Friday, 28 November 2014

ClinicSpeak: early treatment delays onset of SPMS

More data showing early access to DMTs is better than delayed access. #ClinicSpeak #MSBlog #MSResearch

"The Scandinavian countries are blessed with data and the ability to collect it. Why? I suspect because it is cultural and happens at a national level. In Sweden virtually every MSer belongs to the national register and data is collected and added to this register annually. This substudy of the largest treating MS centre in Sweden demonstrates that early access to DMTs reduces your chances of a poor outcome; i.e. of reaching EDSS 4 or beyond. An EDSS of 4 or higher indicates walking difficulties and most in the field (but not me) think this is a good proxy for the onset of SPMS. This is just another data set confirming that early access to DMTs changes the long-term natural history of MS and delays you reaching certain disability milestones. As most of this data was from  the injectable DMT era (interferon-beta and glatiramer acetate) it is likely to get better with time with the emergence of more effective treatments."

"Why don't I think an EDSS 4 is a proxy for SPMS? This is because of therapeutic lag and the asynchronous progressive MS hypotheses that I have discussed many time before on this blog. I think the concept of SPMS is an academic construct to explain a clinical phenotype and is not backed by biology. Most of us accept that the pathological substrates that underpin progressive MS are demyelination, neuroaxonal loss and gliosis, which when combined with a failure of neuronal reserve manifests as progressive MS clinically. If we accept a biological definition of progression then progressive MS is present from the start of the disease, in fact it probably starts before you present with your first clinical attack or symptoms. New data shows that RISers (people with radiologically-isolated or asymptomatic MS) already have brain atrophy. In my opinion, any treatment that reduces or prevents these pathological mechanisms that drive progression will delay the onset of clinically-defined SPMS."

"The problem with our clinical definitions is that they are so unreliable and are a moving target. In the pre-DMT era SPMS used to be diagnosed when MSers had EDSS scores of 2.0-2.5. Now that we have DMTs most people will only diagnose SPMS when MSers are more disabled with EDSS scores above 4.0. Why? Simply because funders will only pay for DMTs in MSers who have relapsing disease. As soon you label someone with SPMS  it makes it difficult to prescribe DMTs. How can we rely on a clinical definition of SPMS, when we are continuously changing the definition?"

"I have sat on countless steering committees that have tried to operationalise time to onset of SPMS as a clinical outcome. It has not been possible to reach any consensus. The proposal to use an EDSS milestone instead, for example time to confirmed disability progression to EDSS 4.0, also has problems. Why 4.0? I agree that most natural history studies suggest that once MSers hit 4.0 the disease progresses relentlessly regardless of whether or not they have superimposed relapses, or not. I am not sure if this is correct when you are on a DMT. A lot of emerging data suggests that things are very different in the DMT era; we cannot rely on the natural history data to make decisions about the onset of SPMS. For one we need to consider the concept of the therapeutic lag; this based on the hypothesis that in MSers with reduced reserve capacity, disease progression occurring now has been primed by inflammation from one to two years ago. If you switch off inflammation now you need to wait three to five years to see an impact."

"The other problem I have is that our definition of SPMS tends to be defined by lower limb motor activity. What about the other neurological systems? This is why I think we need to seriously rethink our definition of what is progressive MS."

"There is little doubt in my mind that if DMTs reduce end-organ damage they will delay disability progression and delay the clinical onset of SPMS, however, you want to define it. Apart from the British Columbia register all the other data sets showed that DMTs delayed the onset of clinically-defined SPMS. The issue for purists is that this data is not collected in randomised trials and is therefore unacceptable. What do they want?"

"When I did my PhD I worked in Marc Feldmann's and Tini Maini's  laboratory; this duo pioneered the clincal development of anti-TNF (tumour necrosis factor alpha) therapy in rheumatoid arthritis. Anti-TNF therapy switched off the inflammation and made RAers feel well. This triggered a debate whether or not this would prevent end-organ joint damage and the need for joint replacement therapy in  the future. Marc Feldmann had no doubt about the longterm impact of these therapies. Why? He understood the biology of RA and knew that inflammation was the driver of end-organ damage; switch it off and you protect joints. Marc has now been proved correct; it is clear that the number of joint replacements required in RAers has plummeted. Maybe we should start counting walking sticks and wheelchair numbers? We already do; EDSS 6.0 and 7.0 are measured surrogates for sticks and chairs. If DMTs are reducing time to EDSS 6.0 and 7.0 they are reducing the needs for sticks and chairs. If the clinical onset of SPMS is linked to EDSS progression then DMTs are delaying the onset of SPMS."

"Unfortunately, unlike joint replacement therapies in RA, or renal dialysis, or transplantation in other end-stage organ failures, we can't replace the brain and spinal cord, nor can we restore their function when they fail. It is time to think of DMTs as preventive therapies; they are preventing the rate MSers acquire disability. We shouldn't get too bogged down in how we define this; particularly clinically. We need to remember the iceberg analogy." 

