key: cord-0986749-p4hkdnde
authors: Sharifian-Dorche, Maryam; Sahraian, Mohammad Ali; Fadda, Giulia; Osherov, Michael; Sharifian-Dorche, Amirhossein; Karaminia, Maryam; Saveriano, Alexander William; La Piana, Roberta; Antel, Jack P; Giacomini, Paul Steven
title: COVID-19 and Disease-Modifying Therapies in Patients with Demyelinating Diseases of the Central Nervous System: A Systematic Review
date: 2021-01-29
journal: Mult Scler Relat Disord
DOI: 10.1016/j.msard.2021.102800
sha: 525c16c1a83617e431b9db55ad4cd630841518c7
doc_id: 986749
cord_uid: p4hkdnde

INTRODUCTION: The Coronavirus disease-19 (COVID-19) pandemic continues to expand across the world. This pandemic has had a significant impact on patients with chronic diseases. Among patients with demyelinating diseases of the central nervous system (CNS), such as Multiple Sclerosis (MS) or Neuromyelitis Optica Spectrum Disorder (NMOSD), concerns remain about the potential impact of COVID-19 on these patients given their treatment with immunosuppressive or immunomodulatory therapies. In this study, we review the existing literature investigating the impact of disease-modifying therapies(DMT) on COVID-19 risks in this group of patients. METHOD: For this systematic review, we searched PubMed from January 1, 2020, to December 3, 2020. The following keywords were used: COVID-19” AND “Multiple Sclerosis” OR “Neuromyelitis Optica.” Articles evaluating COVID-19 in patients with demyelinating diseases of CNS were included. This study evaluates the different aspects of the DMTs in these patients during the COVID-19 era. RESULTS AND CONCLUSION: A total of 262 articles were found. After eliminating duplicates and unrelated research papers, a total of 84 articles met the final inclusion criteria in our study. Overall, the experiences of 2493 MS patients and 37 NMOSD patients with COVID-19 were included in this review. Among them, 46(1.8%) MS patients died(the global death-to-case ratio of Covid-19 was reported about 2.1%). Among DMTs, Rituximab had the highest mortality rate (4%). Despite controversies, especially concerning anti-CD20 monoclonal antibody therapies, a relation between DMT-use and COVID-19 disease- course was not found in many studies. This observation reinforces the recommendation of not stopping current DMTs. Other variables such as age, higher expanded disability status scale (EDSS) scores, cardiac comorbidities, and obesity were independent risk factors for severe COVID-19. Despite the risks of infection, most patients were willing to continue their DMT during the pandemic because of more significant concern about the risk of relapse or worsening MS symptoms. After the infection, an immune response's attenuation was seen in the patients on Fingolimod and anti-CD20 monoclonal antibodies. This may be a critical finding in future vaccinations.

Coronavirus disease-19 (COVID-19) pandemic continues to expand globally with a significant impact on health care systems and economies. (1) . Patients with chronic diseases and those receiving immunosuppressive therapies have an increased risk of infection and severe complications. (2) Especially In the latter group of patients, the pandemic affects many aspects of their disease management, from therapeutic strategies to scheduling routine clinical follow-up and rehabilitation plans. Patients with demyelinating disorders of the central nervous system (CNS) such as Multiple Sclerosis (MS) or Neuromyelitis Optica Spectrum Disorder (NMOSD) deserve particular consideration due to their need for immunosuppressive or immunomodulatory therapies and regular monitoring of disease activity and response to treatment.

(2) In this study, we review the latest evidence on 1) the effect of different disease-modifying therapies (DMT) on the risk of contracting SARS-CoV-2 infection and severe COVID-19 complications; 2) the effect of these therapies on the ability to develop immune responses to vaccines, and 3) the psychological impact of COVID-19 pandemic on patients with chronic demyelinating diseases.

