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  • Updated 02.13.2026
  • Released 02.11.2021
  • Expires For CME 02.13.2029

Management of multiple sclerosis in COVID-19 pandemic

Author
Davide Maimone MD PhD
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Editor
Anthony T Reder MD
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Cite this article

Introduction

In response to the uncertainties concerning the management of multiple sclerosis during the pandemic, we asked Senior Associate Editor Dr. Anthony Reder to answer some key questions regarding COVID-19 and multiple sclerosis.

Key points

• COVID-19 pandemic was and remains a serious health challenge for the general population and even more for fragile individuals like people with multiple sclerosis.

• Although the risk of severe infection is markedly reduced due to the prevalence of less aggressive variants, COVID-19 disease in people with multiple sclerosis could be more severe due to immunosuppressive therapies. However, real world data indicate that overall risk of COVID-19 infection and severity in these people is modestly increased, and the risk factors specifically related to with multiple sclerosis are disease duration, elevated disability, progressive disease phenotype, and the use of anti-CD20 therapies.

• Specific COVID-19 therapies (eg, anti-Sars-Cov2 monoclonal antibodies) may be employed in people with multiple sclerosis, if needed.

• Anti-Sars-Cov2 vaccines are safe and should be recommended to people with multiple sclerosis. Immunization schedules should be adapted according to the treatments for multiple sclerosis, and some therapy may be delayed or temporarily suspended to obtain effective immune responses to vaccines.

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 (62). 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 (38). 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 (52), 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 (57; 47). 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 (39). 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 (43). In addition, indirect damage to the nervous system may ensue from the Sars-Cov-2-induced surge of cytokines, which causes an inflammatory encephalopathy (11). Finally, endothelial damage and hypercoagulability generated by Sars-Cov-2 infection may lead to ischemic stroke (55).

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) (36); perhaps this is because the virus blocks the body’s interferon response in at least seven 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 preexisting 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 (41). In addition, efficient T cell response to Sars-Cov-2 virus plays a major role in controlling disease severity, as it is associated with mild or asymptomatic COVID-19 infection and protective immunity (74).

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) (37). 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 (110). 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 (10).

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) (35). 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 (104). 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 (19; 77). Natural killer cells are also depleted and exhibit an exhausted phenotype in severe COVID-19 disease (102; 111). 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 (99).

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 (34; 111). Aberrantly activated macrophages releasing high levels of IL-6 may promote apoptosis of lymphocytes in the spleen and lymph nodes (20). 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 (20; 30; 111).

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 (29). 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 (29), 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 (85). However, patients with multiple sclerosis often claim they seldom get a “cold” and appeared to have half as many infections as healthy subjects in controlled studies (86), 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 (18; 69; 12). 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 seven times higher (24; 84). 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 (24). 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 people with multiple sclerosis, 761 (0.5%) had a positive rt-PCR swab test (73). 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 three times higher than patients on other treatments, whereas therapy with interferons or glatiramer acetate was associated with a small reduction of risk (73). 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 (40).

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 (58). A large multicenter cohort study based on the MSBase registry reported that COVID-19 infection was associated with a significantly increased relapse rate and greater hazard of time to first relapse, but not with EDSS progression or time to EDSS 3, 4, or 6 (51). An increased relapse risk or MRI activity after COVID-19 infection was also observed in a small group of patients previously treated with autologous hematopoietic stem cell transplantation (56). However, evidence of the detrimental impact of COVID-19 infection on multiple sclerosis disease activity or course could not be replicated by another single center study (61). In addition, work conducted on the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry showed that COVID-19 infection was not associated with immediate changes in symptom severity or disability, nor did it change the trajectories of these outcomes over a median follow-up of 18 months (79). However, an MRI study conducted on people with clinically stable multiple sclerosis during COVID-19 showed that Sars-Cov-2 infection is associated with an increased whole brain, grey matter, and cortical grey matter volume loss, possibly by enhancing dysregulation of innate immune system and amplifying neurodegeneration secondary to smoldering inflammation (98).

Sars-Cov-2 infection during pregnancy in women with multiple sclerosis is not associated with a significant increase of severe outcomes, although it shows a higher risk of maternal, but not fetal, complications (04; 05). Long-COVID condition (intended as the persistence for more than 2 months of symptoms related to Sars-Cov-2 infection) appears to be more prevalent in patients with multiple sclerosis, ranging from 12% to 30% compared to 6.2% in the general population (33; 15). Factors associated with a higher risk of long-COVID are female sex, EDSS greater than or equal to 7.0, and preexisting anxiety or depression.

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 to be confirmed by the small reduction of risk for COVID-19 infection in people receiving interferon-beta compared to other treatments (73).

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 (103).

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 (109). 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 (65). 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 (46; 106).

