Watchful waiting 2

Barts-MS rose-tinted-odometer: zero-★s (still seeing red)

Did you know that MS disease activity defines if you are eligible for therapy and which therapy?

The following is a list of definitions that are generally applied to MS in England. 

Inactive: Patients with MS with no relapses or imaging features of disease activity in the last 2 years. 

Active: Patients with active disease are defined as having one or more relapses in the preceding 2 years and/or evidence of one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI in the last two years. 

Highly active: Patients with high disease activity despite treatment with a platform DMT. This group is defined as patients who have failed to respond to a full and adequate course of a platform or other DMT. Patients should have had at least one relapse in the previous year while on therapy and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI. 

Rapidly evolving severe or RES: Patients with rapidly evolving severe relapsing-remitting multiple sclerosis defined by two or more disabling relapses in 1 year, and one or more gadolinium-enhancing lesions on brain MRI or a significant increase in T2 lesion load compared with a previous MRI. 

Disabling relapse: if the relapse is severe enough to affect the social and/or occupational functioning of the patient.

The problem with these definitions is that they entrench the clinico-radiological worldview of MS and are not based on biology or for that matter data. For example, the RES definition was a negotiation between Biogen representatives and the EMA to get natalizumab licensed in Europe. RES MS was not a prespecified population and there were no requirements for study to subjects to have an increasing lesion load on MRI or to have prior relapses classified as disabling or non-disabling to be included in the AFFIRM study (phase 3 natalizumab study). So in reality the RES population is hypothetical. Despite this, the concept of RES MS has stuck and is likely to be entrenched in our MS algorithms for the foreseeable future, unless we challenge these definitions.

So if you are NEDA-2, i.e. have no relapses or focal MRI activity in the last 2 years, you have inactive MS. The latter definition is independent of disability worsening, accelerated brain volume loss, raised neurofilament levels, worsening cognition, accelerated retinal nerve fibre loss, slowly expanding lesions or progressive spinal cord atrophy. In other words, the definitions are based on clinical relapses and focal MRI activity, which is our concept of active inflammation. None of our current definitions for treatment acknowledges smouldering disease; hopefully, this will change in time.

Clearly, these definitions are subject to change or hacking as technology evolves. So if you move from a 3 tesla to a 7 tesla MRI you may find it easier to show a change in lesion load due to the better definition of lesions and the ability to see cortical lesions. Simply increasing the number of MRI scans will increase the sensitivity of the measure of activity, particularly if you are using Gd-enhanced MRI scans. 

The definition that worries me the most is RES. The number of people with RES is getting smaller simply because we tend not to let someone diagnosed with MS after one relapse wait to have a second relapse before treating them. Therefore the number of patients with RES is going down and this is why so few pwMS are eligible for cladribine, alemtuzumab and natalizumab as first-line therapies. The only highly effective therapy that is allowed first-line for active MS is ocrelizumab. So if you want to flip the pyramid and start on one of the other top-tier DMTs you have to either start on ocrelizumab or wait and hope you have a disabling attack within 12 months of your first attack to become eligible for natalizumab or one of the licensed IRTs (alemtuzumab or cladribine). 

Waiting and hoping to become RES is what I call watchfully waiting 2.

This watchful waiting for the next disabling attack to become eligible is really incompatible with the concept of time-is-brain and hence access to IRTs are not really a first-line option for the majority of people with recently diagnosed MS. 

I hope this makes sense? The following is NHS England’s DMT treatment algorithm that explains things using a flow diagram.


Conflicts of Interest

Preventive Neurology




General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.

34 thoughts on “Watchful waiting 2”

  1. Hi Prof G, would you prescribe Clad/Alemtuzumab to a CIS patient with signs of an average RRMS disease course going forward if the patient wants Clad/Alem, and there is no regulatory restrictions.

    1. Yes, but the patient would have to choose that route. The is what happens in Australia. For example, if I had CIS with a high-risk (abnormal) MRI I would probably want AHSCT or failing that a safer IRT (alemtuzumab or cladribine).

      1. I would not be keen on a long-term immunosuppressive therapy when the risks accumulate and increase with time. With IRTs the risks are frontloaded, except the chemotherapy-related secondary malignancies with HSCT, which take time to emerge.

      2. Prof G – this reads like it is an inevitability. What are the rates of secondary malignancies associated with HSCT please? also, this treatment accelerates BVL by up to 3% before normalising (hopefully). Thats 10 years worth of ocrelizumab related loss but i am guessing it is not as straight forward as that. You can see why MS patients feel hard done to when they are ‘hoping’ for a disabling relapse. It really beggars belief

      3. Yes, you are right. This is why alemtuzumab or cladribine is the safer option over AHSCT and why it is so important to challenge and get the guidelines changed. Or we could accept the status quo and simply accept our roles as robotniks.