According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Figure 1) , (3), we searched PubMed from January 1, 2020, to December 3, 2020. These keywords were used: "COVID-19" AND "Multiple Sclerosis" OR "Neuromyelitis Optica" We included articles that were written in English. The authors evaluated the titles and abstracts of each article. Articles evaluating COVID-19 in patients with demyelinating diseases of CNS were included. This study focuses on evaluating different aspects of the disease-modifying therapies (DMT) in the COVID-19 time (possible increased risk of infection, their effect on the future vaccine, and patients' attitudes to continue or discontinue the medication during a pandemic) in patients with MS and NMOSD.

Studies presented as original articles, case series, case reports, letters, correspondence, or short communications were considered. We evaluated the full text of included articles for the detection of clinical features of the patients. Duplicated results were removed. The final list of included articles was generated according to relevance to the topics covered in this review. Data from each article was extracted into the Microsoft Excel software .

The PRISMA flow chart of this study is shown in Figure 1 . A total of 262 articles were found. After removing duplicates and unrelated research papers, a total of 84 articles met the final inclusion criteria in our study. Overall, the data of 2493 MS patients and 37 NMOSD patients were reported with COVID-19. (Table 1 , 2)(2,5-74) Full-text articles assessed for eligibility (n =89)

Articles excluded regarding to review of full text (n = 39 )

Studies included in qualitative and quantitative synthesis (n =84)

Articles excluded regarding to eligibility (n = 5)

Articles excluded regarding to Duplication (n = 17 ) * Among the selected articles, those with relation to the rate of infection in patients on DMTs, articles related to psychiatric problems and anxiety in MS and NMOSD patients during pandemic ( with focus on the articles which evaluated the risk of different DMT and attitude of the patients about continuing or discontinuing of the DMT) and articles related to vaccination were included. Other articles were excluded (to have a more focused review).

One of the essential concerns of neurologists involved in patient care with demyelinating CNS diseases during the COVID-19 pandemic is the increased risk for infection and complications associated with immunomodulatory or immune-suppressive therapies. The risk of infection during epidemics in these patients has been studied before. For example, Ghaderi S et al. (4) reported that influenza infection is associated with an increased risk for acute hospitalization, and vaccination could prevent this risk among MS patients. (4) Several studies have already reported on SARS -CoV-2 infection in patients with MS and NMOSD and have evaluated the relation COVID-19 course with different DMTs (Table 1 , 2). Although limited by a small sample size and multiple possible sources of bias, these papers provide essential information to understand the risk of infection in patients on different medications. Table 1 and 2 summarizes the cases of COVID-19 in MS and NMOSD patients on different DMTs.

Among DMTs of MS, IFN-B is associated with the lowest risk of infection. (Table 1) 

It was suggested that GA causes a shift from a pro-inflammatory to an anti-inflammatory response. (Figure 2 )This shift could be potentially beneficial in case of COVID-19 infection. Furthermore, GA blocks IFN-gamma mediated activation of macrophages, which is thought to play an essential role in acute respiratory distress syndrome. (6, 19) Moreover, there is no evidence of increased infectious risk during treatment with GA. Accordingly, GA could be a safe medication in the treatment of MS patients during the SARS-CoV-2 pandemic. (6, 19) we found 140 patients on GA who were infected with SARS-CoV-2. Among them, 2 (1.4%) patients died: a 71-year-old man with secondary progressive MS (SPMS), history of obesity, and venous thromboembolism in treatment with anticoagulants (9) and a 64 -year-old man with relapsing-remitting MS (RRMS), an expanded disability status scale (EDSS) score of 2 without known comorbidities. (65) Two studies (8, 14) reported 84 suspicious patients (suspected to have COVID-19) on either Interferon or GA, not further specified.