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 (53; 06; 78; 89). 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 (53; 06; 78; 89). In addition, specific features of multiple sclerosis like long duration, progressive course, and high disability independently contributed to the probability of severe COVID-19 (53; 06; 78; 89). 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 (91). 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 (70).

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 (87; 42). These data were confirmed also by a systematic literature search (83).

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 (78; 89). 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 (87). This controversial finding may result from the fact that untreated patients are more frequently aged, with higher disability, and with a progressive disease phenotype. However, the rate of severe COVID-19 infection also declined in patients with multiple sclerosis from the pre-omicron (14.6%) to the omicron (5.7%) wave, and disability or anti-CD-20 therapy were confirmed as the major risk factors (44).

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

(89)

844 (244/565)

96 (11.4%)

35 (4.5%)

13 (1.54%)

(53)

347 (146/201)

73 (21.0%)

16 (4.6%)

12 (3.46%)

(06)

326 (121/205)

69 (21.2%)

10 (3.0%)

7 (2.1%)

(78)

1626 (1345/281)

320 (19.7%)

104 (6.4%)

54 (3.3%)

(87)

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

(89)

OR 2.37

OR 5.24

-

(53)

OR ocrelizumab 1.63
OR rituximab 4.56

OR 2.62

-

(87)

OR ocrelizumab 1.56
OR rituximab 2.43

-

OR 1.79

(42)

OR ocrelizumab or rituximab 5.2 *


Legend: OR=odd ratio; *only patients with relapsing-remitting multiple sclerosis

According to data collected from the North American Research Committee on Multiple Sclerosis (NARCOMS) Registry, the frequency of post-acute sequelae, including fatigue, post-exertional malaise, and brain fog following severe COVID-19 appears to be lower than expected (80). The overlapping of these symptoms with those commonly experienced by patients with multiple sclerosis (such as fatigue, impaired memory and concentration, sleep problems, and depression or anxiety) may complicate their accurate identification as post-acute COVID-19 effects.

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.

Nonetheless, despite the above theoretical indications, the real world practice during post-pandemic onset exhibited preferential prescription of natalizumab and cladribine over anti-CD20 and fingolimod (49).

How to manage a patient with multiple sclerosis infected by COVID-19. If 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 (50). 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.

Antiviral treatments, including nirmatrelvir-ritonavir, remdesivir, and molnupiravir, should be employed for people with multiple sclerosis with acute COVID-19 who are at risk for severe infection, such as those unvaccinated or not seroconverted after vaccination (107). 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 (54). However, real world experience with tixagevimab/cilgavimab treatment in patients with multiple sclerosis failed to demonstrate its effectiveness in preventing Sars-Cov-2 infection (22; 72). 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 (92).

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 (13). All approved COVID-19 vaccines are not live attenuated vaccines; therefore, concomitant immunosuppressive therapies would not carry the risk of enhanced infection. The preference should go to mRNA vaccines and in particular to mRNA-1273 vaccine as it provides the highest seroconversion rates and anti-spike IgG antibody titers compared to those obtained with other mRNA vaccines (eg, BNT162b2) or with viral vector or inactivated vaccines (90; 21; 67). 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, such as rituximab or ocrelizumab, dramatically impair the production of anti-Sars-Cov-2 antibodies but do not compromise virus specific T-cell responses (94; 97). Lack of seroconversion in patients treated with anti-CD20 correlate with a higher number of drug infusions, shorter intervals since the last infusion, and higher serum drug concentration (101). 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 (95). However, ofatumumab, an anti-CD20 monoclonal antibody to be administered subcutaneously, only moderately reduces the frequency of a specific IgG response to Sars-Cov-2 (07). Fingolimod, a progenitor of sphingosine-1-phosphate modulator, markedly reduces both B-cell and T-cell responses to COVID-19 vaccines, but ozanimod, another drug from the same family, does not prevent adequate seroconversion (94; 97; 23). The result of a third and a fourth dose of vaccine is still controversial in patients on anti-CD20 or fingolimod treatment as Sars-Cov-2–specific humoral and cellular responses were variably boosted depending on the studies (01; 63; 68; 82; 100; 66). However, despite low rates of antibody seroconversion after a third booster, patients treated with ocrelizumab exhibit normal numbers and percentages of CD4+ T cells, whereas those treated with fingolimod lose CD4+ T cells, but compensate with increased percentages of CD8+ T cells, especially IFN-γ+/TNF-α+ CD8 T cells (81). The critical role of cell-mediated immunity in anti-Sars-Cov-2 protection for patients receiving ocrelizumab may also derive from the increase in percentages of memory CD4+ and CD8+ T cells reactive to spike protein up to 70 weeks from vaccination (25). One investigational treatment for multiple sclerosis, evobrutinib, a Bruton tyrosine kinase inhibitor, does not interfere with an efficient production of anti-Sars-Cov-2 antibodies after vaccination or booster dose (09). One predictor of optimal cellular immune response to Sars-Cov-2 vaccines appears to be more than 17 naive CD8 T cells /uL blood (76).