      4. I also think high-dose ocrelizumab can be used as an IRT; i.e. 4 courses and then a wait and see approach. This is what we want to do in the ADIOS study. I am very concerned about decades of anti-CD20 therapy; it doesn’t make immunological or MS-biological senses. The good news is we are testing high-dose ocrelizumab vs. standard dose and will get an answer in a few years time.

      5. But that exacly what your Swedish colleagues are doing

        (decades of anti-cd20 theraphy)

      6. I am also very concerned about decades of anti-CD20
        What would you recommend to a patient who has been on rituximab for 10 years already? Seems to be NEDA

  2. Sorry, i ran out of replies…..I am right that secondary malignancy is an inevitability?

    1. No, it is not inevitable. Not everyone treated with cyclophosphamide gets secondary cancer; it depends on the dose, age and other comorbidities. At the moment we don’t have enough long-term follow-up data to define this risk accurately, which is a problem for AHSCT.

  3. Prof G,

    “The latter definition is independent of disability worsening, accelerated brain volume loss, raised neurofilament levels, worsening cognition, accelerated retinal nerve fibre loss, slowly expanding lesions or progressive spinal cord atrophy.”

    Given the seriousness / grimness of MS described in the sentence above, some of these post are becoming a bit Nero-esque (fiddling while Rome burns). I’m sure that there are other MSers like me who aren’t too interested in definitions of their current stage / level of activity or inactivity of MS. We have no power to change these definitions, and have no influence in convincing neuros that MS is one disease, or that MS should be treated early with the most highly effective therapies…. The MS establishment (researchers, MSologists, pharma, regulators) have concocted the various criteria (eg McDonald criteria) and scales and then redefined them at various points.

    The relevant issue for MSers is what therapy is most effective at addressing accelerated brain volume loss; what therapy can halt worsening cognition; what therapy; what therapy can stop progressive spinal cord atrophy.

    We are now at a point where we know that MS is way more complicated and way more destructive than was thought 25 years ago. However, the MS establishment is still trying to address the disease with anti-relapse drugs, or updating definitions and guidelines, and not developing therapies which properly address the real MS (smouldering MS which destroys brain cells). I keep my fingers crossed that the planned Team G trials deliver a new era of therapies. But a new approach is needed to get these new therapies to patients quicker (given that time is brain). If SIZOMUS, for example, shows real promise in addressing the real MS, it needs to be fast tracked rather than get bogged down in the usual bureaucracy / barriers which seems to be set up to ensure the suffering of MSers is drawn out as long as possible.

    1. Re: “We have no power to change these definitions…”

      Sid, I don’t really have the power to change the definitions either, but by running our campaigns #ThinkCognition, #TreatEarlyandEffectively, #FlippingThePyramid, #ThinkHand, #MS_is_1_not_2_or_3_diseases we hope to nudge the community away from being a community of robotniks and/or refuseniks to thinking differently about MS and to ultimately change the way we manage MS.

    2. Re: “We have no power ….”

      This is why I will be giving up on established MS and focusing on EBV & MS and MS prevention.

      1. What would like to see in terms of a trial being funded targeting EBV in the ms population this year (what type of antiviral) ?

  4. And if you are in a wheelchair but still having relapses and and getting worse you are still not eligible?
    If only your mobility is affected why is no-one interested in saving your bladder all the bowel etc etc??

    1. Yes, upper limb (arm and hand function), bladder & bowel function, bulbar function (swallowing and talking) and cognition (thinking) are not considered worth protecting if you have lost the ability to walk. The problem is there is no data in wheelchair users on DMT efficacy, which is why we don’t have any DMTs licensed for advanced MS. This is why we are doing the #ChariotMS and O’Hand (ocrelizumab in advanced PPMS) studies.

      1. But even with trials like Chariot again it is limiting and implying that unless you have fairly mobile hands and arms drugs cannot help. There is still a a fairly good level of dexterity required to qualify for the trial.
        Is #thinkhand not just marginally improving drug accessibility for wheelchair bound people with MS?
        It is still saying that even if your cognition,bladder,bowel and bulbar functions are currently unaffected we are only interested in protecting these things if if your legs and arms are functioning?
        Believe me a wheelchair bound person with everything working except 100% use of arms and legs can have a very rewarding life. Something which a highly mobile person with severe cognitive problems etc probably cannot.
        I find it all very depressing and extremely tiring having argued this case for so long.

  5. Are you still not eligible for treatment if you are in a wheelchair but having relapses and getting worse?
    If only your mobility is affected is your bladder and bowel and cognition not worth saving?

    1. Yes, wheelchair users are not eligible for treatment and if you are on a DMT your disability worsens until you become wheelchair-bound your DMT has to be stopped.

