Case study: no regrets
This patient is NEDA-3 on fingolimod and is considering derisking his immunosuppression. Does he go lower and switch to teriflunomide or higher and choose an IRT?
Case study
I am a 33 years old male and I was diagnosed with MS 6 years ago. The symptoms which led to my diagnosis were sensory (numbness in both legs). Prior to my diagnosis, I had some other mild symptoms for 2 years, which were dismissed by my GP, and hence I was not referred to a neurologist earlier.
At the time of my diagnosis, I was oligoclonal band (OCB) positive and had a heavy lesion load in both the brain and spine (but not in the brainstem). I was on natalizumab for 5 years but switched to fingolimod a year ago due to the risk of PML.
Both DMTs have done wonders for me; I have not had any relapse nor any new lesions since I started them, I exercise 3 times per week without feeling tired and I've worked in very demanding jobs. In short, I lead a "normal" life and nobody can tell there is something wrong with me unless I disclose my problem.
I have two questions and I would really appreciate your opinion. Given that I have had only one risk factor for MS as:
a) I have been doing very well,
b) nobody in my extended family has MS,
c) I was raised in a country with lots of sunshine (and hence I was getting lots of vitamin D),
d) I have never been a smoker,
e) I eat a healthy diet,
f) I exercise regularly,
g) I had infectious mononucleosis in the past,
would it be hubris to think that there is a possibility I have been misdiagnosed? I have been seen by four top-notch neurologists in three different countries, but it has always been taken for granted that I have MS, therefore we have never discussed whether my initial diagnosis was correct. Or am I just lucky and the real MS has not shown me its ugly face yet? Does it make sense to try to confirm that I have MS?
What would be your suggestion about the most suitable DMT for me? I've been thinking of the following 3 options:
a) Since fingolimod has been working very well for me, it would be reasonable not to switch and stay on it. However, I am concerned about the long-term risk since fingolimod is immunosuppressive.
b) Switch to an IRT (probably cladribine), as there is a possibility of a cure. I acknowledge it is very tempting to think of a cure, yet an IRT is the only choice to achieve it.
c) Switch to a lower efficacy drug (probably teriflunomide). Based on the "flip the pyramid" approach, the rationale is that teriflunomide has a better safety profile and my MS has been stable over the last few years.
Prof G’s opinion
Based on your history and description of your MRI and spinal fluid results the diagnosis of MS seems beyond ‘reasonable doubt’. I have written about misdiagnosis before (Please see ‘Am I sure that I have MS?’ from 09-Jul-2021). I doubt you have been misdiagnosed as the so-called MS mimics, that are commonly misdiagnosed as being MS, usually declare themselves with time. Six years is a reasonable amount of time for these other diseases to cause problems and alert you to having another disease.
As you fulfil the current McDonald criteria for having MS the only way to confirm you have MS is to have a brain biopsy or to stop your therapy and to see what happens. Trust me when I say the risks associated with both a brain biopsy and stopping treatment are not worth taking.
You should be grateful for having your MS treated effectively from the beginning with a very high efficacy DMT that has been successfully derisked to fingolimod. What you describe is exactly how we want MS to be managed; quickly and effectively. Based on what you are telling me you are NEDA-3; i.e. no relapses, focal MRI activity (new lesions) and no disability progression. It would be interesting to know what is happening to your brain in terms of atrophy. Over the last 4-5 years have you developed accelerated brain volume loss? If you could get these measurements this may act as a catalyst to opt for more aggressive treatment. Saying this we don’t have data on whether or not switching somebody who is NEDA-3 on fingolimod to say an IRT (cladribine, alemtuzumab or HSCT) does in terms of brain volume loss or long-term disability.
What about your cognitive functioning? Are you having annual cognitive screening tests? If you did see cognitive deterioration would this motivate you to switch from fingolimod? What about other neurological stress tests, for example, running long distances to see how could your exercise capacity is?
I understand your concern about being on long-term immunosuppressive therapy, in particular fingolimod. You can’t really derisk the latter apart from being extra vigilant, but you are at risk of opportunistic infections (PML, cryptococcal meningitis, etc.), secondary malignancies (skin, lymphoma, etc.) and not responding to vaccines (COVID-19, etc.). As you are young these risks are relatively low, but what will happen when you are older say in your 50’s when immunosenescence kicks in?
You are not the only person with MS concerned about long-term immunosuppression. We have had a flurry of patients asking to come off anti-CD20 therapies and fingolimod for this reason. The most common request has been to be treated with cladribine based on the recent COVID-19 vaccine data. I also would not fault your choice of switching to teriflunomide. However, your baseline MRI scan, with a high lesion load and spinal cord involvement, put you at high risk of rebound MS disease activity and teriflunomide may not be effective enough to prevent this from occurring. However with both these strategies, i.e. cladribine or teriflunomide, you have the option of moving on to alemtuzumab or HSCT if you had recurrent disease activity.
Another issue is if you decide to stay on fingolimod and say in 10 years time you present with worsening disability indicative of the so-called secondary progressive phase of the disease, will you have regrets about not escalating your treatment when you had the option in the past? I have had several patients who are NEDA-3 on high efficacy DMTs who have decided to switch to alemtuzumab or have HSCT abroad for this exact reason. They don’t want to have any regrets in the future about not pushing for the most effective treatment option earlier on in the course of their MS when the advantages of these treatments are greatest. These patients all have had very high MS health literacy and understand the risks associated with these latter two treatments and are willing to take them. Based on your email to me, I think you are in this category.
So you have lots to mull over. My advice would be to try and get your brain volumes measured from your MRI scans over the last four or five years; this is sufficient time to see what the trajectory is. If your average BVL is greater than 0.4% per annum I would seriously consider switching to an IRT. I would also discuss having cognitive screening tests done and then doing it annually. Subtle loss of cognitive function may also help you make a decision about escalating your treatment.
I want to end by saying you are a success story. The fact that I am giving an opinion about optimising someone’s MS treatment who is NEDA-3 and fully functional is remarkable. It shows us how far MS treatment has come in the last 25 years.
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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.
Just to make the point that this patient would not be eligible for HSCT in the UK. However, he will be eligible for alemtuzumab or cladribine based on the criteria that were used to make the decision about starting natalizumab.
Very interesting. Good to know about brain volumn and how it's measured . Thanks for the comments. My neurologist probably inwardly groans when I say I've been reading from Prof G ....