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 (75). For stable patients who have yet to start treatment, vaccine should be administered at least 2 weeks before (3 to 4 weeks before start for B- and B/T-cell depleting drugs). With ongoing treatments, there are no specific times for vaccination, except for patients on anti-CD20 therapies. General consensus exists on performing vaccination and boosters at least 4 months after the last dose of anti-CD20 monoclonal antibodies and before 4 weeks from the next infusion. In patients younger than 50 years and with active multiple sclerosis during the previous year, the interval may be shorten to 3 months (107; 60). For people older than 50 years and low disease activity, a longer interval up to 6 months from the last dose may be advised (107). Vaccine and boosters should be recommended during anti-CD20 treatment, as they reduce the risk of hospitalization for COVID-19 (88). 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 (08). A third booster dose should be recommended for every patient with multiple sclerosis, as it is associated with an increase of anti-Sars-Cov-2 antibodies and milder COVID-19 infection, even if they are treated with ocrelizumab or fingolimod (16; 17). Vaccine boosters also increase the spectrum of humoral response against Sars-Cov-2 emerging variants and reduce the percentage of people with multiple sclerosis remaining seronegative (105). Seronegativity after initial vaccination is predictive of increased risk of breakthrough COVID-19 infection, but a booster dose lowers this risk and that of severe disease (108; 66). In patients treated with anti-CD20 or sphingosine-1-phosphate receptor modulators, protein vaccines may be used as a rescue vaccination in patients lacking adequate immune response to previous mRNA/viral vector vaccines (64).

Would COVID-19 vaccination affect multiple sclerosis course? The effect of COVID-19 vaccination appears to be safe in patients with multiple sclerosis. In a multicenter study mRNA vaccines were not associated with an increased short-term risk of relapse (26). A booster dose of mRNA vaccines did not increase risk of relapses (28; 27). Worsening of multiple sclerosis symptoms, considered as pseudorelapses, can rarely occur after vaccination, but symptoms return to baseline within 96 hours (48). Moreover, in a United States database of 307 million doses, neurologic adverse events were less than one of a million with mRNA vaccines, but 1.5-fold higher with the adenovirus vaccine (32). 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 two 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 (45; 96). Finally, a meta-analysis of studies on the safety of COVID-19 vaccination in multiple sclerosis could not demonstrate an increased risk of relapse (93). To add on this topic, studies on cerebrospinal fluid of patients with multiple sclerosis and a large nationwide study indicate that intrathecal inflammation signature after vaccination is distinct from that following relapse (14; 59). Immunization with mRNA vaccines during relapses may also exacerbate symptoms by amplifying the inflammatory response (71). In a few patients with multiple sclerosis, relapses were reported after COVID-19 immunization with viral-vector vaccines (02; 31).

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.

