Discussion

Coronavirus and the nervous system. Although coronaviruses target mainly the respiratory system, they also demonstrate some degree of neurotropism and can enter the central nervous system (22). Sars-Cov-1 and Sars-Cov-2 bind to angiotensin converting enzyme 2 (ACE2) to gain access into the host cell and ACE2 is also present on vascular endothelial cells of brain capillaries (14). Sars-Cov-1 and Sars-Cov-2 are responsible of neurologic complications and the same has been demonstrated for other strains of coronaviruses (01). Selected coronavirus strains, eg, HCoV-229E and HCoV-OC43, have been repeatedly associated with multiple sclerosis based on serologic and molecular findings, but data are still controversial and inconclusive (01). Sars-Cov-2 is the agent of the Covid-19 pandemic and based on clinical, imaging, and neuropathological evidence it also causes damage to the nervous system by direct and indirect mechanisms. It gains entrance to the brain via the hematogenous route and via the olfactory pathway through a transneuronal route in a subset of patients (17). Although Sars-Cov-2 can be occasionally detected in the brain of patients dying of Covid-19 (21), the most common neurologic symptoms are smell and taste dysfunction and, only sporadically, it has been linked to true forms of meningitis or encephalitis (15). In addition, indirect damage to the nervous system may ensue by the surge of cytokine release, which causes an inflammatory encephalopathy (04). Finally, endothelial damage and hypercoagulability generated by Sars-Cov-2 infection may lead to ischemic stroke (20).

Would immune response to COVID-19 be different in patients with multiple sclerosis?

Response of the immune system to coronavirus infection. COVID-19 virus sometimes has no symptoms (25% to 50% in Iceland) (12); perhaps this is because the virus blocks the body’s interferon response in at least 7 different sites in the interferon signaling pathway. These asymptomatic carriers can spread the virus as it buds out of the endoplasmic reticulum of lung cells into the pulmonary alveoli. COVID-19 is then present in oral and nasal secretions and in cough droplets.

When symptoms appear, there is an initial effort by the body to clear the virus. Interferons are eventually induced at high levels along with other cytokines. In a second very destructive phase, the immune system is over-activated and causes destruction of lung tissues. Age and other medical conditions allow a hyperactive immune response. The mechanism is not clear, but is possibly a consequence of pre-existing immunity to coronavirus plus poor immune regulation in the aged. Factors underlying the wide spectrum of severity in COVID-19 infection are still puzzling, but selected HLA haplotypes possibly exhibiting a more efficient capacity to bind SARS-CoV-2 peptides were associated with mild disease (16).

Based on the notion that type I interferon pathway is protective against Sars-Cov-2, susceptibility to COVID-19 infection has also been linked to a defective IFN response. Patients with severe disease appeared to have an impaired type I IFN signature compared to those with mild or moderate disease and the expression of type I IFN inversely correlates with viral load and NF-kB-driven inflammatory response (ie, IL-6 and TNF-a levels) (13). Vulnerability to severe Sars-Cov-2 infection may associate with rare variants at the 13 human loci that regulate TLR-3 and IRF7 type I interferon immunity to influenza virus, resulting in a loss-of-function effect (36). Furthermore, poor interferon response may also result from neutralizing IgG auto-antibody to interferon-omega, the 13 types of interferon-alpha, or both; this poor response was observed in patients with life-threatening COVID-19 pneumonia (03).

