Tuesday, 30 July 2013

ClinicSpeak: should I start glatiramer acetate?

Question: Relapsing/remitting MS for 7 years; 4.5 years on interferon-beta (Rebif) until pregnancy, no medication for 2.5 years, mild symptoms once a year. I have been offered Copaxone by my consultant. Should I start Copaxone?

Answer: There is no one line answer to this question, I need a lot more information and have numerous questions myself that will need answering before being able to give advice. Please note the emphasis is to give advice; I strongly believe that the person who has the disease should make the final decision about what treatment to start. They're the person who has to live with the disease, with all its uncertainties and disabilities, and its treatments, with their side effects and potential risks, not me. My role, or more accurately the role of the MS team, is to make this process easier for them.

This clinical scenario is not atypical. I am often asked to see MSers for a 2nd or 3rd opinions usually to give advice around disease modifying therapies (DMTs).

In reality, I would need to meet this MSer to get an understanding of what she is like as a person and ascertain how much she understands about MS, its prognosis and the various treatment options. During the consultation I would review the diagnosis of MS. Yes, I always ask does this person have MS? The MS misdiagnosis rate is somewhere between 2-5%; in other words 1 in 20 to 1 in 50 MSers don't actually have MS. One of my hardest tasks as an MSologist is undiagnosing MS; telling someone they don't have MS is not easy.

For arguments sake let's say this woman has a history, examination, MRI, spinal fluid analysis, evoked potentials, other blood tests and clinical course typical of RRMS. Importantly, there are no red flags to make me doubt the diagnosis of MS. Believe it or not the most important job we do as neurologists is make a correct diagnosis; get this wrong and everything downstream of the diagnosis is wrong. This is why I always take a step backwards and question the diagnosis. I hope you realise by the end of this post, which will be longer than usual, that you can't do this via an email or a blog The clinical consultation is too complex to be relegated to an asynchronous communication tool.

Back to the question about giving advice about treatment. This does not occur in a vacuum. Firstly, I would need to ascertain what prognostic category did this lady fall into at baseline when she initially presented with MS? In general I have three prognostic categories:
  1. Inactive MS - a favourable baseline prognostic profile 
  2. Active MS - baseline prognostic profile may be good or bad, but will become better defined over time; this could be on or off a DMT. 
  3. Highly-active MS - baseline prognostic profile is poor. 

Did she respond to interferon-beta (Rebif) that she was on for 4 years prior to her pregnancy? In other words was she rendered disease-activity free (DAF) on Rebif? Was she actively monitored during this 4 year period, both clinically and with annual MRIs? Did she tolerate the subcutaneous interferon-beta (Rebif) injections and were there any other side effects or adverse events? Did she develop neutralizing antibodies (NABs) to interferon-beta?

These questions will allow me to ascertain whether or not she was a interferon-beta responder, sub-optimal responder or a non-responder. If she was a responder and tolerated the injections without side effects she may want to restart interferon-beta. Interferon-beta has been shown to work very well in a minority of MSers and is safe in the long-term. If she didn't tolerate the subcutaneous injections she could always switch to the intramuscular interferon-beta formulation (Avonex). I personally don't think there is much difference between the interferon-beta formulations in terms of their long-term efficacy; they are all part of the same class of drug and work in the same way. Although there is weak evidence that the dosing schedule may be important when it comes to the impact of interferons on brain atrophy; the less frequent weekly administration seems to have a more favourable impact on slowing brain atrophy when compared to the more frequently administered formulations (thrice weekly Rebif or the every other day Betaseron/Betaferon/Extavia) that have no impact on slowing brain atrophy. The interferon-beta preparations also differ when it comes to inducing NABs; more on NABs another time.