References

01
Achiron A, Mandel M, Gurevich M, et al. Immune response to the third COVID-19 vaccine dose is related to lymphocyte count in multiple sclerosis patients treated with fingolimod. J Neurol 2022;269(5):2286-92. PMID 35235002
02
Al-Midfai Y, Kujundzic W, Uppal S, Oakes D, Giezy S. Acute multiple sclerosis exacerbation after vaccination with the Johnson & Johnson COVID-19 vaccine: novel presentation and first documented case report. Cureus 2022;14(4):e24017. PMID 35547449
03
Almqvist J, Granberg T, Tzortzakakis A, et al. Neurological manifestations of coronavirus infections - a systematic review. Ann Clin Transl Neurol 2020;7(10):2057-71. PMID 32853453
04
Aprea MG, Schiavetti I, Portaccio E, et al. Sars-CoV2 infection in pregnant women with multiple sclerosis. Mult Scler 2023;29(9):1090-8. PMID 37232279
05
Aprea MG, Schiavetti I, Portaccio E, et al. Impact of COVID-19 on pregnancy and fetal outcomes in women with multiple sclerosis. Mult Scler 2024;30(6):707-13. PMID 38456445
06
Arrambide G, Llaneza-Gonzalez MA, Costa-Frossard França L, et al. SARS-CoV-2 infection in multiple sclerosis. Results of the Spanish Neurology Society Registry. Neurol Neuroimmunol Neuroinflamm 2021;8(5):e1024. PMID 34168057
07
Bar-Or A, Aburashed R, Chinea AR, et al. Humoral immune response to COVID-19 mRNA vaccines in patients with relapsing multiple sclerosis treated with ofatumumab. Mult Scler Relat Disord 2023a;79:104967. PMID 37769429
08
Bar-Or A, Calkwood JC, Chognot C, et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study. Neurology 2020;95(14):e1999-2008. PMID 32727835
09
Bar-Or A, Cross AH, Cunningham AL, et al. Antibody response to SARS-CoV-2 vaccines in patients with relapsing multiple sclerosis treated with evobrutinib: A Bruton's tyrosine kinase inhibitor. Mult Scler 2023b;29(11-12):1471-81. PMID 37626477
10
Bastard P, Rosen LB, Zhang Q, et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 2020;370(6515):eabd4585. PMID 32727835
11
Benameur K, Agarwal A, Auld SC, et al. Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA. Emerg Infect Dis 2020;26(9):2016-21. PMID 2487282
12
Brand JS, Smith KA, Piehl F, Olsson T, Montgomery S. Risk of serious infections in multiple sclerosis patients by disease course and disability status: Results from a Swedish register-based study. Brain Behav Immun Health 2022;22:100470. PMID 35607517
13
Briggs FBS, Mateen FJ, Schmidt H, et al. COVID-19 vaccination reactogenicity in persons with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2021;9(1):e1104. PMID 34753828
14
Bruno A, Buttari F, Dolcetti E, et al. Distinct intrathecal inflammatory signatures following relapse and anti-COVID-19 mRNA vaccination in multiple sclerosis. Mult Scler 2023;29(11-12):1383-92. PMID 37698019
15
Bsteh G, Assar H, Gradl C, et al. Long-term outcome after COVID-19 infection in multiple sclerosis: a nation-wide multicenter matched-control study. Eur J Neurol 2022:29(10):3050-60. PMID 35751475
16
Capuano R, Altieri M, Conte M, et al. Humoral response and safety of the third booster dose of BNT162b2 mRNA COVID-19 vaccine in patients with multiple sclerosis treated with ocrelizumab or fingolimod. J Neurol 2022;269(12):6185-92. PMID 35879563
17
Capuano R, Prosperini L, Altieri M, et al. Symptomatic COVID-19 course and outcomes after three mRNA vaccine doses in multiple sclerosis patients treated with high-efficacy DMTs. Mult Scler 2023;29(7):856-65. PMID 37165941
18
Castelo-Branco A, Chiesa F, Conte S, et al. Infections in patients with multiple sclerosis: A national cohort study in Sweden. Mult Scler Relat Disord 2020;45:102420. PMID 32736217
19
Cavalli G, De Luca G, Campochiaro C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study. Lancet Rheumatol 2020;2(6):e325-31. PMID 31648992
20
Chen G, Wu D, Guo W, et al. Clinical and immunological features of severe and moderate Coronavirus disease 2019. J Clin Invest 2020;130:2620-9. PMID 32217835
21
Ciampi E, Uribe-San-Martin R, Soler B, et al. Safety and humoral response rate of inactivated and mRNA vaccines against SARS-CoV-2 in patients with multiple sclerosis. Mult Scler Relat Disord 2022;59:103690. PMID 35182880
22
Conway S, Gupta S, Healy B, et al. Tixagevimab/cilgavimab does not prevent COVID-19 in patients with multiple sclerosis and related disorders on B-cell depleting therapies. Mult Scler Relat Disord 2024;87:105680. PMID 38795595
23
Cree BAC, Maddux R, Bar-Or A, et al. SARS-CoV-2 vaccination and infection in ozanimod-treated participants with relapsing multiple sclerosis. Ann Clin Transl Neurol 2023;10(10):1725-37. PMID 37550942
