Progression on Natalizumab


Whilst we sort out what is going on I have agreed to try keep the news coming, as our contributors keep getting run over. However, I am pleased to say I zoomed with Dr Ide Smets today who is well and moving about.

As she now has metal plates following surgery I welcomed her to the MSblog “airline club” as I am sure she and ProfG will now get the feeling I have endured for years of repeately being stopped getting onto planes. With ProfGs pelvic scews no wonder he wants to cut down on air travel:-). During lock down I have done a deed poll to change my name….I wonder if it will work? Did you see the details it in the London Gazette? Anyway I digress

Where’s ProfG when you need him?

Today, I post on a concept of him and his mates (Colleagues).

A few years ago ProfG and others asked what are the drivers for disability progression? They came up with these concepts that an increase in disability could be due to a relapse causing damage. The called this Relapse associated worsening or RAW. However there was disability that accumulated later and this is called progression independent of progression of PIRA. See the diagrams below to explain this. I am sure ProfG would have done a better job explaining this.

Kappos et al. JAMA Neurol 2020 77:1132
A, Composite RAW and B, composite PIRA are the 2 nonmutually exclusive components (or drivers) of overall accumulation of disability, as measured by composite confirmed disability accumulation (CDA) in relapsing and progressive forms of MS. Study baseline is the reference point for disability changes measured over time; in the context of the studies, this is the time of randomization to study treatment, but in the context of the clinic, this would be
the reference disability assessment visit from which subsequent changes are measured over time. The shaded areas represent the intervals around the neurological assessments that had to remain free of relapses to fulfill the criterion of independence from relapses (at initial event and confirmation points). Neurological assessments were scheduled to occur every 12 weeks, according to the protocol of the study; if a relapse occurred, there was 1 neurological assessment outside of the schedule, at a point corresponding to the leftmost point on the relapse triangle. EDSS indicates Expanded Disability
Status Scale; IID indicates initial increase of disability; MS, multiple sclerosis

They looked at the trial data of ocrelizumab and concluded that most disability accumulation was not associated with overt relapses (Kappos et al. JAMA Neurol 2020 77:1132).

So in this study they look at Natalizumab

Graf J, Leussink VI, Soncin G, Lepka K, Meinl I, Kümpfel T, Meuth SG, Hartung HP, Havla J, Aktas O, Albrecht P. Relapse-independent multiple sclerosis progression under natalizumab. Brain Commun. 2021 Oct 9;3(4):fcab229

The objective of this study was to investigate confirmed progression independent of relapse activity in relapsing-remitting multiple sclerosis patients under long-term natalizumab treatment. We performed a retrospective, cross-sectional study of clinical data captured between 1994 and 2019 at two German multiple sclerosis tertiary referral centres. Data files of all relapsing-remitting multiple sclerosis patients treated with natalizumab for ≥24 months were analysed. Confirmed progression independent of relapse activity was defined as ≥12 week confirmed disability progression on a roving Expanded Disability Status Scale reference score by 1 point in patients with an Expanded Disability Status Scale score ≤3 or 0.5 in patients with an Expanded Disability Status Scale score ≥3.5 in the absence of a relapse.

Among the 184 patients identified, 44 (24% = substantiat number according to the authors) developed confirmed progression independent of relapse activity under natalizumab irrespective of the Expanded Disability Status Scale score at natalizumab onset.

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Object name is fcab229f8.jpg

.Analysis revealed disease duration as the main factor for confirmed progression independent of relapse activity development (P = 0.005).

On the plus side the “uber-substantial” majority (67%) did not show PIRA. The authors say “Our data suggest that almost 80% of patients do not develop cPIRA and remain stable despite a mean disease duration of 15.6 ± 7.5 years” and “When comparing our results with existing natural disease course data, the rate for conversion to a secondary progressive disease course may be reduced by 50% under natalizumab”

COI: Multiple

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.  Please note that Professor Gavin Giovannoni has no responsibility for this blog.

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  • Good news for Dr. Smets!!
    Not so good news on PIRA 🙁
    Does starting treatment early mean a better chance of less of that?

    • There are still some positives there. For example the 50 percent reduction in conversion to secondary progressive MS.

      I’m still guessing early treatment is so imprortant at possibly stopping the smouldering MS before it begins.

    • Acording to them only the ones that more mild disease

      Those with agressive disease are in the danger zone or cPIRA

  • Prof G commented on this research on his Twitter account:

    “Smouldering MS, progression independent of relapses (PIRA) or the ‘REAL MS’ is what we should be focusing on. Relapses and focal MRI activity are not MS; these simply represent the immune response to what is causing MS. #ResearchSpeak”

    So it looks like the therapies which focus on relapses / focal inflammation (the DMTs) do not impact on the underlying processes which drive tissue loss and disability. The MSologists need to reach some sort of agreement on this – otherwise it’s giving patients a false sense of security. What’s needed are treatments which address the underlying cause (?a virus) or which get into the CNS to stop the processes causing tissue loss. Once these are addressed the DMTs tackling relapses / focal inflammation won’t be needed.

    Hopefully the Sizomus trial, the trials of BTK inhibitors (the trials covering progressive MS), HAART trial for MS and anti-viral trials for MS might give us a better understanding of what’s going on and a move away from the lucrative therapies focused on relapses / focal inflammation. I’ve had a dig at neuro-immunologist in the past, but I do wonder what the neuro-pathologists have been doing! Something is going on in the CNS, but it’s still a mystery!