Innate immunity plays a fundamental role in the pathogenesis of COVID-19 disease. Hyperreactive immune response in severe disease is characterized by the polarization of monocytes to a M1 phenotype, secreting proinflammatory cytokines (IL-1beta, IL-6, TNFalpha, and IL10) and inflammation-related chemokines (CCL3, CCL4, CCL20, CXCL2, CXCL3, CCL3L1, CCL4L2, CXCL8, and CXCL9) (11). A major activating mechanism of inflammatory monocytes is the pathological stimulation of TLR/IL-1R signaling and the following induction of Bruton tyrosine kinase, leading to activation of NF-kB and nucleotide-binding oligomerization domain-containing protein-like receptor protein inflammasome secretion of IL-1 (33). Patients with severe COVID-19 have increased expression of TLR and IL-1R and a downstream inflammatory cascade. Preliminary observation shows that targeting these pathways may be effective in dampening the hyperinflammatory response (06; 26). Natural killer cells are also depleted and exhibit an exhausted phenotype in severe COVID-19 disease (31; 34). The reduction and dysfunction of natural killer cell compartment has been linked to the excessive release of proinflammatory cytokines (ie, IL-6 and TNFalpha) leading to an impairment of viral clearance (30).

The T cell compartment is also affected in moderate and severe forms of COVID-19 as the characteristic lymphopenia is mainly due to CD4+ and CD8+ T-cell count reduction (10; 34). Aberrantly activated macrophages releasing high levels of IL-6 may promote apoptosis of lymphocytes in the spleen and lymph nodes (07). Surviving lymphocytes may contribute to the hyperinflammatory state in COVID-19 due to the increased proportion of pathogenic Th1 CD4+ T cells secreting IL-6, GM-CSF, and IFN-γ and the decreased percentage of immunosuppressive regulatory T cells (07; 09; 34).

The multiple sclerosis immune system is overactive in some ways (the disease itself, and higher antibody titers against measles and perhaps Epstein-Barr virus), in parallel with many defects in immune regulation and immune suppression (08). This overactivity occurs despite fewer new immune cells emigrating from the thymus and bone marrow, causing a prematurely aged, dysregulated immune system. Plus, patients have low levels of interferons and a defect in interferon signaling (08), the very system that attacks viruses. Several IFN-stimulated gene transcription profiles are impaired in all stages of multiple sclerosis and may impact antiviral responses (27). Multiple sclerosis patients often claim they seldom get a “cold” and appeared to have half as many infections as healthy subjects in controlled studies (28). In the treatment era, the rate may have changed; a number of studies report an increased risk of infections, including viral, in patients with multiple sclerosis, but elevated disability and disease modifying treatments play a determinant role as risk factors (05; 24). Altered IFN-related pathways may contribute to explain both lower and heightened susceptibility. However, despite their overactive immune system, there is no evidence so far that patients with multiple sclerosis are more prone to develop the hyperinflammatory state and, hence, severe COVID-19 disease.

How is this relevant to multiple sclerosis therapy during virus infection?

Are patients with multiple sclerosis more at risk of COVID-19 infection? There are no studies available on the frequency of COVID-19 disease in patients with multiple sclerosis, but they do not seem to be at increased risk, based and on data discussed in a world-wide phone conference on April 1, 2020 (Waubant E, Sormani M, International Federation of Women in MS), followed by publications (18; 29).

How could multiple sclerosis treatments affect COVID-19 infection? Which drugs could enhance antiviral responses? Interferons are one of the most potent arms of the antiviral response. Interferon-beta is produced first, and it then activates many types of interferon-alpha. All of these type I interferons induce enzymes that degrade virus RNA and DNA and activate antiviral NK cells and enhance production of antibodies to the virus. The interferon-beta used to treat multiple sclerosis may, thus, be protective early in Sars-Cov-2 infection.

Teriflunomide and leflunomide exhibit antiviral properties against several viruses, including Epstein-Barr virus, cytomegalovirus, Herpes 1 and 2, and BK poliomavirus. They may prevent viral replication through the inhibition of the enzyme dihydro-orotate dehydrogenase. These drugs also have in vitro antiviral activity against coronaviruses (32).

Some multiple sclerosis therapies seem to have minimal or no effect on viral infections (eg, glatiramer), yet those causing mild immune suppression may allow more virus spread. Evidence accumulated from clinical trials and observational studies shows that with most multiple sclerosis therapies, viral infections are minimally increased, but this may not translate to Sars-Cov-2. Fingolimod and cladribine may increase the risk of herpetic infections, and older patients on these therapies have higher risk of viral and opportunistic infections. Additional concerns include the degree of lymphocyte depletion, but in general there is weak or no correlation between lymphocyte levels and infections with fingolimod and teriflunomide. Alemtuzumab and anti-CD20 may carry a higher risk, as they are more frequently associated with viral and bacterial infections, respectively (35). More importantly, beyond all of these potential influences the main risk factors for severe COVID-19 disease in patients with multiple sclerosis are still medical comorbidities and age, as with non-multiple sclerosis patients.

Reduced traffic of immune cells into the CNS is also a concern, as it could allow virus replication behind the blood-brain barrier. SARS coronavirus spreads through olfactory pathways to the entorhinal cortex (23). A common complaint with COVID-19 is anosmia, suggesting COVID-19 may also spread to CNS through nasal nerves, although the main targets in the nose are olfactory sustentacular cells. Natalizumab and fingolimod reduce T cell penetration into the CNS. The relevance to COVID-19 is unknown.

Do multiple sclerosis treatments increase the risk of severe COVID-19 infection? Several studies to date investigated the risk of COVID-19 infection in patients with multiple sclerosis. Loonstra and colleagues reported on 86 multiple sclerosis patients with suspected or confirmed COVID-19 infection, of which 43 were hospitalized and 4 died (19). None of the disease modifying drugs nor lymphopenia were significantly associated with severe infection, but patients on ocrelizumab were overrepresented among those requiring hospitalization. A multicenter study conducted in France on 347 patients with multiple sclerosis showed that age, Expanded Disability Severity Scale score, and obesity were independent risk factors of severe COVID-19 disease (18). Seventy three out of 347 patients required hospitalization and 7 died, but the use of disease modifying drugs was associated with a lower risk of hospitalization compared to untreated multiple sclerosis, and no treatment significantly correlated with a more severe disease. The largest study so far has been conducted on 844 Italian patients with suspected or confirmed COVID-19 disease, among them 96 were hospitalized, 38 were admitted to ICU, and 13 died (29). A multivariable analysis carried out to explore which factors may increase the risk of poor outcomes revealed that age, sex, Expanded Disability Severity Scale score, use of methylprednisolone within 30 days from COVID-19 onset, and the treatment with anti-CD20 drugs were significantly associated with severe infection (29). Interestingly, patients treated with IFN showed a reduced risk, although the value did not reach statistical significance.

New and ongoing multiple sclerosis therapies. Despite the risks discussed above, it must be remembered that multiple sclerosis patients – have multiple sclerosis. This is a serious inflammatory brain disease. In most cases, it should be treated. We now have an easily transmissible and somewhat lethal virus to add to the treatment equation.

Discussions when starting a new multiple sclerosis treatment must include the antiviral effects of the therapy and the consequences of short-term and long-term immune suppression. “Immune modulation” is a property of all multiple sclerosis drugs. Some are immunosuppressive, but all multiple sclerosis therapies have complex effects on immunity, including worse or better antiviral immunity.

Preliminary considerations before starting a new therapy should include the screening for risk factors associated with a more severe COVID-19 disease (eg, age, elevated disability, comorbidities, etc.) and a careful evaluation of the risk/benefit profile for the drug. Overall, IFNs, glatiramer and glatiramoids, dimethyl fumarate, teriflunomide, and natalizumab would not raise concerns. Natalizumab infusions may be delayed to every 5 to 6 weeks in order to reduce risks of progressive multifocal leukoencephalopathy, but there is no evidence that the drug is associated with an increased risk of COVID-19 infection or with a more severe disease. Fingolimod, ozanimod, and siponimod can be employed, but lymphocyte count should be monitored and if count falls below 200 (current guideline), 500 (in young), or 800 (in aged) dosage may be reduced or the drug stopped. Depleting therapies (alemtuzumab, ocrelizumab, rituximab, ofatumumab, and cladribine) may be started if strictly necessary, and only after appropriate discussion with the patient regarding the potential risk of immunosuppression.

With ongoing therapy during the COVID-19 outbreak, IFNs, glatiramer and glatiramoids, dimethyl fumarate, teriflunomide, and natalizumab should be continued with no dose adjustment, as they do not associate with more severe COVID-19 disease. There is some consensus among multiple sclerosis experts to extend infusions for natalizumab to every 5 to 6 weeks instead of 4 weeks, but the doses should not be extended if there is disease activity.

Fingolimod, ozanimod, and siponimod may be continued with more frequent monitoring of lymphocyte count, and adjusting or stopping the drug when potentially dangerous lymphopenia would occur. For alemtuzumab, ocrelizumab, rituximab, ofatumumab, and cladribine interrupting or delaying the doses until T and B cell counts tend to normal levels, or self-quarantine after the dose (up to 3 months) may be considered. Others feel that the risk of multiple sclerosis exacerbations outweighs these concerns and do not change the course of therapy.

How to manage a patient with multiple sclerosis infected by COVID-19. If a treatment has yet to be started, it may be reasonable to postpone therapy until recovery from infection, unless multiple sclerosis shows elevated activity. In this case, the use of steroids, sphingosine-1P receptor antagonists, or depleting drugs should be avoided or carefully weighed given the possible increased risk of severe COVID-19 disease. Ongoing therapies such as IFNs, glatiramer, teriflunomide, dimethyl fumarate, and natalizumab may be continued, depending on the existence of other risk factors (COVID-19 severity, elevated disability, comorbidities, lymphopenia). Natalizumab infusions may be delayed up to 48 days, allowing the patient to maintain in self-isolation until recovery. Sphingosine-1P antagonists may require interruption or dose adjustments to avoid excessive lymphopenia. Depleting drugs (alemtuzumab, anti-CD20, and cladribine) should be interrupted or delayed until resolution of COVID-19.

Would multiple sclerosis treatments affect COVID-19 vaccines? No data are available yet, but based on guidelines provided by AAN and other neurologic societies regarding other vaccines, patients with multiple sclerosis would not be at higher risk of adverse events when they receive COVID-19 vaccines. All approved COVID-19 vaccines are not live attenuated vaccines, therefore concomitant immunosuppressive therapies would not carry the risk of enhanced infection. The time schedule of vaccine administration should be tailored according to the drug in use. IFNs, glatiramer acetate, dimethyl fumarate, and natalizumab do not require changes in timing of vaccination. Some multiple sclerosis physicians feel the risk of multiple sclerosis itself is greater than theoretical risks of multiple sclerosis therapies on susceptibility to COVID-19. Others, however, suggest that drugs like teriflunomide, sphingosine-1 phosphate receptor antagonists (fingolimod, ozanimod, and siponimod), and B- and B/T-cell depleting drugs (eg, cladribine, alemtuzumab, or anti-CD20 monoclonal antibodies) may need appropriate time schedules (25). For stable patients who have yet to start treatment, vaccine should be administered at least 2 weeks before (3 to 4 weeks before may be recommended for B- and B/T-cell depleting drugs). With ongoing treatments, there are no specific times for vaccination, except consensus opinion suggests at least 6 months after last dose for B- and B/T-cell depleting therapies. Nonetheless, treatment with anti-CD20 monoclonal antibodies attenuate humoral immune response to non-live vaccines by approximately 70% (although the antibody titer often remains in the protective range) and this may apply also to COVID-19 vaccine, reducing its protective effect (02).

Data. It is essential that everyone who treats patients with multiple sclerosis and COVID-19 infections will enter data into the North American, European, and other databases. This will generate large numbers for “real-world” analysis of the effects of multiple sclerosis severity, age, multiple sclerosis therapy, concomitant therapy, and any benefits of antiviral treatments in the multiple sclerosis immune and CNS ecology.