Silent Progression “I saw it first” no “I saw it first!” Why did it take so long to see it?


Recently in the Anals of Neurology we have had a paper by the Hauser group warning of silent progression that insidously occurs during relapsing remitting MS.

This spawned a letter by a group claiming this had already been reported and called Bout Onset Secondary Progression. This was then put down by the original authors who said

“The authors also raise an interesting question with respect to the long-term fate of persons living with MS: are there two groups of RRMS patients, one whose fate is to develop progression and a second who will not? Perhaps this is the case; however, it is more likely that larger numbers of patients with RRMS will be identified as having progression as the observation time lengthens and more sensitive indices of neurologic change are employed. For example, we and others have shown that combining EDSS with other measures such as cognitive function, walking speed, and upper limb function will increase the proportion of RRMS patients found to have relapse-independent progression”.

Indeed the authors, I suspect with help from the manufacturer of ocrelizumab, have determined that a lot of the progression that occurs is not explained by relapses and markers of relapses and they have called this PIRA (Progression independent of relapse activity). Maybe one day ProfG can do an eductional post on this as he has the slide deck and it needs abit of explanation

“We agree with the authors that a common pathophysiology may well underlie silent progression and SPMS”.

Of course it does…..MS is one disease

“The key point of our manuscript is that it is important to recognize silent progression during RRMS thereby prompting a therapeutic switch to treatments known to slow disability accumulation in patients with progressive MS. Whether early escalation to high potency therapies, or their use at disease onset, preventsSPMS remains to be determined”.

So here is the question as they say a therapeutic switch is necessary.

But Switch to What?


Do we honestly believe that these current DMT are good enough to halt progression? I would ask where is this evidence? The evidence is that the trials were loaded with people with active disease likely to respond to these DMT, but do they really target silent progression…I doubt it..

They may get at a central root cause of the progression, which is the driving inflammation, but these are not going to get at the inflammation knocking off the nerves once the damage is initiated.

We have made the case that silent progression occurs from the very beginning of MS and bubbles under the surface, un-noticed (like a shark hunting. Baby Shark Do Do Doo Do Do Do Doo Mummy Shark Do Do Doo Do Do DoDo Dooo Daddy Shark Do Do Doo Do Do Daddy Shark…It is very catchy) until the compensatory mechanisms are exhausted and you start to call MS secondary progressive MS. Perhaps rather than switch treatment, it says we need to be bold and add-on treatment to target pathways not targeted by the treatment

You need more than just a DMT to protect as people (with PPMS) can continue to worsen on ocrelizumab. The extension studies make some observations

People got placebo or ocrelizumab to week 144 and then they all get ocrelizumab. Whatslost is lost.

This was PPMS but RRMS is no different. If you are not protected by taking beta interferon you loose. Normal brain volume loss is about 0.15% a year so by being on beta interferon the people lost 2 years of brain reserve

This is why it is essential that if you go on a weak inhibitor you have to be confident it is working for you…otherwise time is brain

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  • This is why people are doing hsct after diagnosis and not taking DMT’s….would you want
    to engage in an experiment to see if DMT work long term..?

    • But HSCT is a DMT; it is classed as a highly effective DMT. ATG and cyclophosphamide are potent IRTs.

      • “But HSCT is a DMT;”

        Maybe but in responders it increases CD8+ and Tregs..non responders
        start w/ limited Tcell repertoire and hence don’t rejuvenate as well. So
        a sort of immuno therapy.

        Was thinking of woman who go hsct months after diagnosis. Her aunt was on copaxone and died in 8 years. That explained it.

  • Yes, another great post!
    But what to do if you’re now in that non relapsing phase of progressive MS? My doctor is giving Tecfidera or Copaxone.

  • I am having a horrendous day. So my neuro at a xxxxxx hospital refused my request to escalate to lemtrada. While I was arguing with her that I believed I qualified, she gave in, however in the mean time lemtrada was taken off the table by the EMA. She then kept stating her position that I did not need to escalate despite two clear relapses with increased edss but without Mri evidence. I got a second opinion and they said I should go for fingolimod or ocrevus. I chose ocrevus and liaised with my ms nurse who got the ball rolling. I’ve been waiting 6 months but finally last week got an email from the ms nurse to say I’m being lined up to get the infusion in August. I was delighted. I got a call from the hospital in xxxxxxx to come in today for screening bloods and chest X-ray. I turned up and had the bloods. Then there appeared to be a question mark over the chest X-ray. So they messaged my neurologist and she replied to say she hasn’t authorised my escalation. Back to square 1. I have spent the day feeling so much despair and anger. Why? I’ve missed out on lemtrada because of this neuro and now she’s holding up my ocrevus infusion. I’ve no words for it. I’ve no idea what is going on but it is starting to feel personal. With all of these posts about smouldering ms and so on how can a neuro be this difficult with a patient who is having relapses that she has witnessed?

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