Poor tolerability of the injectables will be addressed by the emergence of oral treatments. Fingolimod (Gilenya) already has a license for RRMS in the UK, but can only be used as a second-line agent in MSers falling interferon-beta. Teriflunomide (Aubagio) recently got given the green light by the EMA and should be available in the UK in the next 3-6 months. Another option is BG12 or dimethyl fumarate (Tecfidera), which also got give a green light by the EMA for RRMS. However, Biogen-Idec may not launch this drug in Europe unless they are given the necessary data exclusivity on their trials to prevent the early entry of generics. MSers in the US already have access to both teriflunomide (Aubagio) and BG12 (Tecfidera). If I was a practicing neurology in the US this consultation would almost certainly include a detailed discussion about these new entrants.

This lady describes mild symptoms once a year. I assume these symptoms are due to relapses. I would need to make sure of this on history; the symptoms need to be compatible with involvement of one or more of the nerve pathways in either the brain and spinal cord. To define a relapse the symptoms should last more than 24 hours and should not occur in association with a current infection and fever.

It is important to document relapses, which is why I encourage you to contact your nurse to arrange an appointment so that you can be examined. If this can't be done you should start a diary and document the symptoms of your relapse in writing; you will be surprised how difficult it is to remember specific details of past relapses months or years later.

Relapses indicate that her MS is active, i.e. that an inflammatory lesion is affecting a particular part of her nervous system. This is not good for her as active lesions cause damage; they strip nerves of myelin and can damage nerve processes (axons). Please remember the shredder analogy. You have to remember that for every clinical attack you have there may be 10 or more lesions on MRI that come and go and many more that are beyond the detection threshold of the MRI. This is why most MSologists are now doing regular MRI studies to monitor MS and we are beginning to incorporate additional measures into clinical practice to monitor the activity of MS.

In addition to the number of relapses, it is important to find out if these relapse were disabling or not. I define a relapse as being disabling if affected her ability to function normally; it may simply being unable to walk the dog the usual 2 miles because of a dragging leg or the fatigue associated with the relapse prevented her from going to work. Documenting the frequency and severity of relapse are very important for deciding whether or not MSers can receive certain DMTs under the NHS. I am not sure what country this lady lives in, but access to DMTs vary depending in local guidelines.

I would then examine this lady to assess her baseline neurological function. If I had time I would complete and EDSS, this is not always possible due to time constraints. The EDSS will give me an idea of how disabled she is; remember disability begets disability. MSers who have acquired disability over a short period of time are more likely to become disabled in the future. Knowing your EDSS is important for assessing your prognosis. At the lower end of the EDSS you may not be aware of any problems that the neurologist detects on his or her clinical examination. Therefore you must ask if your examination is normal or not, and if abnormal what part of your nervous system is affected. You will be surprised how you adapt to the deficits of subtle neurological dysfunction; for example not being able to walk heel-to-toe is often ascribed to aging rather than MS. The truth is many MSers hide and/or adapt to their deficits; this is part of having MS. Some call it denial; in reality you cope.

As part of my holistic approach to managing MSers I would actively enquire about hidden symptoms; anxiety, depression, fatigue, cognition, poor sleep, bladder, bowel and sexual dysfunction etc. Although I will address these issues in more detail in future clinic speak postings these hidden symptoms are an indication of whether or not MS is active and causing damage below the clinical threshold. Is MS using up your reserve capacity? 


To complete my assessment I would then request that this lady have a gadolinium-enhanced or contrast-enhanced MRI study of the brain. I would like this MRI to be compared to her last MRI study if that was available. I am particularly interested to see if her MS is active, i.e. does she have enhancing lesions and to see if her lesion load has increased compared to her previous scan. In addition to the lesion load, I would also look for other signs on the MRI that are linked to a poorer prognosis; i.e. black holes on the T1-weighted images, lesions in the the so called posterior fossa or back of the brain and brain atrophy. Atrophy simply means shrinkage of the brain that is greater than is expected for age. Brain atrophy is the hardest thing to look for on MRI with the naked eye; in reality we need to measure brain atrophy using specialised computer software. This software is not available in routine clinical practice; this is something we are trying to address at the Royal London Hospital.