24
Crescenzo F, Marastoni D, Bovo C, Calabrese M. Frequency and severity of COVID-19 in multiple sclerosis: A short single-site report from northern Italy. Mult Scler Relat Disord 2020;44:102372. PMID 32650121
25
Davis-Porada J, Tozlu C, Aiello C, et al. Durable T cell immunity to COVID-19 vaccines in MS patients on B cell depletion therapy. NPJ Vaccines 2025;10(1):98. PMID 40382362
26
Di Filippo M, Cordioli C, Malucchi S, et al. mRNA COVID-19 vaccines do not increase the short-term risk of clinical relapses in multiple sclerosis. J Neurol Neurosurg Psychiatry 2022;93(4):448-50. PMID 34408003
27
Di Filippo M, Ferraro D, Ragonese P, et al. SARS-CoV-2 vaccination and multiple sclerosis: a large multicentric study on relapse risk after the third booster dose. J Neurol 2024;271(1):24-31. PMID 37922069
28
Dreyer-Alster S, Menascu S, Mandel M, et al. COVID-19 vaccination in patients with multiple sclerosis: Safety and humoral efficacy of the third booster dose. J Neurol Sci 2022;434:120155. PMID 35091386
29
Feng X, Bao R, Li L, Deisenhammer F, Arnason BG, Reder AT. Interferon-beta corrects massive gene dysregulation in multiple sclerosis: Short-term and long-term effects on immune regulation and neuroprotection. EBioMedicine 2019;49:269-83. PMID 31648992
30
Feng Z, Diao B, Wantg R, et al. The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly decimates human spleens and lymph nodes. medRxiv 2020;03.27:20045427.
31
Fragoso YD, Gomes S, Gonçalves MVM, et al. New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19. Mult Scler Relat Disord 2022;57:103321. PMID 35158439
32
Frontera JA, Tamborska AA, Doheim MF, et al. Neurological events reported after COVID-19 vaccines: an analysis of vaccine adverse event reporting system. Ann Neurol 2022;91(6):756-71. PMID 35233819
33
Garjani A, Middleton RM, Nicholas R, Evangelou N. Recovery from COVID-19 in multiple sclerosis: A prospective and longitudinal cohort study of the United Kingdom Multiple Sclerosis Register. Neurol Neuroimmunol Neuroinflamm 2021;30;9(1):e1118. PMID 34848503
34
Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex immune dysregulation in COVID-19 patients with severe respiratory failure. Cell Host Microbe 2020;27(6):992-1000. PMID 32320677
35
Guo C, Li B, Ma H, et al. Single-cell analysis of two severe COVID-19 patients reveals a monocyte-associated and tocilizumab-responding cytokine storm. Nat Commun 2020;11:3924. PMID 32764665
36
Gudbjartsson D, Helgason A, Jonsson H, et al. Early spread of SARS-Cov-2 in the Icelandic population. https://doi.org/10.1101/2020.03.26.20044446. medRxiv 2020;03:26.20044446.
37
Hadjadj J, Yatim N, Barnabei L, et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 2020;369(6504):718-24. PMID 32661059
38
Hamming, I, Timens, W, Bulthuis, M, Lely AT, Nevis GJ, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol 2004;203:631-7. PMID 15141377
39
Harapan BN, Yoo HJ. Neurological symptoms, manifestations, and complications associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease 19 (COVID-19). J Neurol 2021:1-13. PMID 33486564
40
Iaffaldano P, Lucisano G, Manni A, et al. Risk of getting COVID-19 in people with multiple sclerosis: a case-control study. Neurol Neuroimmunol Neuroinflamm 2022;9(2):e1141. PMID 35046084
41
Iturrieta-Zuazo I, Rita CG, García-Soidán A, et al. Possible role of HLA class-I genotype in SARS-CoV-2 infection and progression: A pilot study in a cohort of Covid-19 Spanish patients. Clin Immunol 2020;219:108572. PMID 32810602
42
Januel E, Hajage D, Labauge P, et al. Association between anti-CD20 therapies and COVID-19 severity among patients with relapsing-remitting and progressive multiple sclerosis. JAMA Netw Open 2023;6(6):e2319766. PMID 37351881
43
Jarius S, Pache F, Körtvelyessy P, et al. Cerebrospinal fluid findings in COVID-19: a multicenter study of 150 lumbar punctures in 127 patients. J Neuroinflammation 2022;19(1):19. PMID 35057809
44
Jeantin L, Januel E, Labauge P, et al. COVID-19 outcomes in patients with multiple sclerosis: understanding changes from 2020 to 2022. Mult Scler 2024;30(3):381-95. PMID 38247113
45
Khayat-Khoei M, Bhattacharyya S, Katz J, et al. COVID-19 mRNA vaccination leading to CNS inflammation: a case series. J Neurol 2022;269(3):1093-106. PMID 34480607
46
Kister I, Patskovsky Y, Curtin R, et al. Cellular and humoral immunity to SARS-CoV-2 infection in multiple sclerosis patients on ocrelizumab and other disease-modifying therapies: a multi-ethnic observational study. Ann Neurol 2022;91(6):782-95. PMID 35289960
