Coronavirus disease 2019 (COVID-19) is a disease caused by the novel SARS-CoV-2 virus that has resulted in a worldwide pandemic. While the resultant respiratory disease is mild in the majority of patients, a subset of patients can develop severe disease with significant respiratory compromise that may require ventilation and intensive care. Elderly patients and patients with co-morbidities such as diabetes and obesity appear to be more severely affected and are at high risk for a fatal outcome. Patients with multiple sclerosis (MS), who are often treated with immunosuppressive agents, might be more susceptible to complications of COVID-19 because of their inability to make a robust immune response against the virus. Alternatively, it is also possible that immunosuppression might be beneficial in limiting the cytokine storm complications caused by the virus, thereby having some protective effect against the virus.
It has been established that MS patients have an increased risk of infections compared to the general population. These infections can lead to increased morbidity and may also contribute to provoking relapses as well as transiently worsening patients' baseline neurologic symptoms (Chiarini et al., 2020) ). While there have been two case reports published to date of MS patients developing COVID-19 while on fingolimod which also showed that a patient can survive in the context of recent treatment with fingolimod and experience a milder disease course (Barzegar et al., 2020) , this case was also instructive because the authors attempted to determine some of the effects of fingolimod and the SARS-CoV-2 virus on the immune response. Despite being lymphopenic on admission as a result of the fingolimod treatment and potentially also the SARS-CoV-2 virus, the patient was still able to mount an antibody response, presumably directed against the virus, resulting in a favorable outcome for this patient. Of note, the patient's fingolimod treatment was discontinued when hospitalized which could have played a role in impacting the immune response observed. The immune reconstitution appears faster in J o u r n a l P r e -p r o o f Journal Pre-proof the context of stopping fingolimod compared to other oral and infusible therapies. Although, it is not clear whether other potent immune therapies result in a less robust immune response in the setting of COVID-19 infection. This is an area of needed research since this could help further our understanding of the differential impact of specific DMTs on COVID-19 infected patients. Also, it is unclear if there may be an independent protective or deleterious effect with sphingosine-1-phosphate (S1P) receptors modulators in COVID-19 infected MS patients since there are S1P receptors within the lungs (Ebenezer et al., 2016) . If there is truly a protective effect, then it could be secondary to a reduction in pro-inflammatory cytokines in the setting of DMT use that results in a less robust cytokine storm. It is speculated that the host immune response towards COVID-19 may be worse than the infection itself which has been observed with other infections (e.g., PML immune reconstitution inflammatory syndrome).
Other case reports on the coexistence of COVID-19 and MS have been reported with patients receiving other immunosuppressive drugs (Suwanwongse and Shabarek, 2020; Borriello and Ianniello, 2020) . In a patient receiving ocrelizumab, despite being impaired in the ability to mount a normal antibody response based on this medication's main mechanism of action, the patient had a mild disease course and recovered uneventfully from their COVID-19 infection (Suwanwongse and Shabarek, 2020) . One has to speculate that maybe this patient did better than expected because B-cells are a major source of Interleukin 6 (IL-6) production and depleting B-cells may help dampen the typical cytokine storm effects with lower IL-6 levels.
Another patient with MS being treated with natalizumab also had an uneventful disease course, although this patient did receive an extended interval dosing of natalizumab (Borriello and longer disease duration, and co-existing medical co-morbidities that were previously noted to have increased mortality for patients with COVID-19 in general. These demographics are in contrast to some of the patient's characteristics in this report (younger age and less overall disability). In this registry, known as COViMS, no deaths had been recorded in the 11 patients being treated with fingolimod, 1 death recorded in the 48 patients treated with ocrelizumab, and no deaths in 18 patients treated with natalizumab.
While both these registries are in their early stages, it seems to be apparent that the earlier concerns that more potent DMTs were going to make MS patients more susceptible to developing a severe COVID-19 disease course and that they were more likely to experience mortality does not appear to be the case based on what we know at this point. However, more work will need to be done with regard to studies like that published in this issue of JNI to further examine how the immune response to SARS-CoV-2 is affected by specific MS DMTs and treatment strategies (e.g., high efficacy vs. others). In addition, there is an urgent need for clinicians to help the MS community in collecting this important clinical data. If you are a neurologist taking care of a patient with MS who has developed suspected or definite COVID-19, you can enter their clinical data into the registry at COViMS.org.
Dr. Scott Newsome has received consultant fees for scientific advisory boards from Biogen, Genentech, Celgene, EMD Serono, Novartis, is an advisor for BioIncept, a clinical adjudication committee member for a medDay Pharmaceuticals clinical trial and has received research funding (paid directly to institution) from Biogen, Novartis, Genentech, National Multiple Sclerosis Society, Department of Defense, and Patient Centered Outcomes Institute.
Dr. Michael Racke has received consultant fees from Teva Neuroscience and Genzyme. 