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Multiple Sclerosis and Related Disorders 39 (2020) 102073 Contents lists available at ScienceDirect Multiple Sclerosis and Related Disorders journal homepage: www.elsevier.com/locate/msard Commentary The COVID-19 pandemic and the use of MS disease-modifying therapies T ⁎ Gavin Giovannonia, , Chris Hawkesa, Jeannette Lechner-Scottb, Michael Levyc, Emmanuelle Waubantd, Julian Golda,e a Blizard Institute, Barts and The London School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT, UK b School of Medicine and Public Health, University of Newcastle, Callaghan, NSW, Australia c NMO Clinic and Research Laboratory, Division of Neuroimmunology & Neuroinfectious Disease, Massachusetts General Hospital, Boston, USA d Department of Neurology, UC San Francisco, San Francisco, California, USA e The Albion Centre, Prince of Wales Hospital, Sydney, New South Wales, Australia Maria was distraught after reading about the ‘potential’ epidemic, yet It is clear that COVID-19 is a pandemic and global health crisis with to happen, and the horror stories on Facebook needing reassurance and the potential to kill millions of people, particularly the elderly and people certainty about what she should do. She requested an urgent appoint- with comorbidities such as hypertension, smoking and lung disease. At ment to review her treatment plan. Maria was a 26-year-old woman with present we do not know if people with MS are at increased risk acquring relapsing multiple sclerosis who had recently experienced brainstem SARS-CoV-2, COVID-19 or developing severe COVID-19. Individuals relapse with double vision and ataxia despite treatment with pegylated with MS are not unique in their requirement to be treated with im- interferon-beta for the last 18 months. A brain MRI performed one month munosuppressive therapies. We discussed the COVID-19 epidemic with prior had shown 16 new T2 lesions, four of which were enhancing. One our renal transplant team who informed us that at present they are not of the enhancing lesions was at the pontomedullary junction and was taking any specific action about the levels of immunosuppression for certainly the cause of her relapse. Treatment was to be escalated to their transplant patients during the epidemic. Basic measures are re- ocrelizumab with the first dose in a week's time. In view of the emerging commended namely: to improve hand and home hygiene, to avoid high- coronavirus pandemic, she was questioning whether or not she should go risk travel and unnecessary contacts, to self-isolate if necessary and to ahead with ocrelizumab. This was despite only a handful of confirmed reduce contact with the hospital and other medical institutions as much COVID-19 cases in the country and none in her town and region. as possible, because they are more likely to be sources of COVID-19. It is If this scenario sounds plausible what should neurologists do? business as usual. Nor are they necessarily halting their transplant pro- Human coronaviruses are predominantly associated with respiratory gramme. Their argument is that transplanted kidneys and other trans- tract infections and includes those that cause severe acute respiratory planted organs are too precious not to protect them with relevant im- syndrome (SARS), Middle East respiratory syndrome (MERS) and now munosuppressive drugs. Why would we not have the same attitude about the COVID-19 pandemic. the brains and spinal cords of our patients with active multiple sclerosis? In an uncertain world, where we do not have a clear evidence-base, We could argue that solid-organ transplant patients are significantly you often have to default to scientific principles, rather than using the more immunocompromised than pwMS on disease modifying treatment wisdom of the crowd. Not surprising, with Italy being one of the epi- (DMT). Most transplant patients are on triple immunotherapy, com- centres of the COVID-19 epidemic, the Italian society of neurology or pared to pwMS who are on monotherapy and even then, the level of SIN (Società Italiana di Neurologia) broke cover first producing re- immunosuppression is generally low. Hence, the mortality/morbidity commendations on the management of patients with MS during the risk to an individual on a DMT, infected with COVID-19, may be ac- COVID-19 epidemic (see Box 1). The SIN guidelines provide relatively tually quite