  6. What would happen if the relapse you have watchfully waiting for and hoping to become RES leaves you paraplegic? Could you still be treated with alemtuzumab?

    1. No and Yes. No, if you are a Robotnik because you are not meant to start anyone on a DMT when their baseline EDSS is 7.0 or more. However, if you are not a Robotnik and can see past the guidelines you could make the case that the patient is only EDSS 7.0 or worse because of an acute relapse and that we would expect the person to recover function and treat them. In reality, this is what tends to happen. The problem is if the treatment is not an IRT, but a maintenance therapy for example natalizumab and the patient does not recover function; under the current guidelines, you would have to stop their treatment.

      1. I remember being astounded at this as a newly diagnosed patient. A dr (no longer my dr) prescribed GA on the basis it was my first attack I had no cervical lesions and said if it wasn’t enough we’d switch after. I remember being skeptical thinking what if it’s not enough and then I can’t walk and the damage is done? But as a patient I thought they’re the dr and if they’re not worried maybe I shouldn’t be either. 6 months later I got cervical lesions. At that point with 6 months into a crap diagnosis i had finally educated myself enough to know GA is bunk (malpractice IMO given other options) and found a new dr and got ocrelizumab which at the time was newly approved. Even with that, I had new activity the first few months until it stopped because as I now know you don’t wait to wake up the monster. Once it’s awake it’s hard to stop. I consider myself one of the lucky ones because i got that DMT less than a year into diagnosis but my point is it’s unfair and unrealistic to expect patients to be sufficiently educated at diagnosis. They are shellshocked and scared and this isn’t an easily understood disease. The only way realistically to flip the pyramid is to have doctors stop choosing less effective DMTs at diagnosis. Does an oncologist wait to see if the cancer spreads?

      2. Re; “Does an oncologist wait to see if cancer spreads?”

        An interesting analogy. Neurologists are well known for being amongst the most risk-averse clinicians in medicine. Therein lies your answer.

      3. Prof g you are of course correct. But the “risk” calculus needs to change. I propose neuro see the biggest risk is death and therefore being “risk averse” means avoiding side effects that could kill you. As a pwMS I see risk of a disabling relapse as the risk I want to avoid at all costs. So for me being “risk averse” means avoiding that. At all costs. Therefore for me watchful waiting is the riskiest option there is.

      4. Thank you, I’ll be using that analogy with someone I need to have a conversation with. It’s also true in a related sense: one of my physio’s mantras is that ‘disability comes in tiny steps’. i.e. it’s not that you’ll wake up one day and suddenly the MS has completely removed all your motor function. The worsening is slow, can be almost imperceptible, but it’s happening…. just like the lump that you didn’t know was there.

  7. Why was Ocrevus approved for first line for active MS and the others are not? I mean obviously great that it is but it doesn’t make sense considering the rest (to me anyway) and surely the cost isn’t less? And it’s up there effectiveness wise. Is it based on risk?
    Though Tysabri is less risky?

    1. RE: “Why was Ocrevus approved for first-line for active MS and the others are not?”

      Alemtuzumab was licensed for active MS. i.e. it could be used quite liberally and as a first-line treatment, but had its label changed to RES when the thrombotic complications emerged in the US.

      Natalizumab has always being licensed for RES and more recently oral cladribine got RES in its label.

      Fingolimod is different in that it can only be used 2nd-line in first-line treatment failures.

  8. Please try to add SMS, smouldering MS to the list if types of MS. No new lesions but I definitely have MS and it is slowly, steadily and definitely getting worse.
    I am not alone and I’m sure the number of patients is growing.

  9. It seems to me that the “Definition” regarding what constitutes a relapse is so vague, that there is a lot of latitude for the attending physician to use common sense to navigate the economic-political nature of modern day prescribing “Guidelines”.

    1. Yes, but why can’t we be honest? One of my colleagues makes the point ‘he can always find a relapse’ or a ‘new lesion on MRI’ if he wants to. But is this way we want to practice MSology; gaming the system? Anyway if you game the system and do it at scale you are likely to become an outlier when the national audit comes in. Much better to make changes to the guidelines, based on biology and data, so that all patients with MS can benefit.

      1. ” when the national audit comes in”

        When will this audit come in and will we get to see it or are the results going to hidden or masked?

      2. Yes. You are absolutely right. Honesty is important. Changing the system is always possible. I think a review of policy and how it relates to improved patient outcomes is a good feedback mechanism.
        One thing to consider is that a Gaussian distribution has a huge mountain of mediocrity in the center and two tails. Sometimes it is better not to be mediocre. Maybe being out on one of the tails is not so bad, if it is not the wrong one.

  10. These definitions and treatment rules are so absurd and harmful
    How are they framed? Who are the neurologists involved? Aren’t MS specialists involved?

Leave a Reply

%d bloggers like this: