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 (39). 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 (24). Sars-Cov-1 and Sars-Cov-2 are responsible for neurologic complications, and the same has been demonstrated for other strains of coronaviruses (03). 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 (03). Sars-Cov-2 is the agent of the Covid-19 pandemic. 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 (33), although others find no evidence for this. Sars-Cov-2 can be occasionally detected in the brain of patients dying of Covid-19, and viral entry into brain endothelial cells leads to upregulation of interferon-gamma signaling pathways in the neurovascular unit (37; 31). Despite some limited evidence of Sars-Cov-2 localization within the central nervous system, the most common neurologic symptoms are smell and taste dysfunction from damaged olfactory supporting cells, and only sporadically has the virus been linked to true forms of meningitis or encephalitis (25). The cerebrospinal fluid profile in patients with COVID-19 and neurologic symptoms is representative of a disruption of the blood-cerebrospinal fluid barrier and is consistent with a cerebrospinal endotheliopathy (28). In addition, indirect damage to the nervous system may ensue from the Sars-Cov-2-induced surge of cytokines, which causes an inflammatory encephalopathy (07). Finally, endothelial damage and hypercoagulability generated by Sars-Cov-2 infection may lead to ischemic stroke (36).

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) (22); 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 (27).

Based on the notion that the 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) (23). Vulnerability to severe Sars-Cov-2 infection associates with rare variants at the 13 human loci that also regulate TLR-3 and IRF7 components of type I interferon immunity to influenza virus, resulting in a loss-of-function effect (68). Poor interferon response may also result from neutralizing IgG auto-antibody to interferon-omega, the 13 types of interferon-alpha, or both; this blocked interferon response was observed in patients with life-threatening COVID-19 pneumonia (06).

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 IL-10 [in lungs]) and inflammation-related chemokines (CCL3, CCL4, CCL20, CXCL2, CXCL3, CCL3L1, CCL4L2, CXCL8, and CXCL9) (21). A major activating mechanism of inflammatory monocytes is the pathological stimulation of TLR/IL-1R signaling and the subsequent 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 (65). 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 (11; 48). Natural killer cells are also depleted and exhibit an exhausted phenotype in severe COVID-19 disease (63; 69). The reduction and dysfunction of the 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 (62).

The T cell compartment is also affected in moderate and severe forms of COVID-19; the characteristic lymphopenia is mainly due to CD4+ and CD8+ T-cell count reduction (20; 69). Aberrantly activated macrophages releasing high levels of IL-6 may promote apoptosis of lymphocytes in the spleen and lymph nodes (12). 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 in multiple sclerosis (12; 17; 69).

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 (16). 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 (16), 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 (52). However, multiple sclerosis patients often claim they seldom get a “cold” and appeared to have half as many infections as healthy subjects in controlled studies (53), suggesting there are compensatory antiviral mechanisms at play in multiple sclerosis. 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 for COVID-19 severity (10; 43; 08). 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? Studies carried out on single centers during the first wave of the pandemic reported an increased frequency of COVID-19 infection in patients with multiple sclerosis compared to general population, with a risk 1.74 to 7 times higher (13; 51). However, the majority of COVID-19 diagnoses in these studies were suspected based on clinical symptoms and were not confirmed by nasopharyngeal swabs. If only cases confirmed by rt-PCR were considered, the risk of COVID-19 infection resulted higher (2.5 times) in just one study (13). The analysis of IBM® Explorys database, which collects the health data of about 72 million patients in the United States, provided more robust data. Out of 153,663 persons with multiple sclerosis, 761 (0.5%) had a positive rt-PCR swab test (46). However, if the analysis was limited to the 30,478 patients on treatment with disease-modifying therapy, 344 (1.13%) of these had Sars-Cov-2 infection confirmed. Analysis of other factors showed that African-American ethnicity, high body mass index, and comorbidities were associated with increased risk of COVID-19 infection. In addition, patients on treatment with anti-CD20 had a risk of infection more than 3 times higher than patients on other treatments, whereas therapy with interferons or glatiramer acetate was associated with a small reduction of risk (46). A case-control study embedded in the Italian Multiple Sclerosis Registry also indicated that younger age, female gender, and comorbidities were associated with an increased risk of Sars-Cov-2 infection, in addition to long-lasting escalation treatment for multiple sclerosis and therapies, which exposed patients to hospital environment (26).

Would COVID-19 infection affect multiple sclerosis course?

Peripheral inflammation has the potential to exacerbate multiple sclerosis by triggering relapses. Preliminary reports, which need to be confirmed, suggest that this may occur during COVID-19 infection (38).

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, 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. This hypothesis seems be confirmed by the small reduction of risk for COVID-19 infection in people receiving interferon-beta compared to other treatments (46).

Teriflunomide and leflunomide exhibit antiviral properties against several viruses, including Epstein-Barr virus, cytomegalovirus, Herpes simplex 1 and 2, and BK polyomavirus. They may prevent viral replication through the inhibition of the enzyme dihydro-orotate dehydrogenase. These drugs also have in vitro antiviral activity against coronaviruses (64).

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 (67). Beyond all of these potential influences of therapy, 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 (41). 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. Despite hypothetical concerns, a real world study shows that people with multiple sclerosis and Sars-Cov-2 infection develop normal B- and T-cell responses, except for those treated with anti-CD20 or fingolimod, and immune responses do not correlate with COVID-19 clinical severity (30; 66).

Do multiple sclerosis treatments increase the risk of severe COVID-19 infection? Several studies to date investigated the course of COVID-19 infection in patients with multiple sclerosis. The most relevant ones were carried out on multiple centers or national registries and were allowed to evaluate the influence of several factors on the course of COVID-19 infection, including demographic features, course, and severity of multiple sclerosis and comorbidities (34; 04; 49; 55). Factors unrelated to multiple sclerosis, but common to the general population, such as advanced age, high BMI, and comorbidities (eg, hypertension, diabetes, ischemic cardiopathy, chronic renal failure, and broncho- pulmonary diseases) were associated with an increased risk of severe COVID-19 (34; 04; 49; 55). In addition, specific features of multiple sclerosis like long duration, progressive course, and high disability independently contributed to the probability of severe COVID-19 (34; 04; 49; 55). The frequency of pneumonia, hospitalization, and admission to intensive care unit were similar to those of general population (Table I). Mortality rates ranged from 1.54% to 3.9%, with higher values in the studies carried out in France and the United States. The reason for such discrepancy is not clear, but for studies in the United States, the lack of a national registry may result in overreporting the more severe cases. If patients with multiple sclerosis were compared with age- and sex-matched controls from general population, the risk of severe events related to COVID-19 was two times higher, with Expanded Disability Severity Scale score and comorbidities mostly accounting for this increased risk (56). A pooled analysis of cohort studies on COVID-19 in patients with multiple sclerosis suggested a 24% increased risk of death, but data were heterogeneous and may have been affected by collection difficulties during the first pandemic wave (44).

In almost every study, the treatment with anti-CD20 was associated with higher probability of COVID-19 infection and severity (Table II). Such increased risk was independent from other factors included in multivariate analyses (eg, advanced age, high BMI, comorbidities, high EDSS score, and progressive disease phenotype) and resulted in increased rates of hospitalization, intensive care unit admission, and need for assisted ventilation (54). These data were confirmed also by a systematic literature search (50).

In some studies, the use of high doses of glucocorticoids within the prior 1 to 2 months was also correlated with an increased probability of hospitalization and COVID-19 severity (49; 55). No other multiple sclerosis therapy was associated with a significant increase in risk of severe COVID-19. Glucocorticoids are paired with some monoclonal therapies, which may increase the risk for severe COVID.

Untreated patients exhibited a higher probability of hospitalization, but not of intensive care unit admission, need for assisted ventilation, or death (54). This controversial finding may result from the fact that untreated patients are more frequently aged, with higher disability, and with a progressive disease phenotype.