moderate to low. Another hypothesis being considered is straightforward, and one could argue arbitrary, advice on how to that moderate immunosuppression may prevent severe complications manage patients with MS in the short-term, but do not address super- associated with COVID-19 infection. The severe pulmonary complica- vision of these patients in the intermediate or long-term especially tions of COVID-19 infection are consistent with ARDS (acute respiratory those with highly active MS. If the public health measures being taken distress syndrome) caused by an over-exuberant immune response to flatten the peak of the epidemic, but extend its tail, the problemof the virus (Ramanathan et al., 2020). As a result, several exploratory community-acquired SARS-CoV2 infection and COVID-19 may be with trials are currently being undertaken in China and elsewhere using us for many months and potentially years. Are the SIN guidelines immunosuppressants to try and dampen the immune response to the compatible with the best interests of our patients or a knee-jerk re- virus. Interestingly, fingolimod, a S1P modulator licensed for MS,is sponse to an undefined problem that may not be a problem at all? being tested as a treatment for COVID-19 associated ARDS ⁎ Corresponding author. E-mail address: [email protected] (G. Giovannoni). https://doi.org/10.1016/j.msard.2020.102073 2211-0348/ © 2020 Elsevier B.V. All rights reserved. G. Giovannoni, et al. Table 1 Main attributes of licensed MS DMTs in relation to the COVID-19 pandemic At risk category Class Trade name Mode of action Efficacy Class Safe to Advice regarding In the event of Immuosuppression? Attributes and caveats start treatment COVID-19 treatment infection? Very low Interferon-beta Betaferon, Avonex, Immunomodulatoy (not Moderate Maintenance Yes Continue Continue No Has antiviral properties that Rebif, Plegridy immunosuppressive), immunomodulatoy may be beneficial in the pleitropic immune effects case of COVID-19 Very low Glatiramer acetate Copaxone Immunomodulatoy (not Moderate Maintenance Yes Continue Continue No immunosuppressive), immunomodulatoy pleitropic immune effects Very low Teriflunomide Aubagio Dihydro-orotate Moderate Maintenance Yes Continue Continue Possible (no well- Has antiviral properties that dehydrogenase inhibitor (1st-line) / immunomodulatoy defined may be beneficial in the (reduced de novo pyrimidine Moderate to immunosupressive case of COVID-19 synthesis), anti-proliferative high (2nd- signature) 3rd-line) Low Dimethyl fumarate Tecfidera Pleotropic, NRF2 activation, Moderate Maintenance Probably Continue / Continue Yes, continous The risk can only be downregulation of NFΚβ (2nd-3rd- immunosuppressive Switch if considered low in paients line) / High lymphopaenic who don't develop a (1st-line) persistent lymphopaenia. Patients with a total lymphocyte count of less than 800/mm3 should be considered be at a higher risk of develping complications from COVID19 infection. 2 Low Natalizumab Tysabri Anti-VLA4, selective Very high Maintenance Yes Continue Continue or Yes, continous Low risk, but theoretical adhesion molecule inhibitor immunosuppressive miss infusion concerns of creating an depending on environment in mucosal timing surfaces and the gut that may promote prolonged viral shedding. Also risk that as COVID-19/SARS-CoV-2 is neurotropic it may prevent viral clearance from the CNS. Intermediate S1P modulators Fingolimod Selective S1P modulator, High Maintenance Probably Continue Continue or Yes, continous Theoretical risk that S1P (Gilenya), prevents egress of immunosuppressive temporary modulators may result in Siponimod lymphocytes from lymph suspension of prolonged viral shedding. Multiple SclerosisandRelatedDisorders39(2020)102073 (Mazent), nodes dosing Paradoxically S1P Ozanimod, modulators may reduce the Ponesimod severity of COVID-19; fingolimod is currently being trialed. Intermediate Anti-CD20 Ocrelizumab Anti-CD20, B-cell depleter Very high Maintenance Probably Risk assessment - Temporary Yes, continous Theoretical risk that (Ocrevus), immunosuppressive continue or suspension of ocrelizumab and other anti- Ofatumumab. suspend dosing dosing CD20 therapies may result Rituximab, depending on in prolonged viral shedding. Ublituximab timing Intermediate Cladribine Mavenclad Deoxyadenosine (purine) High / Very IRT (semi-selective) Probably Risk assessment - Temporary Yes, intermittent