47
Krasemann S, Haferkamp U, Pfefferle S, et al. The blood-brain barrier is dysregulated in COVID-19 and serves as a CNS entry route for SARS-CoV-2. Stem Cell Reports 2022;17(2):307-20. PMID 35063125
48
Labani A, Chou S, Kaviani K, Ropero B, Russman K, Becker D. Incidence of multiple sclerosis relapses and pseudo-relapses following COVID-19 vaccination. Mult Scler Relat Disord 2023;77:104865. PMID 37418929
49
Lal AP, Foong YC, Sanfilippo PG, et al. A multi-centre longitudinal study analysing multiple sclerosis disease-modifying therapy prescribing patterns during the COVID-19 pandemic. J Neurol 2024;271(9):5813-24. PMID 38935148
50
Landi D, Cola G, Mantero V, et al. Safety of natalizumab infusion in multiple sclerosis patients during active SARS-CoV-2 infection. Mult Scler Relat Disord 2022;57:103345. PMID 35158454
51
Levitz D, Chao Foong Y, Sanfilippo P, et al. The impact of COVID-19 infection on multiple sclerosis disease course across 12 countries: a propensity-score-matched cohort study. Ther Adv Neurol Disord 2024;17:17562864241278496. PMID 39525878
52
Liu JM, Tan BH, Wu S, Gui Y, Suo JL, Li YC. Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement, in the lethality of SARS-CoV-2 infection. J Med Virol 2021;13(3):4713-30. PMID 33002209
53
Louapre C, Collongues N, Stankoff B, et al. Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis. JAMA Neurol 2020;77(9):1079-88. PMID 32589189
54
Manzano GS, Rice DR, Klawiter EC, et al. Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: an observational study. Mult Scler 2022;28(7):1146-50. PMID 35475382
55
Mao L, Jin H, Wang M, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol 2020;77(6):683-90. PMID 32275288
56
Mariottini A, Lotti A, Innocenti C, et al. Effect of the COVID-19 pandemic on disease activity in multiple sclerosis patients treated with hematopoietic stem cell transplantation. Eur J Neurol 2023;30(10):3362-6. PMID 37483174
57
Matschke J, Lütgehetmann M, Hagel C, et al. Neuropathology of patients with COVID-19 in Germany: a post-mortem case series. Lancet Neurol 2020;19(11):919-29. PMID 33031735
58
Michelena G, Casas M, Eizaguirre MB, et al. Can COVID-19 exacerbate multiple sclerosis symptoms? A case series analysis. Mult Scler Relat Disord 2022;57:103368. PMID 35158474
59
Moisset X, Leray E, Chenaf C, et al. Risk of relapse after COVID-19 vaccination among patients with multiple sclerosis in France: a self-controlled case series. Neurology 2024;103(5):e209662. PMID 39141880
60
Monschein T, Zrzavy T, Rommer PS, et al. SARS-CoV-2 vaccines and multiple sclerosis: An update. Neurol Neuroimmunol Neuroinflamm 2025;12(3):e200393. PMID 40279527
61
Montini F, Nozzolillo A, Tedone N, et al. COVID-19 has no impact on disease activity, progression and cognitive performance in people with multiple sclerosis: a 2-year study. J Neurol Neurosurg Psychiatry 2024;95(4):342-7. PMID 37857497
62
Morgello S. Coronaviruses and the central nervous system. J Neurovirol 2020;26(4):459-73. PMID 32737861
63
Moser T, Otto F, O'Sullivan C, et al. Recall response to COVID-19 antigen is preserved in people with multiple sclerosis on anti-CD20 medications – a pilot study. Mult Scler Relat Disord 2022;59:103560. PMID 35093840
64
Mueller-Enz M, Woopen C, Katoul Al Rahbani G, et al. NVX-CoV2373-induced T- and B-cellular immunity in immunosuppressed people with multiple sclerosis that failed to respond to mRNA and viral vector SARS-CoV-2 vaccines. Front Immunol 2023;14:1081933. PMID 37545513
65
Netland J, Meyerholz DK, Moore S, Cassell M, Perlman S. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol 2008;82(15):7264-75. PMID 18495771
66
Novak F, Nilsson AC, Christensen EB, et al. Humoral and cellular immune response from first to fourth SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patients-a longitudinal cohort study. Front Immunol 2024;15:1432348. PMID 39301017
67
Ozakbas S, Baba C, Dogan Y, Cevik S, Ozcelik S, Kaya E. Comparison of SARS-CoV-2 antibody response after two doses of mRNA and inactivated vaccines in multiple sclerosis patients treated with disease-modifying therapies. Mult Scler Relat Disord 2022;58:103486. PMID 35032878
68
Palomares Cabeza V, Kummer LYL, Wieske L, et al. Longitudinal T-cell responses after a third SARS-CoV-2 vaccination in patients with multiple sclerosis on ocrelizumab or fingolimod. Neurol Neuroimmunol Neuroinflamm 2022;9(4):e1178. PMID 35523569
69
Persson R, Lee S, Ulcickas Yood M, et al. Infections in patients diagnosed with multiple sclerosis: a multi-database study. Mult Scler Relat Disord 2020;41:101982. PMID 32070858
