Research: Discontinuing treatment

R
Meyniel et al. Country, Sex, EDSS Change and Therapy Choice Independently Predict Treatment Discontinuation in Multiple Sclerosis and Clinically Isolated Syndrome PLoS One. 2012; 7(6) :e38661.

OBJECTIVES: This was a prospective study, MSBASIS, to assess factors leading to first treatment discontinuation in MSers with a clinically isolated syndrome (CIS) and early relapsing-remitting multiple sclerosis (RRMS).

METHODS: The MSBASIS Study, conducted by MSBase Study Group members, enrols MSers seen from CIS onset, reporting baseline demographics, cerebral magnetic resonance imaging (MRI) features and Expanded Disability Status Scale (EDSS) scores. Follow-up visits report relapses, EDSS scores, and the start and end dates of MS-specific therapies. A multivariable survival analysis was performed to determine factors within this dataset that predict first treatment discontinuation.

RESULTS: A total of 2314 MSers with CIS from 44 centres were followed for a median of 2.7 years, during which time 1247 commenced immunomodulatory drug (IMD) treatment. Ninety percent initiated IMD after a diagnosis of MS was confirmed, and 10% while still in CIS status. 

  • Over 40% of these MSers stopped their first IMD during the observation period. 
  •  Females were more likely to cease medication than males (HR 1.36, p = 0.003). MSers treated in Australia were twice as likely to cease their first IMD than MSers treated in Spain (HR 1.98, p = 0.001).
  • Increasing EDSS was associated with higher rate of IMD cessation (HR 1.21 per EDSS unit, p<0.001), and intramuscular interferon-β-1a (HR 1.38, p = 0.028) and subcutaneous interferon-β-1a (HR 1.45, p = 0.012) had higher rates of discontinuation than glatiramer acetate, although this varied widely in different countries.
  • Onset cerebral MRI features, age, time to treatment initiation or relapse on treatment were not associated with IMD cessation.

CONCLUSION: In this multivariable survival analysis, female sex, country of residence, EDSS change and IMD choice independently predicted time to first IMD cessation.


“This study looks at features that appear to determine adherence to your exisiting medication; a 40% discontinuation rate is very worrying. The aim of DMTs is to prevent relapses and focal areas of inflammation and by doing this prevent the accumulation of disability in the longterm. If MSers stop taking their drugs this strategy falls down at stage one. People think the emergence of oral therapies will sort this problem out. I am not so sure. I think this is an education issue. In our first audit, at the National Hospital for Neurology and Neursurgery, we had adherence rates of over 95% at 2 years and even in the 5% who had stopped taking their DMT we had a reason for it. I suspect MSers in this study were not receiving the necessary information and assistance when starting DMTs to persist with the treatment.”



“What is the point showing that IFNbeta has a positive impact on clinical course at 16 years and survival at 21 years when 40% of MSers are off the drugs at 2.7 years? We have a problem!”


“Are you all adherent with your medication? If not, please let us know why?”

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

25 comments

  • how many of those are shifting from a drug to another and how many are dropping out all together? (no more DMDs whatsoever)

  • 100% adherent. Not a single shot missed in almost 4 years of subcutaneous interferon, even after it stopped working, till the shift to natalizumab

  • I think Tony Fonda has a good point!

    I used to take rebif (interferon ß 1-a) for 9 month but it failed.
    Only missed 1 shot during that period because of a panic attack.

    Now I am using Mitoxantron (Ralenova) and it's the first time that a lot of the symptomes get better. I also have an aggressive MS course with a lot of relapses last years.

    And I don't think that interferons work THAT well. If I remember right only about 20% of all patients benefit from interferons.

  • I discontinued interferon after 8 months of adherence because it was making my symptoms worse (vertigo) and did little for my mild spasticity. I did it without consultation with my neuro because I knew he would not agree with me. Now I am getting a drug through some crazy ways and we will see in a couple of weeks who was right (i.e. MRI control). I feel overall better and my vertigo is much better now and the stiffness roughly the same as with interferon.

  • I had been religiously stabbing myself with Copaxone for seven and a half years, after an accident and injury I stopped for three months recently. I was in two minds about re-starting as I have not relapsed for almost five years, being off the drug I did not notice any changes. Daily stabbings are not a major inconvenience but the lure of a tablet is tempting. I won't take anything that is immunosuppressive whilst I don't have to, but I do worry that I might be compromising on disability progression. I discussed this with my neuro – I said I was 50/50 about re-starting, she said that she was 60/40 for me to resume. In the end I have gone back on Copaxone, I suppose because it is better the devil I know, and I am not willing to try any of the current offerings and have been advised that at this point they are not needed.