Having poor clinical and MRI prognostic features may swing this lady's decision towards currently licensed highly effective therapies, i.e. fingolimod (Gilenya) or natalizumab (Tysabri). This would then trigger a detailed discussion with regard to risks and benefits of the treatments including a discussion about the PML (Progressive Multifocal Leukoencephalopathy). To complete the latter discussion we would have to arrange for her to have her JC virus serology checked to see if she has been infected with the virus in the past. The risks of PML in seronegative, or low titre positive, MSers is low. If fingolimod is a serious consideration we would need to check her varicella-zoster virus (VZV) status and make sure she does not have latent tuberculosis (TB). MSers who are VZV seronegative - who don't have antibodies to the virus need to be vaccinated before starting fingolimod. TB screening requires a specialised blood test or a skin test. In MSers exposed to people with active TB in the past, so called high-risk MSers, also get a chest x-ray at our hospital. The chest x-ray is not mandatory, some neurologists feel it is unnecessary. All MSers considering fingolimod have to have their hearts examined and an ECG performed. I am confident enough to do these two things myself, however, some MSologists prefer MSers to see a cardiologist before starting fingolimod.

When discussing highly-effective therapies it is important to balance the risks of this strategy with the risks of MS. I would therefore enquire if she knew about the prognosis of MS; its impact on physical and cognitive functioning, survival, employment status, relationships and quality of life. I tend to layer this information depending on the level of knowledge the MSer has already and their emotional state. How much information I give and how I give this information is a judgement call. This is why medicine is still an art and not a science. How we communicate with MSers is very important; it is critical that you understand your disease and why we are treating it and what the aims of treatment are.

Most MSers who come and see me for a second or third opinion already know that I am aggressive treater. In other words I favour the hit hard and early strategy over the safe and smooth one. Despite this I have constraints that prevent me from prescribing highly-effective therapies as first-line treatments. I have to explain this to MSers if they don't meet our NHS guidelines for treatment with the more effective treatments.

Another aspect that will affect this MSer's decision about treatment is family planning. Have her and her partner completed their family? If not she may well want to choose glatiramer acetate (Copaxone) as a treatment. Although none of the current licensed DMTs should be prescribed during pregnancy glatiramer acetate (Copaxone) has a good safety record in pregnancy and a large number of MSologists are allowing MSers under their care to fall pregnant on the drug and to continue taking it throughout pregnancy.

Although alemtuzumab is not officially licensed yet it will be an appealing drug for woman wanting to start or extend their families. Alemtuzumab works as an induction agent and once you have completed your two course and you have no evidence of disease activity (NEDA) you could fall pregnant. Alemtuzumab is not administered continuously therefore it does not stay in your body and hence is not associated with any effects on the developing baby. However, to be eligible for alemtuzumab this MSer would have to have active MS. I suspect she has active disease as she is having relapses and she therefore may be eligible for the drug if it gets it European license as recently suggested by the EMA.

I note this woman has already had a baby. I will enquire whether or not she is aware of the familial clustering of MS. If she has a daughter her daughter's risk of getting MS is approximately 2.5% or 1 in 40 and if it is a boy his risk is less; approximately 1.25% or 1 in 80. Please note that these figures are rough estimates and relate to the Canadian data that is not too dissimilar to the UK. The closer you live to the equator the lower your risk. 

The discussion of familial risk rarely goes down well in a consultation; the typical response from most MSers is 'I thought MS was not genetic'. MS is not typical of Mendelian genetic disorders in that it is not linked to a single gene. However, there is clearly a genetic component to MS. Several genes linked to MS increase your chances of getting the disease by interacting with environmental risk factors that trigger MS. I would discuss these risk factors; i.e. vitamin D, sunshine, latitude, EBV and smoking. I would explain to her that we believe that if you keep yourself vitamin replete throughout life you will drastically lower your chances of getting MS; Prof. George Ebers thinks this may reduce your chances by up to 85%. 