70
Prosperini L, Tortorella C, Haggiag S, Ruggieri S, Galgani S, Gasperini C. Increased risk of death from COVID-19 in multiple sclerosis: a pooled analysis of observational studies. J Neurol 2022;269(3):1114-20. PMID 34533590
71
Quintanilla-Bordás C, Gascón-Gimenez F, Alcalá C, et al. Case report: exacerbation of relapses following mRNA COVID-19 vaccination in multiple sclerosis: a case series. Front Neurol 2022;13:897275. PMID 35572939
72
Rath L, Yeh WZ, Roldan A, et al. Real-world efficacy, roll-out and uptake of intramuscular tixagevimab/cilgavimab as COVID-19 pre-exposure prophylaxis in people with multiple sclerosis and neuroimmunological conditions during the COVID-19 pandemic. BMJ Neurol Open 2024;6(1):e000667. PMID 38736583
73
Reder AT, Centonze D, Naylor ML, et al. COVID‑19 in patients with multiple sclerosis: associations with disease‑modifying therapies. CNS Drugs 2021;35(3):317-30. PMID 33743151
74
Reder AT, Stuve O, Tankou SK, Leist TP. T cell responses to COVID-19 infection and vaccination in patients with multiple sclerosis receiving disease-modifying therapy. Mult Scler 2023;29(6):648-56. PMID 36440826
75
Riva A, Barcella V, Benatti SV, et al. Vaccinations in patients with multiple sclerosis: a Delphi consensus statement. Mult Scler 2021;27(3):347-59. PMID 32940128
76
Rodero-Romero A, Sainz de la Maza S, Fernández-Velasco JI, et al. Blood CD8+ naïve T-cells identify MS patients with high probability of optimal cellular response to SARS-CoV-2 vaccine. Vaccines (Basel) 2023;11(9):1399. PMID 37766078
77
Roschewski M, Lionakis MS, Sharman JP, et al. Inhibition of Bruton tyrosine kinase in patients with severe COVID-19. Sci Immunol 2020;5(48):eabd0110. PMID 32503877
78
Salter A, Fox RJ, Newsome SD, et al. Outcomes and risk factors associated with SARS-CoV-2 infection in a North American registry of patients with multiple sclerosis. JAMA Neurol 2021;78(6):699-708. PMID 33739362
79
Salter A, Lancia S, Cutter GR, Fox RJ, Marrie RA. Effects of COVID-19 infection on symptom severity and disability in multiple sclerosis. Neurology 2025a;104(2):e210149. PMID 39715473
80
Salter A, Lancia S, Cutter GR, Fox RJ, Marrie RA. Post-acute sequela of COVID-19 infection in individuals with multiple sclerosis. Mult Scler 2025b;31(3):314-23. PMID 39749575
81
Saxena S, Zhirova A, Krishnan R, et al. SARS-CoV-2 spike antibody and T cell response in MS patients on high efficacy therapies post vaccine. J Neuroimmunol 2025;407:578694. PMID 40749532
82
Schiavetti I, Inglese M, Frau J, et al. Antibody response elicited by the SARS-CoV-2 vaccine booster in patients with multiple sclerosis: Who gains from it? Eur J Neurol 2023;30(8):2357-64. PMID 37154406
83
Schiavetti I, Ponzano M, Signori A, Bovis F, Carmisciano L, Sormani MP. Severe outcomes of COVID-19 among patients with multiple sclerosis under anti-CD-20 therapies: A systematic review and meta-analysis. Mult Scler Relat Disord 2022;57:103358. PMID 35158467
84
Sepulveda M, Llufriu S, Martınez-Hernandez E, et al. Incidence and impact of COVID-19 in MS: A survey from a Barcelona MS unit. Neurol Neuroimmunol Neuroinflamm 2021;8(2):e954. PMID 33504634
85
Severa M, Rizzo F, Srinivasan S, et al. A cell type-specific transcriptomic approach to map B cell and monocyte type I interferon-linked pathogenic signatures in multiple sclerosis. J Autoimmun 2019;101:1-16. PMID 31047767
86
Sibley WA, Bamford CR, Clark K. Clinical viral infections and multiple sclerosis. Lancet 1985;1(8441):1313-5. PMID 2860501
87
Simpson-Yap S, De Brouwer E, Kalincik T, et al. Associations of disease-modifying therapies with COVID-19 severity in multiple sclerosis. Neurology 2021;97(19):e1870-85. PMID 34610987
88
Smith JB, Gonzales EG, Li BH, Langer-Gould A. Analysis of rituximab use, time between rituximab and SARS-CoV-2 vaccination, and COVID-19 hospitalization or death in patients with multiple sclerosis. JAMA Netw Open 2022;5(12):e2248664. PMID 36576740
89
Sormani MP, De Rossi N, Schiavetti I, et al. Disease modifying therapies and Coronavirus disease 19 severity in multiple sclerosis. Ann Neurol 2021a;89(4);780-9. PMID 33480077
90
Sormani MP, Inglese M, Schiavetti I, et al. Effect of SARS-CoV-2 mRNA vaccination in MS patients treated with disease modifying therapies. EBioMedicine 2021c;72:103581. PMID 34563483
91
Sormani MP, Schiavetti I, Carmisciano L, et al. COVID-19 severity in multiple sclerosis: putting data into context. Neurol Neuroimmunol Neuroinflamm 2021b;9(1):e1105. PMID 34753829
92