  • Perhaps we need better drugs! Seriously, it's a cost:benefit analysis for people like me who's ms is not that bad. I have two small children and a demanding (part-time) job, self-injecting a drug with fun side effects of flu-like symptoms and injection site reactions would probably make me feel worse, not better. I know my ms will get worse, but not by how much. And a 3rd less relapses is not that big a carrot. Half the number of relapses and a significant slowing of progression would tempt me a whole lot more. I'm not sure dmds are even an option for me, as i'm not sure my relapses are bad enough to be clinically significant…

  • Re: "I'm not sure dmds are even an option for me, as i'm not sure my relapses are bad enough to be clinically significant."

    If you are having relapses you should be on a DMT. The next one may be disabling.

  • Prof G – what counts as a relapse? I mean, if you do an MRI and there is no difference over the years but subjectively you have episodes of worsening of symptoms and then improval of symptoms but it's not detactable. What is it? Grey matter shrinkage? Or progression? Or remission? Or psychosomatization? I don't understand what's going on, seriously.

  • Re: "Prof G – what counts as a relapse?"

    This is very difficult question and there is no consensus in the field. We have hard definitions we use in clinical trials. Some of us are beginning to count asymptomatic MRI activity as asymptomatic relapses. Gray matter atrophy is another topic all together. We don't have enough data on how to measure it and we don't know whether or not DMTs impacts on it reliably enough to use in individual MSers. More on this in the future. There is a dedicated meeting being held later this year at the Cleveland clinic to look at this issue.

  • Re: asymptomatic relapses – perhaps it would be good to look into this one a bit deeper somehow Prof G – and solving another piece of the puzzle 🙂

    MRI – I read about a computer programme which counts the lesions much more effectively than manual counting – are you using such a programme at Barts or thinking about it?

  • Re: "MRI – I read about a computer programme which counts the lesions much more effectively than manual counting – are you using such a programme at Barts or thinking about it?"

    These programmes are research tools at present and have not been validated in the clinical setting. In addition, it requires a lot of post-data acquisition image processing, i.e. a technician or pair of hands. With the NHS in super-austerity mode who is going to fund such a luxury?

  • When the brain or spinal cord rewires itself after an attack, could this cause a new "symptom" and could this later remit and perhaps explain some of the MRI silent relapses?

  • Re: "When the brain or spinal cord rewires itself after an attack, could this cause a new "symptom" and could this later remit and perhaps explain some of the MRI silent relapses?"

    Rewiring may cause intermittent symptoms such as pain, pins-and-needles, flexor spasms, hemi-facial spasms, facial myokymia, trigeminal and other neuralgias and seizures. All of these are positive phenomena. yes, they can remit.

    Spinal cord disease may cause MRI-negative activity as we tend to image the brain only. However, disease activity tends to come in clusters and spinal activity is typically associated with brain activity hence the need to only monitor the brain. The brain is one region or 20 minutes scanning time. The spinal cord is three regions or 60 minutes scanning time. Hence it is not time or cost effective to monitor the spinal cord for sub-clinical disease activity.

  • From personal experience, I'd say one reason people drop DMTs completely is that neurologists have a difficult time determining if they are really having a positive impact. "You are not getting worse, so the medication must be working," isn't really convincing when the patient is living with the side effects of the DMT (and other meds). My wife went off the medication for exactly that reason. She thought the side effects were awful and she wasn't convinced the DMT was doing anything for her. She stopped after 5 years of use and has been off all MS related medications for >5 years.

  • Re: "She …. wasn't convinced the DMT was doing anything for her."

    This is the problem in a nutshell. Her team should have educated her about what to expect and monitored the effectiveness of the drug with NAB testing and yearly MRIs. Was this done?

    It is not good enough to put someone on a DMT and not monitor them. In the current era of personalised medicine active management and engagement should be the rule.

  • "She thought the side effects were awful and she wasn't convinced the DMT was doing anything for her"

    She was right:

    http://jama.jamanetwork.com/article.aspx?articleid=1217239

    Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

    "Conclusion: Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability."

  • Hi Dr. G,
    I'm in full agreement with you. Did she have and annual MRI?… No. It seemed this was discouraged as "not necessary" if there were no worsening of the symptoms. I think she had two in the first two years of her diagnosis and none thereafter. Her neurologist didn't see the need for it, and I suspect, neurologists in general (here in the USA) are discouraged by the insurance companies from running them if there is no absolute need.