    • I have been following. Thank you for explaining. What still confuses me: for Tysabri in particular, if I have had no relapses and no changes in MRI that would suggest that the med is keeping something out of my CNS??? Otherwise would the “real” culprit not just keep doing damage? There is just starting to be a whole generation of pwMS and on DMT starting to convert to progressive forms. Should be interesting to follow the research.

    • BTK inhibitors (the trials covering progressive MS), HAART trial for MS and anti-viral trials for MS might give us a better understanding of what’s going on and a move away from the lucrative therapies focused on relapses / focal inflammation……If the BTK inhibitor work that will be the new lucrative agents

      I agree that different treatments are needed but are we sure that anti-virals will work? ProfG has some very compelling views, but they are not the main stream

      • “I agree that different treatments are needed but are we sure that anti-virals will work?” That’s why we need trials to find out. If you never get glandular fever / mono (I assume no antibodies in the blood), then you can’t get MS. So ebv is doing something to trigger or drive MS.

        The other issue is rebound – natalizumab keeps the peripheral immune system out of the CNS, but once a patient comes off natalizumab they often get a massive relapse. The peripheral immune system must see something is going on in the CNS (worse than usual) and wades in.
        We know that B cells and plasma cells are resident in the brains of MSers. Are they good guys or bad guys? Perhaps the plasma cells are just doing their job – pumping out antibodies as there is something going on in the CNS causing damage.
        There are some fundamental questions that research has not yet answered. The process is all very hit and miss ie try a drug and then try and draw some conclusions about what MS is!

        • “That’s why we need trials to find out. If you never get glandular fever / mono (I assume no antibodies in the blood), then you can’t get MS”.

          So the question is what do you use as an anti-viral because if you fail…..will you get a second bite? I believe ProfGold was aiming to do such a study before the pandemic but are anti-virals good enough for EBV? We have had a number of anti-HERV trials and all failed so far, drug not good enough antibody doesnt reach the CNS.

          You could argue that giving people EBV at a differnt age may also work, is some places with low MS EBV infection is earlier in life.

          Rebound…..So the solution could be simple….Look into the brains of natalizumabers and see what is there…There are PML post mortems look in areas where there is no JC virus and natalizumab biopsies (Wolfgang Bruck has these)……but rebound can simply be alternatively explained that cells able to cause damage in the brain are held up in the blood, take the brakes off and in they go. Yes they need to see something to destroy the tissue but is it virus or autoimmunity or a sick oligodendrocyte. You dont need to evoke there is massives of infection calling them in and if this were true why would 67% of the natalizubers in this study not show the progression….or do they not have the real MS?

          It is clear from the need to biopsy natalizumabers that natalizumab is not 100% effective and if lesions form they smoulder and we know that lesions can form without relapses I can easily see PIRA in animals but the natural history there is RAW.

          Sizimous may answer the plasma cell question…if drug it is working and plasma cells are being removed then they are bad guys as the trial hasnt been stopped for safety signals.

          There are indeed fundemental questions but you have to have people interested in answering them and the community needs to believe it to fund them. They have poured funds into the microbiome, only last week I heard the candidate that everyone finds is a good guy. But mention EBV and the hatchet falls.No funding, no study.

          I know ProfG has tried

          • I love MD always give reasons and the thinking process, learning a lot from all these comments.

  • This is exactly me! I have tried to have this conversation with my Neuro and mostly get a shoulder shrug. So since by all accounts I appear stable. What are the more subtle signs we should be looking for??? Standard MRI at this point seems quite useless IMO. In addition for many women during these 15 years, we will have gone thru menopause and so little is understood about how the drop off in hormones affects the course of MS. I am normally so calm day to day, but this discussion frightens me.

    • Agree with you. Been on tysabri since 2004 being no new lesion feeling getting worse. Neuro shrug off too. Like to try stem sell before too late.

  • Nice post

    Our findings suggest that natalizumab does
    not completely prevent immune cells from entering the CNS and is associated
    with an accumulation of plasma cells, the pathogenic and clinical significance
    of which is not known. As B cells are considered to serve as a reservoir of the JC
    virus, the observed plasma cell accumulation and reduction in dendritic cells
    in the CNS of natalizumab-treated
    patients may potentially play a role in PML

    CNS inflammation after natalizumab therapy for multiple sclerosis:
    A retrospective histopathological and CSF cohort study

    DOI: 10.1111/bpa.12969

  • If equivalent retrospective data was available for all the other ‘more effective’ therapies in use today would the findings be very different ie 67% do not show PIRA? They all work differently but are there any level playing field comparisons of eg Tysabri and Lemtrada where people with with similar symptoms and clinical background at time of diagnosis are compared over time for PIRA?

  • 10 months on tysabri and continous progression for me and relapses that left me hospitalised. I was diagnosed 18 months ago and am now under barts having hsct! Lets hope this does the trick 😊 p.s every single member of staff here is incredible such an amazing facility and staff.

  • This so-called PIRA could be very well dependent on relapse. RAW = direct damage, PIRA = Neuron dying off slowly for various reasons, or neuro elasticity could not be maintained for various reasons.

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