. On the one hand, neuros are scientists and can't recommend anything that's not evidence based. On the other hand, the recommendations of neurologists – right to down to diagnosis, treatment and even prognosis – vary from one to another. That cannot be evidence based, of it if is then there is something wrong with the evidence. The answer, I guess – is the dogmas. But dogmas are not evidence. So neuros seem to have been operating on… well, not evidence.

  9. There are currently dozens of MS patients in the UK, desperately ASKING to be diagnosed as SPMS. Why, you may ask? Because then they can access HSCT in London, without the need to fail either Tysabri or Lemtrada. Happy days! ��

    1. Isn't a funny world, Mindy. All these musings about the effect of ocrelizumab on progressive MS are mirrored throughout the various HSCT trials. If only neuros actually read them to tried to and understand them. They could have mused earlier about the utility of it all.I guess it's much easier to label patients irrational and desperate.

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