UCSF MS-EPIC Team, Cree BAC, Hollenbach JA, Bove R, Kirkish G, Sacco S, Caverzasi E, Bischof A, Gundel T, Zhu AH, Papinutto N, Stern WA, Bevan C, Romeo A, Goodin DS, Gelfand JM, Graves J, Green AJ, Wilson MR, Zamvil SS, Zhao C, Gomez R, Ragan NR, Rush GQ, Barba P, Santaniello A, Baranzini SE, Oksenberg JR, Henry RG, Hauser SL.
Ann Neurol. 2019 Mar 9. doi: 10.1002/ana.25463. [Epub ahead of print]
Rates of worsening and evolution to secondary progressive multiple sclerosis (MS) may be substantially lower in actively treated patients compared to natural history studies from the pre-treatment era. Nonetheless, in our recently reported prospective cohort more than half of patients with relapsing MS accumulated significant new disability by the 10th year of follow-up. Notably, “no evidence of disease activity” at 2-years did not predict long-term stability. Here, we determined to what extent clinical relapses and radiographic evidence of disease activity contribute to long-term disability accumulation.
Disability progression was defined as an increase in Expanded Disability Status Scale (EDSS) of 1.5, 1.0 or 0.5 (or greater) from baseline EDSS = 0; 1.0-5.0; and 5.5 or higher, respectively, assessed from baseline to year 5 (± 1 year) and sustained to year 10 (± 1 year). Longitudinal analysis of relative brain volume loss used a linear mixed model with sex, age, disease duration, and HLA-DRB1*15:01 as covariates.
Relapses were associated with a transient increase in disability over one-year intervals (p = 0.012) but not with confirmed disability progression (p = 0.551). Relative brain volume declined at a greater rate among individuals with disability progression compared to those who remained stable (p < 0.05).
Long term worsening is common in relapsing MS patients, is independent of relapse activity, and is associated with accelerated brain atrophy. We propose the term silent progression to describe the insidious disability that accrues in many patients who satisfy traditional criteria for relapsing remitting MS.
You get worse if you have relapsing MS and here it is suggested we call it “silent progression” as it was not predicted from relapses. Perhaps we should simple call it “ineffective disease control and shitty outcome measures”.
We have said that MS is one disease , which is inflammatory from beginning to the end and neurodegenerative from beginning to the end.
If you have relapses (clinical or sub-clinical) you get lesions that will probably follow a destructive course. If you do not get this under control then there will be disability consequences. It is simply biology and should come as no surprise. If you can’t find this you are probably not looking in the right way.
Look at the mice. Do the number of relapses say which animals go progressive, I would say yes but also no. Some mice strains go progressive after on attack, some two, some fourif depends on their sex etc., so it is not going to a simple relationship in humans.
You don’t notice a sub-clinical relapse. We know there can be are over ten lesional events per clinical relapse and you don’t see all stuff by MRI. In this study only 50% of the relapses were associated with MRI activity. However, this study is basing ideas on a tool that misses absolutely masses of nerve loss. This is because the nerve loss is being replaced by scar and fluid. So if we measure change in the spine it shrinks by say less than 5% when there has been 50-60% of nerve loss. So again I say not so much “silent progression” but “shitty outcome measure”. Furthermore a brain MRI is not going to inform on spinal cord movement function.
This week we have seen some animal work showing that if you have spinal lesions it can affect brain atrophy, so when pathologists say they have nerve loss without demyelination again it may be look at the biology and the cause of the problem does not have to be in the same tissue section.
Do nothing and you may relapse and convert to progressive MS in time. Based on the Cambridge cohort, it appears if you treat early that conversion to progressive MS is lower. As ProfC said to me, those that were more disabled at the start of treatment did not do as well as people without accumulated disability. But then we have the story from the CRAB drugs and we have had whiffle waffle, leading to some eminent neuros to say relapses aren’t important allowing the naysayers to sit on the fence. Whilst your brain is being shredded.
If we look at past reports published in 2016. Mobility worsened in half of the cohort over 10 years. If people had PPMS 100% disability worsened is they had an EDSS over 3. The risk of change to SPMSS was 6% after 10 years and 24% over twenty years. There was less loss of hand function.
However, if we look at the treatment most people (60%) were on platform i.e. CRAB drugs, which we know are not that effective, 40% weren’t treated and on 1-2% were on high efficacy drugs. So fast forward here and the conclusion is that people on treatment still progressed.
I guess I say what else should we expect?
Show me the same data when people are treated first line with highly effective DMT and I will shut up. It may be that progression will still continue, but give it your best shot. Progression did not correlate with lesions but one important lesion in an important site is going to do more damage than 10 in non-important sites.
We make a play on NEDA and how we want to achieve this. The problem is that if we start highly effective treatment too late, once nerve damage has occurred, no matter what we do to stop relapses the consequence of previous lesions will continue. Lesion formation and relapses should be responsive to DMT, however we, or maybe I should say , I at least know that the progression aspect is not explained by relapsing effects. It is biology. So once a nerve tract starts to progressively worse, this damage is going to worsen no matter how good the DMT is
It’s like a fuse, once it is lit with a match, blowing out the match is not going to stop the fuse burning and you can’t blow out a fuse. The longer you have untreated MS the more fuses are lit and the longer it takes for them to finish burning Likewise the more fuses lit the likelihood of a bigger explosion occurs once the fuses react the dynamite or nerve cell body. I wonder if this is the problem here. So rather than inventing the term “silent progression” we should say “ineffective treatment-should do better”.
In the study they report “These analyses showed that treatment with platform therapy reduced brain atrophy and that escalation to natalizumab is potentially associated with further stabilization of brain volume loss despite natalizumab treated participants having lower baseline brain volumes, which we interpret as a marker of disease severity”
ProfG has intimated that ProfH has said that people on rituximab may convert to SPMS. Maybe ProfHauser should use the disclosed “writing assistance” to write about that experience if it is true.