Saturday, 6 January 2018

Walking the talk, but too slowly: one #MSBrainAttack too many

How quickly should we treat MS? As soon as possible. 

I made the case on behalf of DrK last month for a natalizumab Brain Attack Trial? I now have a personal clinical anecdote why we should not delay things any longer.



I saw a new referral in my MS clinic about 6 weeks ago. She was from an ethnic minority (red flag) with highly-active disease. Her imaging was very active but slightly atypical; she had a confluent lesion around the aqueduct that has been described in anti-aquaporin-4 positive patients with NMO spectrum disorder. I, therefore, delayed making the diagnosis to repeat her imaging, do a lumbar puncture and check her anti-AQU-4 results. As this, all occurred over the Christmas period it took 6 weeks for her to come back to me with all the results. In this period she has gone onto to have a very disabling brainstem attack. All her tests are back and confirm the original diagnosis of MS. If only I had started her on natalizumab whilst I was doing all the tests we would probably have prevented her having this attack. 

She is now coming into hospital as an urgent admission for a course of intravenous steroids and to be started on natalizumab. Please note we have decided to start natalizumab without knowing her JCV serostatus. If she is JCV-ve we will leave her on natalizumab and if she comes back JCV+ve we will then decide on what DMT to transition her onto after a 12 month period of treatment. 

What this patient illustrates is that MS activity tends to be clustered. A powerful predictor of a relapse is a recent relapse. The case for putting patients with possible early active MS at risk from having to wait is well illustrated in this example. Why don't we to treat all patients like this with natalizumab to protect their brains and spinal cords while we complete their diagnostic work-up? This is analogous to treating stroke.

Why natalizumab? (1) It is one of our most effective DMTs, (2) it works very quickly, (3) it is given as an IV infusion, hence there is no problem with adherence and (4) it is very safe for up to 12 months. (5) It is also relatively safe in pregnancy. During this 12 month period, the neurologist and the patient can then decide what strategy they want to pursue in the long-term. This could be to continue natalizumab long-term or to switch to another DMT, or in the case of an alternative diagnosis the drug can be stopped.

To make the Brain Attack Trial a reality we need the EMA to license natalizumab as a 1st-line treatment. This will probably require data. Hence we are proposing that Biogen sponsor a 'Brain Attack Trial'. This would become even more important if you can derisk the PML problem associated with natalizumab. Imagine if we can reduce the risk of PML to zero? Who wouldn't want to start on natalizumab as a first-line therapy? Natalizumab will become the one and only platform therapy. The problem with this is that Biogen has other DMTs in the MS space and the Brain Attack Trial will potentially result in natalizumab cannibalizing their other DMT market. How bold is Biogen?


ProfG    

7 comments:

  1. "She was from a ethnic minority (red flag). Does that mean course of MS is worse in non Caucasian people? Or particular ethnic minority? If so why and which ethnic community. Also given all dmt are tested on Caucasian populations. Are they as effective on ethnic minorities? As MS is rising quickly in non European countries. These questions will become increasingly relevant!

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  2. So you disagree with these recommendations?

    Update on the diagnosis and treatment of neuromyelitis optica: Recommendations of the Neuromyelitis Optica Study Group (NEMOS)

    Natalizumab

    The treatment of NMO with natalizumab should be avoided; a recent retrospective study reported clinical deterioration after natalizumab treatment in five NMO patients initially misdiagnosed with MS [212]. In line with this, Barnett et al. [213] and Jacob et al. [214] have also described natalizumab treatment as causing disease exacerbation in NMO patients.

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3895189/

    Why a simple course of steroids cannot be used to delay a second relapse till results are out?

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    1. But you won't treat NMO with natalizumab. Once you make a diagnosis of another condition, in this case NMO, you will discontinue the natalizumab and start another treatment, e.g. steroids +/- azathioprine or mycophenolate, or rituximab.

      It is unlikely natalizumab makes NMO worse; it is simply an ineffective treatment for NMO. Natalizumab blocks cell migration only and not antibodies from entering the CNS.

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    2. Re: "steroids"

      Steroids are ineffective in preventing relapses. There have been many trials showing this. The latest and best controlled data is the that on the use of steroids to prevent rebound post-natalizumab; high-dose prednisolone had no effect.

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  3. Unfortunately, the NHS seems to be in such trouble that lengthy delays are the norm for many. Following a visit to my GP a few years ago with symptoms, I was referred to a specialist physio who linked the numbness to my lower back. Two years later I was finally given an appointment with a neurologist and waited a while for an MRI; I was not given a follow up appointment to discuss the results until three months later and then informed that I had MS. I received a more recent scan early September last year (two months after seeing my neurologist) and had to wait again more than three months for the follow up appointment. Unfortunately there was more activity on the scan so I chose to change treatments and start on one of the most potent DMTs. I am still waiting to hear when I can actually start. Lots of waiting and worrying in the meantime whilst realizing the MS is worsening. Neurologists and MS nurses appear to be totally overstretched and there are not enough of them to carry the load. It's good to aim to treat early but until the staff shortages and NHS delays are sorted then it all looks rather bleak.

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  4. Is there an average period of time you would expect a cluster to cover?

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    1. MS activity clusters occur over months (~3 months). There have nice frequent MRI studies showing this with a suggestion they may be linked to the seasons. Could vD play a role?

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