The therapeutic mechanism of DMF in MS is not fully elucidated. A significant portion of patients treated with DMF experience variable lymphopenia (with CD8 T cells being affected more than CD4 T cells and memory cells more than naive T cells and B cells). (24) Although there was little difference in infection risk between DMF and placebo during clinical trials, DMF can induce grade 3 lymphopenia in 5-7% of the patients. Moreover, severe opportunistic infections have been reported in few patients treated with DMF. (19, 24) In vitro studies showed that DMF blocks pro-inflammatory cytokine production and can inhibit macrophage function, which results in suppressing inflammation (19) . These immunomodulatory effects could be potentially beneficial in the context of the COVID-19 cytokine storm. (19) (Figure 2 ) Current studies did not report an increased risk of severe outcome COVID-19 in patients on DMF; however, the presence or absence of lymphopenia did not evaluate in the course of disease in these patients.

We found 314 patients on DMF infected with SARS-CoV-2. One (0.3%) of these patients died from complications of COVID-19. He was a 68-year-old man with SPMS, EDSS of 6.0, and past medical history of cerebrovascular disease and hypertension, both known negative prognostic factors for COVID-19. (65)

Teriflunomide, an active metabolite of leflunomide, selectively and reversibly inhibits dihydroorotate dehydrogenase, an essential mitochondrial enzyme in the de novo pyrimidine synthesis pathway. (25, 28) Through this mechanism, Teriflunomide reduces immune activation without significant immunosuppression. This function may be potentially beneficial in SARS-CoV-2 infection and may prevent an excessive/fulminant host immune response. (25, 28) Moreover, Teriflunomide may affect the replication of SARS-CoV2 inside the infected cell. (75) (Figure 2) Past studies have suggested a possible effect of Teriflunomide against several viruses, including respiratory syncytial virus (RSV), Ebola, cytomegalovirus, Epstein-Barr, and picornavirus. (25) Accordingly, Teriflunomide could be useful against SARS-CoV-2 through dual antiviral and immunomodulatory actions. (25, 19) On the other hand, Teriflunomide could reduce leukocyte count by approximately 15%, and upper respiratory tract infections and influenza are more common among patients taking Teriflunomide. (19) Overall serious infections resulting in increased morbidity and mortality have not been reported. (19) .

In this study, we found 132 patients on Teriflunomide and COVID-19. There have been reports of the benign course of COVID-19 in many of these patients. (25) However, one (0.7%) died. This patient was a 55 -year-old woman with SPMS, EDSS of 7.5, and an additional diagnosis of myotonic dystrophy, which confers its own cardiac risks. (6) Of note, in one study, patients who contracted COVID-19 while on treatment with Teriflunomide developed antibody levels following seroconversion like those detected in immunocompetent patients. (27) This observation should be taken into account because it can mimic the vaccination outcome in patients treated with Teriflunomide.

Fingolimod is a sphingosine-1-phosphate receptor modulator that sequesters lymphocytes in lymph nodes, preventing them from contributing to an autoimmune reaction by blocking trafficking to the target organ. It reduces the total mean circulating lymphocyte count by 73% from baseline and preferentially sequesters the naive and central memory lymphocytes rather than effector memory T cells. (19, 24, 35) Fingolimod is associated with an increased risk of mild infections, mainly involving the lower respiratory tract, and increased risk for Herpes virus infections/reactivations (19) . Accordingly, there are some concerns about the increased risk of SARS-CoV-2 infection in these patients. COVID-19 was reported in 257 patients on Fingolimod. Most patients had a relatively benign disease course despite lymphopenia and showed complete recovery. Only one Fingolimod (0.3%) patient died. She was a 42-year-old woman with RRMS and EDSS: 6.0. She had severe cognitive impairment, a history of struma treated with radioiodine, and refused Intensive Care Unit (ICU) admission. (68) On the other hand, blunting the immune response and potential of sphingosine-1-phosphate enhancing the lung endothelial cell integrity may be the possible explanations that make Fingolimod a potential therapy to control the severe respiratory disease. (Figure 2 )Gomez-Mayordomo V et al. (33) reported a case of clinical exacerbation of SARS-CoV2 infection after Fingolimod withdrawal in a 57-year-old man with RRMS and EDSS 6.0. The patient showed hyper-inflammation syndrome one week after Fingolimod withdrawal, and he progressively improved following steroid therapy.

