The coronavirus/COVID-19 pandemic is getting people with MS (pwMS) who are on a DMT to rightly question whether or not their immune systems are competent to deal with a COVID-19 infection. Unless you are on interferon-beta, glatiramer acetate or teriflunomide, the so-called immunomodulatory therapies, your immune systems are likely to be compromised and hence you are at risk of getting more severe COVID-19 infection or secondary complications of an infection.
Based on the immunological principles that antiviral responses are mainly driven by T-cells and natural-killer cells and less so, at least initially, by B-cells there is a hierarchy of immunosuppression on the DMTs. At the top of the list must be the immune reconstitution therapies during the depletion phase fo the treatment, i.e. HSCT, alemtuzumab [Lemtrada] and cladribine [Mavenclad]. For the maintenance treatments, I would rank them in descending order as being natalizumab [Tysabri], S1P modulators (fingolimod [Gilenya] / siponimod [Mazent] / ozanimod / ponisemod), anti-CD20 (ocrelizumab [Ocrevus] / rituximab / ofatumumab / ublituximab) and in the rear the fumaric acid esters (DMF [Tecfidera] / diroximel fumarate [Vumerity]). With the fumaric acid esters, this low ranking will not apply applies if your lymphocyte counts are low, i.e. generally lower than 0.8×109/L or 800/mm3.
I have put natalizumab at the top of the list as we don’t know how neurotropic this virus is. If it is neurotropic, i.e. has the ability to infect the brain natalizumab is risky. Natalizumab creates a compartment that is protected from the immune system and hence puts people at risk of COVID-19 encephalitis.
Because of the coronavirus/COVID-19 pandemic should I stop my DMT? No, you should not. My advice is for you to discuss this with your HCP. There are many factors that need to be taken into account, in particular, the risk of you being exposed to COVID-19 in your country. The risk can be mitigated by hygiene measures and avoiding high-risk travel and places and contacts that may expose you to the virus. The latter strategy will become more difficult as the pandemic spreads and more people in the general population become infected and shed the virus.
Just stopping MS DMTs, particularly natalizumab and S1P modulators, could result in MS rebound disease activity that is potentially serious.
Because of the coronavirus/COVID-19 pandemic should I delay further infusions with natalizumab and ocrelizumab? No, you should not make this decision yourself. My advice is for you to discuss this with your HCP. If you are going to stop natalizumab you need to transition yourself onto another DMT. Ocrelizumab and the other anti-CD20 therapies are slightly different in that their treatment effect takes many months and possibly years to wear off so you have more time to think.
As I am about to start cladribine, fingolimod, siponimod, alemtuzumab, natalizumab or ocrelizumab, should I delay treatment? This will need to be discussed with your HCP and the advice will depend on the state of the COVID-19 epidemic in your country or area. For example, if you live in Milan the advice is not to start these treatments. I suspect the COVID-19 epidemic may trigger a large number of pwMS who have yet to start treatment to reconsider their choice of DMT, based on the potential risks of getting a more severe infection on immunosuppressive therapies.
I have been treated with an IRT several years ago am I at risk of infection with coronavirus/COVID-19? Yes, you are. The risk of becoming infected will be no different from that in the general population.
The advantage of the so-called IRTs (HSCT, alemtuzumab and cladribine) is that they allow immune reconstitution, which refers to the restoring of your immune system to a state of competency after a cycle, or cycles, of depletion. Immune competence in the context of an IRT refers to the ability of the immune system to respond to infections, in particular opportunistic infections, mount an antibody response to vaccines and tumour surveillance. This has been best shown in the context of hematopoietic stem cell transplantation (HSCT) but is likely to be the case for alemtuzumab and cladribine. Please note reconstitution takes years, so if your last course was in the last 12-24 months you may still be immunocompromised. You can get a rough idea of the state of your immune system by looking at your total lymphocyte count, ideally, you want this to be above 1.0 x 109/L or 1000/mm3.
Should I switch my DMT to interferon-beta, glatiramer acetate of teriflunomide? This may seem like a logical thing to do, but it is seldom that simple. Most pwMS are on a higher efficacy DMT because they have failed these treatments in the past. Therefore de-escalating your therapy to a previous DMT you have failed may result in your MS getting worse.
Teriflunomide is an interesting option because it has been shown to have broad antiviral activity and hence has the potential to protect pwMS against COVID-19 infection and its complications. I would propose Sanofi-Genzyme doing urgent studies to test this hypothesis. The Coronavirus pandemic will take months to years to play out and knowing that teriflunomide has anti-coronavirus activity will be useful information for the MS community.
In summary, there are no easy answers. The pandemic is evolving at a rapid rate and country-specific information will emerge depending on the state of the epidemic in each country. At the same time, there are many anti-viral studies been run and there is a race on to develop a vaccine. My money would be on a DNA-vaccine winning the race, because of the ease of production of these sorts of vaccines. But as always there will be regulatory hurdles to overcome and hence any vaccine studies will be months away. So don’t rely on there being a vaccine or effective anti-viral drug anytime soon.
Hill-Cawthorne et al. Long Term Lymphocyte Reconstitution After Alemtuzumab Treatment of Multiple Sclerosis. J Neurol Neurosurg Psychiatry, 83 (3), 298-304 Mar 2012.
Background: Alemtuzumab is a lymphocyte depleting monoclonal antibody that has demonstrated superior efficacy over interferon β-1a for relapsing-remitting multiple sclerosis (MS), and is currently under investigation in phase 3 trials. One unresolved issue is the duration and significance of the lymphopenia induced. The long term effects on lymphocyte reconstitution of a single course, and the consequences that this has on disability, morbidity, mortality and autoimmunity, were examined.
Methods: The lymphocyte reconstitution (n=36; 384 person-years) and crude safety data (n=37; 447 person years) are reported for the first patients with progressive MS to receive alemtuzumab (1991-1997). Reconstitution time was expressed as a geometric mean or, when a non-negligible number of individuals failed to recover, as a median using survival analysis.
Results: Geometric mean recovery time (GMRT) of total lymphocyte counts to the lower limit of the normal range (LLN; ≥1.0×10(9) cells/l) was 12.7 months (95% CI 8.8 to 18.2 months). For B cells, GMRT to LLN (≥0.1×10(9)/l) was 7.1 months (95% CI 5.3 to 9.5); median recovery times for CD8 (LLN ≥0.2×10(9) cells/l) and CD4 lymphocytes (LLN ≥0.4×10(9) cells/l) were 20 months and 35 months, respectively. However, CD8 and CD4 counts recovered to baseline levels in only 30% and 21% of patients, respectively. No infective safety concerns arose during 447 person-years of follow-up.
Conclusions: Lymphocyte counts recovered to LLN after a single course of alemtuzumab in approximately 8 months (B cells) and 3 years (T cell subsets), but usually did not recover to baseline values. However, this long-lasting lymphopenia in patients with a previously normal immune system was not associated with an increased risk of serious opportunistic infection.