Sormani MP, Schiavetti I, Inglese M, et al. Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy. EBioMedicine 2022;80:104042. PMID 35526306
93
Stefanou MI, Palaiodimou L, Theodorou A, et al. Safety of COVID-19 vaccines in multiple sclerosis: A systematic review and meta-analysis. Mult Scler 2023;29(4-5):585-94. PMID 36722184
94
Tallantyre EC, Vickaryous N, Anderson V, et al. COVID-19 vaccine response in people with multiple sclerosis. Ann Neurol 2022;91(1):89-100. PMID 34687063
95
Tolf A, Wiberg A, Müller M,et al. Factors associated with serological response to SARS-CoV-2 vaccination in patients with multiple sclerosis treated with rituximab. JAMA Netw Open 2022;5(5):e2211497. PMID 35544139
96
Toljan K, Amin M, Kunchok A, Ontaneda D. New diagnosis of multiple sclerosis in the setting of mRNA COVID-19 vaccine exposure. J Neuroimmunol 2022;362:577785. PMID 34922126
97
Tortorella C, Aiello A, Gasperini C, et al. Humoral- and T-cell-specific immune responses to SARS-CoV-2 mRNA vaccination in patients with MS using different disease-modifying therapies. Neurology 2022;98(5):e541-54. PMID 34810244
98
Uher T, Stastna D, Menkyova I, et al. SARS-CoV-2 Is linked to brain volume loss in multiple sclerosis. Ann Clin Transl Neurol 2025;12(8):1548-55. PMID 40443113
99
Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: current state of the science. Immunity 2020;52(6):910-41. PMID 32505227
100
van Kempen ZL, van Dam KP, Keijser JB, et al. Longitudinal increase of humoral responses after four SARS-CoV-2 vaccinations and infection in MS patients on fingolimod. Mult Scler 2024;30(3):443-7. PMID 37942812
101
Verstegen NJM, Hagen RR, Kreher C, et al. T cell activation markers CD38 and HLA-DR indicative of non-seroconversion in anti-CD20-treated patients with multiple sclerosis following SARS-CoV-2 mRNA vaccination. J Neurol Neurosurg Psychiatry 2024;95(9):855-64. PMID 38548324
102
Wilk AJ, Rustagi A, Zhao NQ, et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat Med 2020;26(7):1070-6. PMID 32514174
103
Xiong R, Zhang L, Li S, et al. Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2. https://doi.org/10.1101/2020.03.11.983056 bioRxiv 2020;03:11.983056.
104
Yap JKY, Moriyama M, Iwasaki A. Inflammasomes and pyroptosis as therapeutic targets for COVID-19. J Immunol 2020;205(2):307-12. PMID 32493814
105
Yeola A, Houston S, Aggarwal A, et al. COVID-19 vaccine boosters in people with multiple sclerosis: Improved SARS-CoV-2 cross-variant antibody response and prediction of protection. Neurol Neuroimmunol Neuroinflamm 2025;12(5):e200443. PMID 40694731
106
Zabalza A, Arrambide G, Tagliani P, et al. Humoral and cellular responses to SARS-CoV-2 in convalescent COVID-19 patients with multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2022;9(2):e1143. PMID 35105687
107
Zabalza A, Thompson A, Rotstein DL, Bar-Or A, Montalban X. Multiple sclerosis and COVID-19: interactions and unresolved issues. Lancet Neurol 2025;24(4):361-70. PMID 40120619
108
Zaloum SA, Wood CH, Tank P, et al. Risk of COVID-19 in people with multiple sclerosis who are seronegative following vaccination. Mult Scler 2023;29(8):979-89. PMID 37431627
109
Zappulo E, Buonomo AR, Saccà F, et al. Incidence and predictive risk factors of infective events in patients with multiple sclerosis treated with agents targeting cd20 and cd52 surface antigens. Open Forum Infect Dis 2019;6(11):ofz445. PMID 31723572
110
Zhang Q, Bastard P, Liu Z, et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 2020;370(6515):4570. PMID 32972995
111
Zheng M, Gao Y, Wang G, et al. Functional exhaustion of antiviral lymphocytes in COVID-19 patients. Cell Mol Immunol 2020;17(5):533-5. PMID 32203188

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All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.

Author

  • Aupdm1

    Davide Maimone MD PhD

    Dr. Maimone of Cannizzaro Hospital in Catania, Italy, received consultant honorariums from Alexion, Amgen, Biogen, Boehringer Ingelheim, Merck, Neuraxapharm, Novartis, Roche, and Sanofi.

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Editor

  • Apar1

    Anthony T Reder MD

    Dr. Reder of the University of Chicago received honorariums from Genentech, Genzyme, and TG Therapeutics for service on advisory boards and as a consultant and stock options from NKMax America for advisory work and an unrestricted lab research grant from BMS.

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Former Authors

  • Anthony T Reder MD
  • Veronica P Cipriani MD MS

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