The risk of aggressive rebound of MS activity with Fingolimod's discontinuation (18, 19) should be carefully weighed when considering treatment discontinuation due to the risk of infections. The ultimate decision should be individualized through discussion between physician and patient.

The other concern about patients on Fingolimod is the effect of vaccination and immunoglobulin response. Bollo L et al. (27) reported a 34 -year-old female with RRMS, EDSS 2.5 on Fingolimod, who had a reduced immunoglobulin response (IgG serum response) to SARS-CoV-2 as compared to immunocompetent controls. (27) Natalizumab Natalizumab is a humanized monoclonal antibody against α4-integrin indicated for the treatment of MS and Crohn's disease. By inhibiting the binding to VCAM and MAdCAM, it prevents the migration of lymphocytes through the brain and guts endothelial microvasculature. The impairment of CNS immune surveillance caused by Natalizumab may contribute to opportunistic infections. (35, 40) A registry-based cohort study performed by Luna G et al. (40) showed no significant increase in the general risk of infection with Natalizumab compared to platform therapies.

Until now, 233 patients on Natalizumab with SARS-CoV-2 infection were reported. Three (1.2%) of these patients died. These patients were aged 60 -year-old, 51 -year-old, and 52 -year-old, and two had other underlying comorbidities (coronary artery disease, hypertension, and obesity). (Table 1) Aguirre C et al. (38) suggested that Natalizumab treatment could even be helpful in the COVID-19 pandemic context. Based on the recent studies showing that SARS-CoV-2 may use integrin to enter the human cells, Natalizumab as an antibody against α4-integrin might be protective toward the infection. (Figure 2 )

Alemtuzumab is a fully-humanized IgG1 directed against CD52 and used to treat chronic lymphocytic leukemia (CLL) and MS. It acts via antibody-dependent cellular cytotoxicity and complementdependent cytotoxicity. In addition, it activates pro-apoptotic pathways on CD52 expressing cells. (19) Alemtuzumab reduces T and B-lymphocytes count for many months following administration. The incidence of infection in the early months after treatment with Alemtuzumab is high, given the profound lymphopenia (45), but the rate of severe infection was <3%. (45) Considering significant infectious risks with Alemtuzumab -particularly in the first two years of treatment -the risk of COVID19 may be higher in these patients. (35) We found 37 reported patients on Alemtuzumab and COVID-19. Most of them had a benign course and recovered completely. None of them died. (43) However, there is insufficient evidence from the published cases to indicate whether patients at the beginning of the treatment are at greater risk.

Following the initial depletion, Alemtuzumab produces a lymphocyte reconstitution from a new lineage. This lymphocyte reconstitution, including changes in composition, phenotype, and lymphocytes' function, may cause a potential resistance of this new lineage to the virus or blunts the cytokine storm associated with life-threatening complications of SARS-CoV-2 infection. (42)

Oral Cladribine, a purine nucleoside analog prodrug, interferes with cellular metabolism and inhibits DNA repair, which causes apoptosis, especially in lymphocytes. (19, 35) The effect of Cladribine is mainly on CD4+ and CD8+ T cells, and also B cells. Accordingly, transient lymphopenia (most often mild to moderate) is a common adverse event. The effect on innate immune cells such as neutrophils, monocytes, and NK cells are minor. (19, 35) Due to the lymphopenia, the risk of infection with SARS-CoV-2 may be increased in patients on Cladribine. Regarding immune responses and antibody formation to SARS-CoV-2, Celius EG (49) reported adequate immune response with detectable antibodies three months after i nfection in a 35 -yearold female with RRMS on Cladribine.

