Case study: Ocrelizumab to Teriflunomide switch

Prof G discusses the case for using ocrelizumab as an induction therapy followed by teriflunomide maintenance therapy. This is how he envisages using the class of anti-CD20 therapies in the future.

Case study

I am a 55-year old woman who was diagnosed with RRMS in 2009 (age 43).

My first symptoms were tingling in the right hand, which over a week progressed to numbness along the right side of my body. This was followed shortly by difficulty walking, unsteadiness and nystagmus (jerking of the eyes). I was hospitalised for three days and was treated with intravenous steroids. During my admission, I had MRI's and a lumbar puncture and was told my diagnosis was likely to be multiple sclerosis. 

Over the next three months, I regained nearly 100% of my function. A repeat MRI showed about a dozen old lesions in the brain and a large active lesion in the brain stem. I also had a few spinal lesions.

I had no previous symptoms to suggest MS except fatigue.

A wait-and-see approach regarding disease-modifying therapies was recommended.

I started glatiramer acetate after a relapse in 2012, which left me with a foot drop. I have not made a full recovery from this. In 2015, I was switched to dimethyl fumarate (Tecfidera) after a relapse left me with double vision. I did not make a full recovery from this and still have double vision with extreme left gaze. 

I noticed that my walking and balance were getting worse so in Sept 2020 I was switched to ocrelizumab (Ocrevus) and had my second infusion in March 2021.

I have been double vaccinated with the Oxford-AstraZeneca COVID-19 vaccine in late Jan and late Feb; four weeks apart and four weeks before my second ocrelizumab infusion in March 2021. I have not had COVID-19, but have been very cautious.

I am having a meeting with my neurologist next week to discuss switching DMT.  I am very happy with ocrelizumab, except for fear of being constantly vulnerable to COVID-19.  What do you recommend? 

Prof G’s opinion

This patient is clearly tolerating anti-CD20 therapy relatively well and is happy with its efficacy. I am aware that she has been reading the MS-Blog and has been receiving the MS-Selfie Newsletters and is acutely aware of the issues regarding vaccine readiness on ocrelizumab and her vulnerability to severe COVID-19. She is also aware that infectious complications are more common in older people with MS who are on anti-CD20 therapy. Yes, from about 55 years of age immunosenescence starts to affect the immune system and infectious complications on immunosuppressive therapies, including anti-CD20 therapies such as ocrelizumab, increase quite dramatically. 

I suspect she does not have hypogammaglobulinaemia (low antibody levels), which tends to develop after several years on ocrelizumab.  If she was hypogammaglobulinaemic her risk of infection would be even higher. 

What is clear from my email exchange with this patient is that she is not comfortable with not being able to respond adequately to vaccines, the potential long term immunosuppressive effects of ocrelizumab and her persistent fear or anxiety of getting COVID-19, particularly severe COVID-19. This is why I would recommend derisking her treatment and for her to switch to a maintenance immunomodulatory DMT such as teriflunomide or interferon-beta. I would not recommend glatiramer acetate as this treatment failed her in the past.  

Of these two choices, I would favour teriflunomide simply because it is an oral therapy and has a greater impact on disability progression and slowing brain volume loss compared to interferon-beta. Interestingly in the recent ofatumumab vs. teriflunomide trials, teriflunomide was as good as ofatumumab (anti-CD20) therapy on brain volume loss. This implies it is doing something to smouldering MS, i.e. downstream of focal inflammation as it was inferior to ofatumumab in suppressing relapses and MRI activity.

Switching from ocrelizumab to teriflunomide is an example of an induction-maintenance strategy, which makes a lot of sense, particularly in older patients who have immunosenescence or comorbidities. Another reason to use teriflunomide is that it has broad antiviral effects, including effects against EBV, which may prevent EBV reinfecting new memory  B cells as they are formed in the lymph nodes. I would therefore recommend that teriflunomide is onboard when B-cell reconstitution starts to happen, i.e. from at least 6 months after her last infusion of ocrelizumab. 

Please note the induction-maintenance EBV-B-cell hypothesis should not be the primary reason for this particular switch as there is no hard evidence yet to support this practice. This is why it needs to be tested in clinical studies. 

This patient will have to have the recommended baseline checks before switching treatments and will need to have the monthly liver function and full blood counts done for a period of six months followed by 3-monthly blood tests thereafter.  I don’t think there are any major concerns with this switch. I am aware that patients with rheumatoid arthritis have been switched from rituximab to leflunomide (pro-drug of teriflunomide) and some have been treated with rituximab in combination with leflunomide without any problems arising. 

Hindsight

Hindsight is perfect vision. If this patient presented now, i.e in 2021 with MS, she would not be managed with watchful waiting and would almost certainly be offered treatment for MS after her first attack. It is amazing how our treatment approach has changed over the last decade; yes, time is both brain and spinal cord. Similarly, it is unlikely that a patient with a similar baseline profile would be treated with glatiramer acetate followed by dimethyl fumarate in the modern era. Her baseline profile has several poor prognostic features that would mean that she would be guided to a more effective therapy first-line, i.e. flipping the pyramid. There is now overwhelming data that on average pwMS who are treated with high-efficacy therapies first-line do better than those managed with a stepped-care approach. 

COVID-19 and vaccination

I would also recommend that this patient remains vigilant about COVID-19 and that she must assume her vaccine response is suboptimal. I would recommend a booster dose of the COVID-19 vaccine once she has some evidence of peripheral B cell reconstitution. What level of B-cell reconstitution is required for an adequate vaccine response is currently being studied, but it looks like she will need at least ten CD19+ B-cells per mm3 of blood; this is the level that is associated with antibody responses to the COVID-19 vaccine. 

Please feel free to ask questions if you are unsure about this Newsletters content.

MS-Selfie

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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.