Table 1. Severity and Mortality of COVID-19 in Patients with Multiple Sclerosis

Reference	Number of patients with COVID-19 (confirmed/ suspected)	Number of patients hospitalized	Number of patients in the intensive care unit	Number of deaths
(55)	844 (244/565)	96 (11.4%)	35 (4.5%)	13 (1.54%)
(34)	347 (146/201)	73 (21.0%)	16 (4.6%)	12 (3.46%)
(04)	326 (121/205)	69 (21.2%)	10 (3.0%)	7 (2.1%)
(49)	1626 (1345/281)	320 (19.7%)	104 (6.4%)	54 (3.3%)
(54)	2340 (1683/657)	489 (20.9%)	127 (5.4%)	73 (3.9%)

Table 2. Anti-CD20 Treatments and Risk of Hospitalization for COVID-19

Reference	Anti-CD20	Methylprednisolone within prior 30 to 60 days	No treatment
(55)	OR 2.37	OR 5.24	-
(34)	OR ocrelizumab 1.63 OR rituximab 4.56	OR 2.62	-
(54)	OR ocrelizumab 1.56 OR rituximab 2.43	-	OR 1.79
Legend: OR=odd ratio

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 versus the benefit on their multiple sclerosis.

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. However, natalizumab infusions during COVID-19 infection may be safe, with no worsening of infection or recovery delay (32). 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, although this is only relevant during active infection.

The use of monoclonal antibodies to treat Sars-Cov-2 infection may be safe and helpful when people with multiple sclerosis are receiving anti-CD20 or sphingosine 1 phosphate modulators (35). Two-dose vaccination is protective against the early variants of COVID-19 disease in patients with multiple sclerosis but is less efficacious in the presence Omicron. The risk of infection inversely correlates with Sars-Cov-2 antibody levels, and this risk can be reduced with a booster dose (57).

Would multiple sclerosis treatments affect COVID-19 vaccines? Patients with multiple sclerosis are not at higher risk of adverse events when they receive COVID-19 vaccines, and their reactogenicity profiles appear similar to those reported in the general population (09). All approved COVID-19 vaccines are not live attenuated vaccines; therefore, concomitant immunosuppressive therapies would not carry the risk of enhanced infection. Although most disease-modifying treatments for multiple sclerosis do not substantially affect immune responses to COVID-19 vaccines, some exhibit a profound effect on humoral and/or cellular responses. Anti-CD20 drugs dramatically impair the production of anti-Sars-Cov-2 antibodies but do not compromise virus specific T-cell responses (58; 61). The inhibitory effect of anti-CD20 on anti-spike IgG response could be prevented by delaying drug administration to reach at least 40 circulating B-cells/microliter (59). Fingolimod, a sphingosine-1-phosphate modulator, markedly reduces both B-cell and T-cell responses to COVID-19 vaccines (58; 61). A third dose of vaccine may boost Sars-Cov-2 specific humoral and cellular responses in patients on anti-CD20 therapy, but not in those on fingolimod (01; 40; 42).

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, anti-CD20, cladribine, or alemtuzumab) may need appropriate time schedules (47). 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 5 to 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 (05).

Would COVID-19 vaccination affect multiple sclerosis course? The effect of COVID-19 vaccination on the course of multiple sclerosis is still controversial. In a multicenter study mRNA vaccines were not associated with an increased short-term risk of relapse (14). A booster dose of mRNA vaccines did not increase risk of relapses (15). Finally, in a United States database of 307 million doses, neurologic adverse events were less than 1 out of million with mRNA vaccines, but 1.5-fold higher with the adenovirus vaccine (19). In contrast to the 1.5 fold rise with that vaccine, there was a 617-fold rise in neurologic events from COVID-19 disease itself. However, in at least 2 anecdotal reports, neurologic symptoms related to central nervous system demyelination developed after mRNA vaccines in a few patients and were diagnosed as new onset or relapses of multiple sclerosis (29; 60). Immunization with mRNA vaccines during relapses may also exacerbate symptoms by amplifying the inflammatory response (45). In a few patients with multiple sclerosis, relapses were also reported after COVID-19 immunization with viral-vector vaccines (02; 18).

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.