Kavaliunas et al. The Influence of Immunomodulatory Treatment on the Clinical Course of Multiple Sclerosis. GeNeDis 2014 Advances in Experimental Medicine and Biology Volume 822, 2015, pp 19-24. Date: 30 Oct 2014

Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system. One of the major questions concerning the clinical progression of MS, still insufficiently elaborated or confirmed, is if it can be slowed down or augmented by external factors. Immunomodulatory treatment is a disease modifiable factor shown to influence disease progression of various medical conditions.

Objective: To investigate if treatment affects the long-term clinical progression of MS, measured as time from diagnosis to score of 4 or higher of Expanded Disability Status Scale (EDSS).

Methods: Longitudinal, prospective data concerning treatment status and EDSS were collected by health professionals in the Swedish MS Registry. Study cohort comprised new diagnosed MS patients at Karolinska Hospital between 2001 and 2005. Survival analysis adjusted for suspected confounders was used with the outcome variable time from diagnosis to EDSS ≥4.

Results: Early treatment was correlated with longer time from diagnosis to EDSS ≥4 (HR: 1.77; 95 % CI: 1.15–2.73; p = 0.01). Additionally, the influence of the covariates—age at onset and the baseline EDSS, which were statistically significant with hazard ratios of 1.03 and 2.1, respectively, was found.

Conclusion: Early treatment was associated with a better clinical outcome.



  1. Could not we start with Therapeutic window 1: Bladder as clearly most MS patients suffer from it.
    How many people are doing research on Bladder and MS? Why is it simply ignored (in my country)?
    How to prevent it?
    How to treat it?

  2. I think there are some neuros who view SPMS as a distinct disease with a different pathology and that the DMTs no longer have benefit. How can this mindset be altered so that patients with progressive disease still receive treatment?

  3. Do you mind not showing the same picture of a shrunken MS brain? It's difficult enough living with this disease. Why don't you have a banner at the top of the page 'TREAT RRMS HARD AND EARLY TO PREVENT BRAIN DAMAGE AND SEVERE DISABILITY - THERE'S NO OTHER OPTION'. Too many of your posts cover the same message. Rather than keep hitting MSers with the message, why not get your governing body to change the MS training for neuros?

    1. Perhaps we can use a picture of a wallnut?

    2. Oh no, why did you have to mention walnuts ... The shrunken brain picture looks just like a walnut and it's already making me walnut phobic. Have pity, I usually eat a handful of walnuts every day.

  4. A well respected neuro told me about 12 months ago not to seek a DMT to treat the spms which is now the diagnosis. She seemed to think that a DMT would only be effective for inflammation. I really don't know what to think, having had rrms for 13 years and no medic discussed DMTs with me. The diagnosis may be spms now but there are many symptoms I don't have, and I wonder if a DMT would slow this down. Surely it's worth trying.

  5. No issues with shrunken brain images personally. Perhaps they should be made into flyers and sent to those of influence complete with the hit hard and early tag line anon quotes. I think most MSers are pro treatment. Who does this message need to get to? The ABN? NICE? A cultural change is needed at organisational level.

  6. Question for Prof G:
    In the Asynchronous hypothesis diagram above is it meant to be indicating that the various systems which are affected will be affected in the order illustrated? That is, bladder first, then legs, then balance, and so on down the line. Or is it just meant to be a "generic" representation, and the various systems will choose their own order?

    I ask because I believe that my MS has been pretty much progressive since the start, with no acute episodes/relapses which were identifiable, even in hindsight, but the order in which symptoms appeared was different to the Asynchronous diagram, and started with balance, and then over time included leg coordination, sensory (mainly in feet), bad fatigue, bladder, then some mild visual "glitches" (scintillating scotomas), and most recently intention tremors in upper limbs and loss of fine motor coordination in my hands. So far I seem to have pretty much escaped the cognition one, apart from the occasional MS Moment where the words are not there, and some problems with short term memory (my life is now ruled by lists of things to be done - not on list = doesn't get done!). It took around six years for things to get bad enough to really start chasing up some answers to the increasing number of symptoms, and I finally had a diagnosis just over 12 months ago.

    1. I have the same question : is it just meant to be a "generic" representation, and the various systems will choose their own order?

      Because my experience does not follow this order either

    2. Pretty consistently across nearly all of the information I have found about Progressive MS it is said that:
      It is more commonly diagnosed in people over 40 or 50 (or even later)
      The first and most frequent symptom for most PPMS people is difficulties with walking and problems with leg weakness
      Fatigue is the most frequent second sign
      This does not fit with the sequence outline in the diagram above, but it is also generally noted that as always each person's course is different, but that the main feature is steady increase in symptoms/disability without clearly defined relapses

  7. I didn't suffer with bladder problems until I had a cystoscopy looking for bladder cancer and the surgeon decided to do a procedure that I didn't need because I had MS. I also lost the use of my hands and eyesight, but not the ability to walk. Thankfully I recovered. So you are right Prof G you can't judge us on our lower limbs. However, some of us gave up going to the doctor every time we had a relapse and we didn't even realise we had SPMS, because we were just getting on with our lives


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