I would explain that the current RDA (recommended daily allowance) of vD is woefully too low and give her advice on what is appropriate for her and her family to take. If her child was older (6 or older) we would enrol them onto our new 'Digesting Science' course to teach them about MS. One of the aims of this course is to get the message across that 'vD supplementation may prevent MS'. I am hoping that this message will get through to children of MSers so they don't forget to take their daily vD supplements. This last comment is speculative, we need to research this aspect of the 'Digesting Science' course; there is little point in preaching the virtues of evidence-based practice without being able to demonstrate that what we are trying to do actually works. We are in the process of putting together a grant application so that we can get a PhD student to study this formally. However, more on this another time.

Finally, I always give MSers I see the option of participating in clinical trials. Clinical trials are part of the MS service we provide. I would estimate that about half of my new MS referrals are for possible inclusion in clinical trials. If MSers did not volunteer themselves for clinical trials we would never move the field forward. The fact that we have so many DMTs available today is a testament to all the MSers out there who volunteered for trials in the past. At the present time we are recruiting MSers with active disease for our raltegravir (INSPIRE) trial and for a study of a new monoclonal antibody targeting B cells via the CD19 receptor.

So in conclusion you can see this simple yes no question has generated more questions than answers. So should this lady go onto glatiramer acetate (Copaxone)? Maybe.

When writing this post, which has taken me longer than I anticipated, it has become clear to me how specialised MS has become and that we are truly in the age of personalised medicine. No algorithm will be able to answer this woman's question. In reality, what this lady need is a face-to-face consultation with her MSologist, which I think she has already had. He/She has recommended glatiramer acetate (Copaxone).

CoI: multiple

18 comments:

  1. Very helpful, thank you! More of this please. I thought you were on holiday?

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    1. Thanks. Yes, I am still on holiday. I am veteran insomniac and got up early to write this post. It took close to 3 hours to write and edit; something I will need to take into account if it becomes a regular feature. I am still not convinced that Clinic Speak belongs on this site; I will wait to hear what the feedback is before deciding its future. Should it continue or not?

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    2. Seriously, don't do this, G. You'll only disappoint yourself by not being able to keep it up and letting down your readers. Concentrate on MS research. Treatments for Progressive MS is still woefully unmet. We need treatments. That's what we all need.

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    3. I am in agreement with Sanjay. There is nothing useful for the treatment of progressive MS and that is a shameful reality. I begrudge that so much time will be wasted in offering online counselling via this blog. This is not where your priorities should be, Prof G.

      The research into treating progressive MS recalls the old Jewish proverb of the medical mensch looking for his lost keys under the light of a street lamppost. When a passerby asks him if that's where he lost his key, the mensch replies, 'no, I lost it in the garden, but under this lamppost is where the light shines brightest, so I continue to look here.'

      Your mouse models are simple organisms where the light shines brightest. It’s failing us sufferers of progressive MS, badly.

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    4. Yoir simple mouse models.
      I take exception to this comment........these simple models are anything but simple they have delivered two new studies aimed at progressive ms. Theyhave identifoed moe candidates than we have time in the day to investigate.
      The thing you learn frm reading thid blog is that things take timeto materialise. This not in. Our control and we cannot do everything in the world. We could do more if we had moreresource so if you are a benefactor talk to G. It would more useful that shooting from the hip

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    5. Good answer. Don't let them wind you up.

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    6. Anonymous 5.43pm.
      You shouldn't throw the baby out with the bathwater re (anything but)simple mouse models as MD says.
      When the only tool in your box is a hammer, every problem looks like a nail but in contrast we have the most comprehensive tool-kit available.
      We will continue in our search for treatments for progressive MS and again as MD says large strides have been made.
      Any contributions gladly received!