Therapy with anti-CD20 monoclonal antibodies, such as Ocrelizumab and Rituximab, has demonstrated high efficacy in reducing MS relapses by targeting B cells. Moreover, these agents reduce pro-inflammatory B-cell cytokines. (19) A higher risk of infection was reported with Rituximab than with platform MS DMTs (IFN-β and GA)(40), although infection rates were only slightly higher with Ocrelizumab than interferon β-1a. (19, 40) Hypo-gammaglobulinemia may be observed in the patients who had prolonged use of anti-CD20 therapies but is rarely associated with severe infection. (19, 35) In this pandemic, it was shown that a direct role of B cells in SARS-CoV-2 infection is less likely. Soresina A et al. (61) reported two cases of COVID-19 with pneumonia and lymphopenia in patients with X-linked agammaglobulinemia, both of whom recovered.

There are several reports of COVID-19 in patients receiving anti-CD20 monoclonal antibodies. In another study from Iran, it was demonstrated that the risk of SARS-CoV-2 infection among patients on B-cell-depleting therapy was higher than patients on other DMT (5, 13) . Although the use of the drug was not associated with increased odds of hospitalization. (13) However, most patients, especially those without underlying comorbidities, had a complete recovery, and other studies did not have similar findings. (7) In published case reports, the number of B cells does not seem to impact the prognosis. (Table 1 ) It was even suggested that a moderately reduced immune response due to a lack of peripheral B cells in the patients on anti -CD20 monoclonal antibodies might play a favorable role in these patients. The lack of a significant increase of IL-6 (that might be released by the peripheral B cells) seems to support this hypothesis. (54) (Figure 2) Another relevant consideration for anti-CD20 monoclonal antibodies is their effect on vaccination since they are partially blunt antibody responses to vaccines. Anti-CD20 monoclonal antibody therapy is not expected to affect responses of the innate immune system, which are critical for initial viral control. (19, 35) It also remains to be seen how this class of therapies will impact the vaccine response to some of the candidate vaccines with novel mechanisms, particularly those that express mRNA to generate an immune response .

Conte WL (57) 

Overall, 379 MS patients with COVID-19 were reported who did not receive any medications. (6)(7)(9)(10)(12)(13)(14)(15)(16)(23)(65)(67) (68) . In this group, 14(3.6%) patients died. The mean age of the patients who died was 64.2(range:50-84) year-old. Mean EDSS was 7.2 (range 4-9)(EDSS was reported in 12 cases). In addition to being older and having higher disability scores, most of these patients also had underlying comorbidities, which would make them more vulnerable to COVID-19 complications. These comorbidities included: congestive heart disease, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, cardiomegaly, and obesity. 

Only two studies evaluated the COVID-19 in pediatric-onset MS. (9) . In the first, nine patients were reported: one on GA, two on Ocrelizumab, four on Rituximab, one on Natalizumab, and one without medication. Comorbidities in this group were obesity (n = 3), type I diabetes (n = 1), or both (n = 1). Two of these patients with reported comorbidities were hospitalized and required supplemental oxygen but not invasive ventilation. (9) The other study from Italy on 26 pediatric-onset MS patients on Natalizumab did not find a higher risk of SARS-Cov-2 infection in these patients. ( With respect to mortality rates, we found that 46 MS patients overall were reported as having died due to COVID-19 complications. Clinical data of 28 of these MS patients was available. The mean age was 60.0(Range: 42-84); 16 patients were male. In 24 patients, the type of MS was reported.( RRMS:5, SPMS:17, PPMS:2) .

