The following is a modified and anonymised email I received from a very concerned patient with MS. His treatment plan has been changed because of the COVID-19 epidemic. How would you advise him?
Dear Prof Giovannoni
I am a 51-year-old lady with active RRMS. I have only had MS for 3 years.
I am due to have my first ocrelizumab infusion in 2 weeks time.
My MS is active; I had a new lesion on my last MRI and my disability is progressing rapidly. My EDSS has moved from 2.5 to 3.5 in the last year. I was on glatiramer acetate, which I stopped a week ago.
My MS team have advised me to delay ocrelizumab treatment indefinitely and to start dimethyl fumarate next week.
My job involves dealing with many members of the public in a very busy retail environment.
Could you advise me if it is okay to start ocrelizumab if my MS team are willing to provide treatment and whether I should self-isolate after treatment because of the amount of contact I have with the public?
I realise that the Coronavirus situation is a very fast-moving situation, but as I am now only a few weeks away from my treatment date, I want to think through and carefully consider what to do. I don’t want to end up not having the most effective treatment for potentially another 6 to 12 months and missing the therapeutic window to slow down the progression of my MS.
Any advice you can give me is greatly appreciated.
With best wishes
This case illustrates the clinical issues the COVID-19 epidemic is raising and is only one example of what we are having to face in the clinic. There are no easy straightforward answers.
Post-script 14-March 2020
The core issue is that this patient appears to want to get on top of their MS disease activity as soon as possible and doesn’t want to take a chance on a lower efficacy option. If this is the case it excludes interferon-beta and teriflunomide as option, which would be the logical choices based on their putative anti-viral effects.
I would not recommend DMF. Firstly, DMF is less effective as a second-line DMT and it is immunosuppressive with about 15% of treated patients developing a treatment-related lymphopaenia of <800/mm3. As this usually comes on within the first 6-12 months in may not be the best DMT to start with.
In a normal treatment environment, fingolimod would be an option, but as it is immunosuppressive I would probably steer away from it as a treatment option. In addition, if a COVID-19 vaccine does emerge quite soon and high-risk patients get early access to the vaccine you don’t want to be on fingolimod. Fingolimod has been shown to blunt vaccine responses.
Based on its impact on T-cells and innate immunity alemtuzumab is a no-no. You could make the same argument about cladribine, which is now enshrined in print in the Italian and ABN COVID-19 DMT guidelines. However, the data does not necessarily support these positions. The level of T -cell depletion post-cladribine is ~50% for CD4+ T-cells and ~40% for the CD8+ T-cells making a much safer IRT than alemtuzumab. The data on infections in patients who received cladribine in the phase 3 CLARITY trial, including the subgroup who developed grade 3 & 4 lymphopaenia, is very reassuring with no severe viral infection signal. The advantage of cladribine is that with immune reconstitution occurs this patient will be able to receive a COVID-19 vaccine if and when it becomes available.
For similar reasons to cladribine, ocrelizumab will be relatively safe. However, once you start ocrelizumab you need to commit to at least 3 or 4 courses to prevent neutralizing anti-ocrelizumab antibodies. As ocrelizumab blunts vaccine responses it is not the ideal DMT thinking ahead to a vaccine. Ocrelizumab blunts vaccines responses.
This leaves natalizumab. Natalizumab is a high efficacy DMT, with a rapid onset of action and can be reversed by plasma exchange if necessary. It also will not exclude vaccination from a component (non-live) COVID-19 vaccine. From a theoretical perspective, natalizumab cannot be assumed to be safe if this patient became infected with COVID19. Natalizumab has been shown to slightly increase your chances of getting an upper respiratory tract infection and may hence increase the chances of a more severe COVID-19 infection. Then there is the theoretical risk that natalizumab may select for neurotropic strains of COVID-19, but I think this is only a theoretical risk at present. I would also predict that natalizumab has a chance of creating potential COVID-19 superspreaders as it blocks trafficking of T-cells into the gut. Even if this patient was JCV+ve I would still potentially go ahead with natalizumab treatment. To reduce the PML risk this patient could be converted to extended interval dosing of natalizumab after 6 months or switched to another DMT in sy 6-12 months. The elephant in the room is NHS England (NHSE); this patient doesn’t appear to fulfil the current criteria for treatment under the NHSE treatment algorithm. This case, however, highlights, why it is important that NHSE relaxes is criteria for using natalizumab to address the unmet need during the COVID-19 epidemic.
The other aspect is this patient is in contact with the general public that may increase his chances of being exposed to COVID-19, which may be more important than the other factors predicted above. So if this patient can’t reduce their risk of potential exposure to the virus in the hope of hanging on until a vaccine or anti-COVID-19 anti-viral become available then one of the immunomodulatory DMTs will make the most sense. This is why I would favour teriflunomide as the DMT of choice. It is also worth mentioning that when teriflunomide is used 2nd- or 3rd-line it is more effective. Teriflunomide also does not exclude vaccines later on; vaccine responses to component vaccines is maintained on teriflunomide.
If this patient is unhappy with the logic of going onto teriflunomide, my second choice would be natalizumab, followed by cladribine or ocrelizumab.
This case demonstrates the complexities of treating active MS during the COVID-19 epidemic. There are no right or wrong answers. Whatever decision you make there will be compromises. You may have to compromise on efficacy to increase the safety of the patient concerned and to potentially leverage the other attributes of DMTs to justify your treatment decision, for example in the case of teriflunomide that it is broadly antiviral and does not affect vaccine responses.