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  2. Thank you for this post, Prof. G. It has indeed given me food for thought. The case of this lady resembles mine (except for the gender :-)), and I am now more sure of what kind of information I should be expecting from my MSologist (let's keep her on the neurologist level). The picture looks clearer to me too, as to all the information our neuros must process, and how difficult (although not impossible) to get a decision-making algorithm to treat us must be. I will also take your advice (vit. D supplementation) for my 6 yo son (although living in sunny Spain).
    Sorry for taking your personal holiday time for this post. It did really help me.

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  3. I respect the time involved, but I found this analysis very useful. Thank you.

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  4. Prof G,

    Many thanks.

    Like most things in life it can be boiled down to: analysis, options, decision.

    In these scenarios the patient really wants a steer on what is he best solution for them - an answer to he question "if I was your brother / sister, what would you recommend".

    Much will depend on the bent of the neuro - early and hard, or start on a first line treatment.

    The other part of the scenario is the long term stuff. It didn't seem that long ago that neuros were talking about a cure in a decade. Patients to want a tiny bit of crystal ball gazing eg hopefully there might be some neuroprotective therapies in the next 5 years, remyelination might be feasible within 10 years,
    We do need a little bit of hope for the future.

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  5. Good post. I was starting to think the purpose of this site was to promote the most toxic drugs to suppress your immune system. But I'm glad you explained what is involved in evaluating a patient and that in some cases the existing therapies may be adequate for some. You should explain to your mouse colleuges that MS is not about their reputations or egos, it is about patient treatments and the options available to them.

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  6. Thanks Prof G, extremely helpful, particularly to see it from the your side - appreciated...

    The one thing this highlights to me (being from the UK) is that MRI is really very important in this process. Several parts of the discussion relied on MRI to know about activity/inactivity from a baseline or last scan. I know what I'm asking for next time I can! I have RRMS (diagnosed for 2 years on DMT's for 1 year) and have constantly asked for an MRI scan, just to know, but been refused....

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  7. I found it tremendously insightful about the thought processes involved in answering a seemingly simple question. It helped me appreciate the complexities of patient counseling. Understanding the reasons particular questions are asked will doubtless help in making sound treatment decisions.

    Is there a reason Clinic Speak must become a regular feature? If the primary concern is one of taking time from other matters you might consider monthly or bi-monthly?

    Personally, the article was valuable and I will be able to share some of the knowledge gained by reading it. Thank You.

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  8. Tremendously valuable. Of course, the nature of the content of clinic speak will vary from case to case. However, it is the process of thinking and questioning that is vitally constructive to patients and researchers.

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  9. Thank you very much for this, I agree with Anon 2.18 - really interesting and can help to educate people on what a consultation can/does involve, and also the thought processes and things for the MSologist and MSer to take inot consideration. Monthly or bi monthly could work without detracting from your research?
    Thanks and hopefully you'll get a better night's sleep - try and relax on holiday!

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  10. The objective behind the clinic speak posts is to show, or educate, you about how an MSologists applies or translates research and trial results into clinical practice. Nothing more and nothing less.

    I will do a few more and we can then assess their value.

    What you need to realise is that clinic speak is the way I practice; you may find that your neurologist or MSologist disagrees. Consensus is uncommon in the practice of medicine.

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  11. Hi Prof G,

    This was very interesting. I am a women dxed with MS march 2007 had a child in April 2009(I have never been on any DMTs I have not had a relapse for 5 and a half year). I am now pregnant again. Last time around I was asking about vitamin D during pregnancy and my consultant at the time didn't seem to see the link between lack of vit D and MS. He thought I was asking for myself, when my worry was more for the baby and it's risk of MS in the future. I am now in the same situation, but more people are of course aware of the potential link. But there seem to be quite conflicting advice out there, I am currently taking normal pregnancy multivitamins, which is far less than the VIT D dose I was on before I fell pregnant. What I'd like to know is, what dose do you recommend for pregnant MSers to take?

    Thanks for a great blog
    Helena

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    Replies
    1. Regarding vD and pregnancy I adopt the vD councils recommendations:

      http://www.vitamindcouncil.org/further-topics/vitamin-d-during-pregnancy-and-breastfeeding/

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