Most of the patients in this group had high EDSS and multiple underlying comorbidities. (Table 1) Overall, according to the different reports, we found the mortality rate in MS patients was about 1.8%( the global death-to-case ratio of Covid-19 was reported about 2.1%) (77) ; however, in the patients on Rituximab (4.0%) and patients without medication (3.6%), the rates were higher. ( Figure  4) The similarity in mortality rate in these two populations(Patients on Rituximab and patients without medication) may be due to independent risk factors, such as age, disability (EDSS), or other underlying co-morbidities. The further possible explanation for this can be the protective effect of other DMTs in the other groups. In NMOSD patients, we found reports of 37 patients. Of these patients, five died or were admitted to the ICU due to COVID-19 complications, the mean age of these patients was 43.2 years (range: , and 3 were males. Four of these patients were on Rituximab, and most of them had higher EDSS. (Table 2 )

The safety and efficacy of approvedvaccines for SARS-CoV-2 in MS patients on treatment with DMTs should be carefully considered. (78, 79) First, live, and attenuated viruses are contraindicated in immunosuppressed patients, and under these circumstances, DNA-RNA vaccines will be useful in patients on immunosuppressive agents. In a review article, Ciotti JR et al. (78) evaluated the immune response to existing vaccines in patients on different DMTs to infer potential results of a vaccine against SARS-CoV-2. They showed that there were adequate immune responses in patients on Interferon-beta. However, a reduced immune response was reported after GA (not statistically significant in some studies), Teriflunomide, Fingolimod, Siponimod, Natalizumab, and anti-CD20 monoclonal antibody treatments. (78) A recent study by Bar-Or A et al. (80) provides Class II evidence confirming that the humoral response to nonlive vaccines in RRMS patients after Ocrelizumab treatment was attenuated compared with untreated or Interferon-beta treated patients; however, they can still be expected to be protective.

A relatively poor vaccine response in patients treated with DMTs, especially in patients treated with anti-CD20 therapies, was predictable. (78) .

For instance, in Rheumatoid Arthritis, it has been shown that following treatment with Rituximab, there is a more markedly blunted seroconversion and titer after vaccination during periods of peripheral B cell depletion and a more significant, but still blunted, vaccine response 6-10 months after infusion. (79) Accordingly, it is possible to create a time-window to vaccinate an individual on the base of differential kinetics of repopulation with pathogenic memory B cells and naive B cells. (79) In anti-CD20 antibodies, the duration of treatment may also have a significant effect. (78) At least with Rituximab, it is possible to extend interval dosing or dosing interruption to allow immature B cells to recover (repletion starts to occur within about six months of treatment and is completed within 12 months due to repopulation of the naive cell pool). The required timing for this to occur for Ocrelizumab is likely to be longer. (79) In this case, it seems that there is marked variability in repopulation kinetics between individuals, and the intensity of B cell depletion and repopulation speed relates to the body mass index of the patients. Therefore, dose-adjustment for weight may have some benefit. (79) Ultimately, in the case of approved SARS-CoV-2 vaccine, it may be reasonable to consider a treatment interruption or delay to create a window for effective vaccination.

In the other DMTs, such as Cladribine, the medication is rapidly eliminated, allowing CD19 naive B cells to recover within a median of 30 weeks. (79) Alemtuzumab markedly depletes memory B cells, but naive B cells rapidly repopulate, and vaccine-related antibody responses can be induced six months after infusion. (79) Besides, serological confirmation of a sufficient response to vaccination may be required in DMT patients after vaccination.

in RA following treatment with Rituximab, with a more markedly blunted seroconversion and titre when vaccinated during periods of peripheral B cell depletion with influenza further knowledge will emerge that may help guide treatment selection within the COVID-19 and post-COVID-19 era.

Hopefully, further studies will emerge to help guide treatment strategies to optimize success with vaccination protocols while minimizing treatment interruption risks. Despite these encouraging findings, the pandemic's long-term psychological consequences still need to be fully elucidated. Therefore, it continues to appear appropriate to monitor high-risk MS patients, especially those with pre-existing psychiatric disturbances, through the use of anxiety and depression scales and considering therapeutic options such as online support, home exercise programs, and also anti-anxiety and anti-depression medications when needed. (91)

In the setting of COVID-19, some early studies have reported a rate of hospitalization that was higher among MS patients than the general population (13) , and that MS patients on B-cell-depleting therapy had an increased risk of SARS-CoV-2 infection (5), or a worse clinical course (65), however, other studies could not confirm these observations. (67) (68) . Furthermore, it appears that most MS patients with COVID-19 do not require hospitalization despite being on DMTs (9) .

