COVID-19 pandemic and the risk of infection in multiple sclerosis patients on disease modifying therapies: “what the bleep do we know?”

The novel coronavirus which emerged in Wuhan province of China has taken world by surprise. Since been diagnosed in December 2019, it has been termed a “Pandemic” and there is a growing concern in physicians across the globe. As new evidence is emerging, there are various preventative strategies which are being deployed. Multiple sclerosis patients who are on disease modifying therapies (DMTs) might be at a higher risk of acquiring or a poorer outcome due to their immune status. This review looks at the available evidence in managing this global crisis.


Background
Coronavirus (COVID-19) has been termed as a global pandemic by the World Health Organization after being first diagnosed in December 2019 (https://www.who.int/ emergencies/diseases/novel-coronavirus-2019/events-asthey-happen). The number of people infected with the virus is rising at an exponential rate with data from the World Health Organization (WHO) being updated regularly (https://www.who.int/emergencies/diseases/novelcoronavirus-2019/situation-reports). The mortality rate is reported to be between 1 and 5% [1][2][3].
There is a growing concern in physicians across specialities as the situation is evolving. A practicing neurologist is facing a difficult clinical decision in relation to disease modifying therapies in multiple sclerosis and to the risk of COVID-19.

Virology
The coronavirus that is linked to COVID-19 is from a family of Betacoronavirus which is from the same subgenus that caused the severe acute respiratory syndrome (SARS) virus. There is a structural similarity between the receptor-binding sites. Angiotensinconverting enzyme 2 (ACE-2), for viral entry, is the proposed binding region [4].
Similarly, the cell response in COVID-19 patients showed a decrease in lymphocyte subsets B cells, T cells, and natural killer cells [5]. There was a lower level of helper T cells and memory helper T cells while an increased percentage of naïve helper T cells in patients who had severe disease [5]. Patients with COVID-19 also have lower level of regulatory T cells, and more obviously damaged in severe cases [5].
Both the rise in inflammatory cytokines and decrease in cell counts were related to the severity of the disease [5].

Disease modifying therapies
There are many disease modifying treatments that are available at present with difference in their mechanism of action, as shown in Table 1.
At present, the evidence is in its preliminary phase for what is safe and what might pose an increased risk for acquiring the COVID-19 infection and may lead to severe form of the disease. The Association of British Neurologists released guidelines dividing disease modifying therapies into risk groups (https://cdn.ymaws. com/www.theabn.org/resource/collection/6750BAE6-4 CBC-4DDB-A684-116E03BFE634/ABN_Guidance_on_ DMTs_for_MS_and_COVID19.pdf). These risk groups are shown in

Glatiramer acetate Shifts T cells from proinflammatory Th1 T cells to regulatory Th2 T cells reducing inflammation [6]
Safe to start or continue Teriflunomide Inhibiting rapidly dividing activated T cells and limited action on immune system [7] Safe to start or continue Interferon beta 1a, interferon beta 1b

Suppresses expression of inflammatory cytokines and increases expression of anti-inflammatory cytokines [8]
Safe to start or continue Dimethyl fumarate Activates NrF2 pathway, leading to increased humoral anti-inflammatory effects [9] Safe to start or continue Natalizumab Monoclonal antibody that blocks T lymphocyte migration to CNS by interfering with α4β1-integrin receptor molecules on the surfaces of cells [10] Safe to start or continue with highest efficacy Fingolimod Blocks release of lymphocytes acting on S1P1-5 receptor sub type [11] Moderate risk Alemtuzumab Monoclonal antibody that decreases predominantly CD-52 positive B and T cells [12] Significant risk Selectively targets the B lymphocytes that express the CD20 antigen triggers cell death [13] Significant risk Siponimod Inhibits the migration of the lymphocytes to the location of the inflammation by binding to sphingosine-1-phosphate receptor [14] Could pose a significant risk Ofatumumab Antibody to anti-CD20 that inhibits early-stage B lymphocyte activation (https://www.centerwatch.com/directories/1067-fdaapproved-drugs/listing/3172-arzerra-ofatumumab)] Could pose a significant risk be carefully considered before starting in new patients and those who are scheduled for their next infusions. 5. Could pose a significant risk. Ofatumumab and siponimod are not yet available in the UK or Ireland but might pose a significant risk.

Discussion
The current recommendation by the Association of British Neurologists (ABN) lacks class 1 evidence (https://cdn.ymaws.com/www.theabn.org/resource/ collection/6750BAE6-4CBC-4DDB-A684-116E03 BFE634/ABN_Guidance_on_DMTs_for_MS_and_ COVID19.pdf). The COVID-19 pandemic at present is expanding at an alarming rate, which may put these multiple sclerosis patients at a higher risk due to their immune status. The data from the World Health Organization (WHO) has not yet been translated in relation to this cohort of COVID-19 patients who are on disease modifying therapies. The risk estimate for the multiple sclerosis patients therefore still remains unknown.

Recommendation
We recommend a careful consideration of disease modifying therapies in the current health crisis which is still unfolding. In relation to multiple sclerosis, we strongly urge clinicians to educate patients on disease modifying therapies and a potential risk of COVID-19. Patients should be urged to follow strict preventative measures and if possible to postpone or defer potentially high-risk disease modifying treatments.