Case study: rapidly-evolving severe MS and pregnancy

This is a very complex case of someone with recently diagnosed rapidly evolving severe MS with apparent breakthrough activity on natalizumab on a background of recurrent miscarriages.

Sep 27, 2021

Case study

I am a 33-year old woman with MS and had my first attack in January of this year and was formally diagnosed as having MS in March. Unfortunately, I have had 3 miscarriages in the last year. My first MS relapse came after my second miscarriage and I relapsed again after my third miscarriage in April.

I have been told that I have rapidly evolving RRMS and was started on natalizumab (Tysabri) in April. I am waiting on a new MRI of the brain and spine with contrast because my neurologist is concerned I may be failing natalizumab.

My first symptoms were a numb feeling on the right side of my face and a heavy arm in January. At the moment I have :

Pain in both arms and legs (left side relapse was in April shortly after my 3rd miscarriage).
Blurry vision in one eye and dull vision in the other, with eyelids that occasionally partially close (June)
MS Hug (August)
Debilitating pain in both shoulders. It was particularly bad in the right shoulder and I couldn’t move my right arm properly for 48 hours. This was different to the previous arm pain that I had a few weeks ago.
Last week I experienced foot drop for the first time; it happened twice in 3 days very briefly and hasn’t happened again
I have brain fog and I am very fatigued

My symptoms have all, for the most part, gone away, but tend to flare up quite often, especially when I am tired or stressed.

A fertility blood test showed a positive test for lupus anticoagulant (treatable with heparin and aspirin). I am waiting for the results of a follow-up test to make sure it wasn’t a false positive.

My husband and I are very keen to have a family so my question is: would you recommend staying on natalizumab and trying for a baby again now while things are still early (better chance of successful pregnancy I now know what the issue is) even though natalizumab doesn’t appear to be doing a good job of stopping relapses? Or do you feel the speed of new symptoms would make that an irresponsible decision?

I know it’s impossible to see into the future, but if my husband and I are going to try for a baby I feel it needs to be now before I consider either alemtuzumab or HSCT.

Prof G’s opinion

My opinion is based on the assumption that you have MS and have not been misdiagnosed. Please be aware a misdiagnosis rate can occur in about 5% of pwMS. Can you please ask your neurologist to make sure you don’t have lupus or an overlap syndrome, which can occasionally mimic MS in the early stages? However, I suspect this is unlikely because lupus usually declares itself quite quickly (weeks to months) after the initial neurological presentation.

The most critical question to answer is whether or not you have breakthrough disease activity on Natalizumab. If a relapse or relapses occur in the first two months after starting natalizumab this could have been a relapse, or relapses, destined to happen before natalizumab has started working.

Another possibility is that you have developed neutralizing anti-natalizumab antibodies. These anti-drug antibodies (ADAs) stop the drug from working. Please note that 3 out of patients with ADA to natalizumab develop infusion reactions, but 1 in 4 don’t and the only way you can find out is by having a test for ADAs. About 10% of pwMS treated with natalizumab develop ADAs with 5% persisting at 12 months. Anti-natalizumab ADAs should be checked in all patients having an infusion reaction and routinely at 12 months in all patients after starting natalizumab. Being on natalizumab with ADAs has been shown to be equivalent to being on placebo. In other words, ADAs stop natalizumab from working.

It seems like your new symptoms have occurred more than 2 months after starting natalizumab, which suggests it is failing you. If your MRI shows new lesions then it would very important to have ADAs checked and if positive you will have to switch treatments.

The question is which treatment would you switch to? It seems like you have very active MS and therefore you need a high-efficacy DMT, which needs to be balanced against your wish to start a family.

Anti-CD20

As your fertility problems may be immune-mediated you may want to switch to a treatment that is immunosuppressive and could improve your chances of falling pregnant. Lupus anticoagulant is found in patients with antiphospholipid syndrome, lupus or SLE and several overlap syndromes. These conditions are frequently treated off-label with rituximab (anti-CD20), which is why by analogy ocrelizumab or ofatumumab may be the best DMT to switch to if natalizumab has failed you.

Immune reconstitution therapies or IRTs

Other treatment options are cladribine or alemtuzumab. Both of these are immune reconstitution therapies and ideally, if you choose to go this route you should have both courses before trying to fall pregnant. This would mean at least an 18-month delay. This delay may be important to get your disease under control. You can’t assume that by falling pregnant your disease activity will settle down. Although on average MS disease activity goes down during pregnancy there are a small number of women in whom the opposite happens. My advice is to get your disease under control first and then to focus on the pregnancy.

The choice between cladribine or alemtuzumab depends on how risk-averse you are. Alemtuzumab is probably more effective than cladribine, particularly in relation to its impact on end-organ damage (brain volume loss) and recovery of function. However, alemtuzumab comes with the need for (1) high-dose steroids to reduce infusion reactions, (2) a Listeria diet, antibiotics and antivirals to lower the risk of infections when immuno-depleted, (3) monthly urine and blood monitoring for secondary autoimmunity and (4) a 45% chance of developing a second autoimmune disease.

In comparison, cladribine comes with none of these issues and is one of the easiest DMTs to use; two cycles of 4-5 days of tablets orally (week 1 & week 5) in year 1 and year 2. In the current COVID-19 environment cladribine is clearly the safer option and importantly doesn’t appear to blunt vaccine responses regardless of where you are in the treatment cycle.

AHSCT (autologous haematopoietic stem cell transplant)

What about AHSCT? This would be an option in the UK; our guidelines state that patients can be considered for AHSCT if they have highly active MS and have failed at least one high-efficacy DMT. The downside is that the cyclophosphamide is toxic to ovaries and about 45% of women with MS who are treated with AHSCT have premature ovarian failure. To overcome this women who want to start or extend their families have to have eggs harvested and stored. This requires ovarian stimulation and egg harvesting, which all takes time. In addition, in some areas of the country, the costs of egg storage are not covered by the NHS.

So based on what you have told me above AHSCT may not be the best option for treating your MS at the present time. Please note that whatever choice you make at present AHSCT will remain a backup option. Saying that some neurologists are reluctant to refer their patients for AHSCT because they feel it is too risky as an MS treatment.

A premature opinion?

My opinion is probably too premature. I would want to know what your MRI scans show and whether or not you have anti-natalizumab ADAs. Another bit of information that may help in the decision-making process is if your MRIs show no new lesions to do a lumbar puncture to measure your CSF neurofilament light chain levels. In our centre, approximately 10% of patients have raised CSF NFL levels without any clinical or MRI activity of disease activity.

Another factor is your cause of recurrent miscarriages. If it is immune-mediated you may want to switch from natalizumab even if it doing its working, i.e. you have NEIDA (no evident inflammatory disease activity), and are anti-natalizumab ADA negative.

In response to your question ‘do you feel the speed of new symptoms would make that an irresponsible decision?’; I don’t think you are being irresponsible, but to reiterate my advice would be to prioritise your own health before trying to fall pregnant again.

I hope this helps. Please feel free to ask questions if anything is unclear to you. Try not to make the questions too specific or personal so that other readers are able to identify you.

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