Moreover, most current data do not support an increased risk of worse outcomes related to DMTs or even low lymphocyte count (68) , reinforcing the recommendation of not stopping MS treatment despite pandemic risks. (7, 5, 13, 23) We found the risk of mortality of COVID-19 in MS patients overall similar to what was seen in the non-MS population. (1) However, we did see relatively higher mortality among patients on anti-CD20 therapies or patients without medication. Most of the MS patients who died from COVID-19 complications appeared to have had multiple underlying comorbidities and higher EDSS scores.

Different studies showed that other variables such as age, EDSS, cardiac comorbidity, and obesity were independent risk factors for severe COVID-19 and death in MS and NMOSD patients. (7, 9, 23) The overall COVID-19 outcome was favorable in patients with MS and NMOSD receiving DMTs. However, it is still highly recommended that all MS patients undertake personal protective measures to reduce the risk of SARS-CoV-2 infection, particularly when immunocompromised.

Regarding approved COVID-19 vaccines, for patients on DMTs such as Teriflunomide, Fingolimod, Siponimod, and anti-CD20 monoclonal antibodies, attenuation of the post-vaccine immune response is possible.

Finally, among patients with known neuropsychiatric symptoms, careful follow-up of the patients is essential, regardless of the DMTs they are taking.

In conclusion, neurologists should be aware of the potential risks of morbidity and even mortality with COVID-19 in MS and NMOSD patients. Each patient has an individual risk profile, including their underlying comorbidities, disability level, disease activity, age, and therapy. These factors need to be carefully weighed and considered before deciding if any change in therapy is warranted, and every plan should be individualized to that patient's circumstances.

A limitation of this manuscript is that it is likely weighted towards the experiences from certain regions and academic centres that had a large number of cases in the first wave, and were able to publish their experience earlier on, thus, leading to inclusion in this review. Moreover, the articles used in preparation of this review represent raw numbers of COVID-19 cases occurring in patients on specific DMTs, but unfortunately, we do not know the denominator, or overall number of patients on those specific DMTs. Therefore, we cannot deduce what proportions of patients on those individual DMTs actually developed COVID-19 complications to get a more precise risk estimate.

In this review, we tried to gather and summarize the results of all the studies reporting COVID-19 in MS and NMOSD patients since the beginning of the pandemic. We considered both confirmed and suspected patients in this study; accordingly, some suspected patients may have other diagnoses rather than COVID-19. The type of DMT was not reported in some studies, and we reported this group as undetermined. Clinical characteristics were not available for all patients.

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COVID-19 Dashboard by the Center for Systems Science and Engineering

Effects of MS disease-modifying therapies on responses to vaccinations: A review

COVID-19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases

Effect of Ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study

Social and professional consequences of COVID-19 lockdown in patients with multiple sclerosis from two very different populations

Changes in patient and physician attitudes resulting from COVID-19 in neuromyelitis optica spectrum disorder and multiple sclerosis

Evaluating the perspective of patients with MS and related conditions on their DMT in relation to the COVID-19 pandemic in one MS centre in Australia

Neuropsychiatric changes during the COVID-19 pandemic in multiple sclerosis patients

Evaluation of the Opinion of Patients With Multiple Sclerosis on the Outcomes of Catching COVID-19 and Its Effects on the MS Symptoms

The impact of COVID-19 on patients with neuromyelitis optica spectrum disorder; a pilot study

Psychological status of patients with relapsing-remitting multiple sclerosis during coronavirus disease-2019 outbreak

Psychological consequences of COVID-19 pandemic in Italian MS patients: signs of resilience?

Naser Moghadasi A. Neuropsychiatric and cognitive effects of the COVID-19 outbreak on multiple sclerosis patients

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