Case study: should I start glatiramer acetate?
A simple yes-no question this is not. Making a decision about which disease-modifying therapy to use to treat MS is complex. This case illustrates how complex the process is.
Case study
I am a 34-year-old woman with relapsing-remitting MS for 6+ years. For 4.5 years I was on interferon-beta (Avonex) until I fell pregnant then I stopped my injections. Whilst I was on interferon-bet I had mild sensory symptoms that would happen annually; I am not sure if these were definite relapses. I had a successful pregnancy and I am now breastfeeding. I want to extend my family in the future. I have been recommended to start glatiramer acetate by my MS consultant. Should I start glatiramer acetate or would you recommend another DMT?
Prof G’s opinion
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 patients for a 2nd or 3rd opinion, usually to give advice around disease-modifying therapies (DMTs).
In reality, I would need to meet this patient to get an understanding of what she is like as a person and ascertain how much she understands 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 people with MS (pwMS) 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 argument’s 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 to 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 Newsletter, which will be longer than usual, that you can’t do this via email. 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 this lady fell into at baseline when she initially presented with MS? In general, I have three prognostic categories; good, intermediate or poor.
Did she respond to interferon-beta prior to her pregnancy? In other words, was she rendered disease-activity free or NEIDA (no evident inflammatory disease activity) on interferon-beta? Was she actively monitored during this 4 year period, both clinically and with annual MRIs? Did she tolerate the intramuscular interferon-beta (Avonex) 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 an 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 pwMS 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 has been addressed by the emergence of oral treatments. Fingolimod (Gilenya) has a license for highly active RRMS in the UK, but can only be used as a second-line agent in pwMS failing therapies. Teriflunomide (Aubagio) is not an option for this woman because of her plans to have more children; teriflunomide is teratogenic. Dimethyl fumarate (Tecfidera) is an option and its safety record in pregnancy is good. The newer generation S1P modulators, i.e. ozanimod and ponesimod, are likely to be licensed as first-line or platform therapies but are potentially teratogenic so not an option.
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 the 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 not uncommon for people with MS to ignore mild symptoms as not being that important, but in my experience, these symptoms could mean MS being active, i.e. with new lesions occurring in the relevant pathway.
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 maybe 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 we do 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 relapses were disabling or not. I define relapse as being disabling if it affected her ability to function normally; it may simply be 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 pwMS can receive certain DMTs under the NHS. Access to DMTs varies depending on local guidelines.
I would then examine this lady to assess her baseline neurological function. If I had time I would complete an 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. PwMS 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 ageing rather than MS. The truth is many pwMS 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 pwMS I would actively inquire 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 Newsletters, these hidden symptoms are an indication of whether or not her 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 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 generally not available in routine clinical practice.
Having poor clinical and MRI prognostic features may swing this lady’s decision towards currently licensed highly effective therapies, i.e. fingolimod (Gilenya), natalizumab (Tysabri), alemtuzumab (Lemtrada), cladribine (Mavenclad), ocrelizumab (Ocrevus) or ofatumumab ((Kesimpta). This would then trigger a detailed discussion with regard to the 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, pwMS is low.
If immunosuppressive therapies are a serious consideration we would need to check her varicella-zoster virus (VZV), HIV, hepatitis B&C status and make sure she does not have latent tuberculosis (TB). pwMS 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 pwMS exposed to people with active TB in the past, so-called high-risk pwMS, also get a chest x-ray at our hospital. The chest x-ray is not mandatory, some neurologists feel it is unnecessary.
When discussing highly effective therapies it is important to balance the risks of this strategy with the risks of MS. I would therefore inquire 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 pwMS 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 pwMS 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 pwMS who come and see me for a second or third opinion already know that I am an active 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 pwMS if they don’t meet our NHS England guidelines for treatment with the more effective treatments.
Another aspect that will affect this pwMS’s decision about treatment is family planning. As she has not completed her family she may well want to go back onto interferon-beta or choose glatiramer acetate (Copaxone), dimethyl fumarate (Tecfidera) or one of the so-called immune reconstitution therapies or IRTs as a treatment. IRTs have the advantage of depleting the immune system and allowing it to repopulate itself hopefully without evidence of ongoing MS activity. IRTs don’t remain on board for very long and hence are safe in relation to pregnancy. Interferon-beta and glatiramer acetate have a good safety record in pregnancy and most MSologists recommend pwMS under their care to fall pregnant on these drugs and to continue taking them throughout pregnancy.
I note this woman has already had a baby. I will inquire 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 pwMS 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 lower your chances of getting MS; maybe 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 into 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 pwMS so they don’t forget to take their daily vD supplements.
Finally, I always give pwMS that 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 pwMS 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 pwMS out there who volunteered for trials in the past.
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? Maybe.
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust. The advice is intended as general advice and should not be interpreted as being personal clinical advice. If you have problems please tell your own healthcare professional who will be able to help you.
Prof G - what is the recommended dose of vitamin D for a child age 5 where the parent has MS please? is there a point at which they should begin supplementation?