    On the topic of personalized medicine, I'm not sure most Neuros either have the time or want to take the time to engage the patient as you describe. Either that, or we (neuro and patient) had communication issues. I believe it is the former, but I understand that it is a two-way relationship. I think it certainly would have been better in my Wife's situation if her doctor had framed her better for what to expect.

    I will say this: My personal experience is that the Doctors dealing with MS start in a position of disadvantage. Not knowing the cause or not having a clearly defined path of treatment (here's three DMT's let's pick one and see how it works),will make many patients question their Doctor's recommendations.

    Thanks for your response and I do appreciate the work you and Mouse Dr. put in on this blog.

  • Oh, I'm glad VV brought up the JAMA article about the ineffectiveness of interferons on disease progression.

    Just a few days earlier, another study seemed to say the exact opposite:

    Italian Researchers Find that MS Disease-Modifying Therapies Reduce the Risk of Future MS Progression
    (Link http://www.nationalmssociety.org/news/news-detail/index.aspx?nid=6578)

    I came over here to ask you how we should make sense of these seemingly conflicting findings.

  • In response to the new stories about interferons NOT halting progression – I guess it was always known that they halt progression by mere 7% which is not much – if you look around and see people in wheelchairs who look about 50 yrs old do basic maths and you will see that the drugs don't help (diagnosis at 30+20 years of interferon treatment (since mid 90's = disabled people at 50). Just seen a women today which fits the calculation, unfortunately.

  • NABs testing
    Neutralising antibodies (Ab) can occur if the body makes an immune response against a drug . e.g beta interferon. If the antibody binds to the active site it neutralises the drug and stops it working. So if someone gets NABS to interferon beta it stops it working.

    What is a T2 MRI
    http://en.wikipedia.org/wiki/Magnetic_resonance_imaging

    This is not a simple one to explain.

    MRI works using a magnet.
    This can make the charged particles in water align with the magnetic field. This field is oscillated and the way the magnetic particles spin and relax in relation to the magnetic field can be used to define a T1 and T2 image. This makes no sense to me.

    What it actually detects is difficult to describe and has no direct histological correlates but it can pick up lesions associated with MS.

    We need a MRI person to explain it

  • Interferons and Progression,

    Depending on the outcome it depends what you get. We have known about the Canadian data cohort for some time, George Ebers has been talking about this and whether relapses influence progression. He suggests that after the first few years no, but tell that to someone who has had a disabling relapse.

    We are moving into the era of markedly effective agents I think these will influence the rate of progression

    G can comment on the papers

    Science is full of conflicting data and this is why studies are repeated and eventually you get consensus.

    CCSVI is another example first studies looked great later studies not so great. The consensus is…

  • "I came over here to ask you how we should make sense of these seemingly conflicting findings."

    The Italian group did not use a specific EDSS score as an endpoint, but a relapse-dependent definition of SPMS:
    "In this study, secondary-progressive MS was considered to have begun after an individual experienced continuing deterioration without a relapse or remission, for at least one year, severe enough to lead to an increase of at least one point on the EDSS disability scale."

    So, two different patients could have reached SPMS at different EDSS scores. Alternatively, an EDSS score of 6 with a relapse in the previous year would not have counted as SPMS, whereas an EDSS score of 4 without a relapse would have.

    On the contrary, the Canadian study used a more straightforward definition of SPMS as reaching sustained EDSS 6.

  • Re: ""I came over here to ask you how we should make sense of these seemingly conflicting findings."

    The problem with this data is that it is not controlled and hence their will a lot of bias that cannot be taken into account. For example, the untreated contemporary and historical cohorts had a longer disease duration for the same level of disability at baseline; this would imply that they had more benign disease. They would therefore expect to do better than a cohort with more active disease (shorter disease duration for same level of disability). The fact that they did as well as each other to EDSS 6.0 implies that IFNbeta must have been doing something.

    The bottom line is IFNbeta is not a very effective treatment; this study confirms this. That doesn't mean we shouldn't use it as some MSers respond better than others and in the UK, at least, you have to fail first-line treatments to access the more effect second-line treatments. For this reason alone IFNbeta has many years left in its legs and rush to develop long-acting preparations and cheaper biosimilars. My main worry with them is the legacy NABs to INFbeta will leave behind.

  • VV, if you are interested there are two metrics that have been used to integrate EDSS and disease duration; the one is called the Poser Score (EDSS / disease duration) and the other the MSSS (MS Severity Score). The latter is based on the where you fall on the distribution of EDSS/disease duration scores.

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