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Vaccine Considerations for Multiple Sclerosis in COVID-19 Era

In December 2019, COVID-19, caused by infection with SARS-CoV-2, was discovered and since, has rapidly spread around the world. To date, 56.3 million documented cases have been reported in the US with 825,000 deaths and a death rate of approximately 1.54%, based on data from the Centers for Disease Control and Prevention (CDC). Many people with multiple sclerosis (MS) take disease-modifying therapies (DMTs) that suppress or alter their immune systems, which could impart higher risk for worse COVID-19 outcomes.

COVID-19 Outcome Risk Factors in MS

An evaluation of electronic health records (EHRs) from 39 large US health systems identified over 150,000 patients with MS, including more than 30,000 who were taking a DMT at the time of analysis, November 30, 2020. The incidence of COVID-19 at that point in time was 0.5% for people with MS. Among those using DMTs, polymerase chain reaction (PCR)-confirmed COVID-19 rate was 1.13% (344/30,478).2 At the time, the mortality rate of COVID-19 in the general US population was approximately 3.1%, whereas the overall, unadjusted COVID-19 mortality rate among those with MS in the EHR records analyzed was between 3% and 4.5%.

The COViMS registry was created early in the pandemic as a North American database collecting information from patients with demyelinating diseases of the central nervous system (CNS), primarily MS, with confirmed/suspected SARS-CoV-2 infection. Data in the COViMS registry is reported voluntarily by healthcare professionals. Data collected from COViMS as of December 31, 2021, showed 85 deaths among 3,660 people with MS and COVID-19, a 2.32% mortality rate. Approximately 90% of the reported cases had positive laboratory confirmation of COVID-19. Based on COViMS data through December 23, 2021, risk factors for increased COVID-19 severity among people with MS were similar to those for the general North American population. In COViMS, male sex, older age and increased disability were all associated with increased risk of severe COVID-19 requiring admission to an intensive care unit (ICU) and/or ventilator support, as well as death from COVID-19. Notably, people with MS who were non ambulatory had a mortality rate of 14%, a 25 times higher rate than in ambulatory people with MS after adjustment for other risk factors (P<.001). Black North American persons with MS had a 50% increased odds of hospitalization alone and more than twice the increased risk of ICU admission and/or ventilation, but did not have a statistically significant increased risk of death compared with white individuals in the COViMS registry. Individuals with progressive MS in the COViMS registry were more likely to have a worse clinical course of COVID-19 than seen with relapsing-remitting MS. These COViMS data were in line with other observational studies, which also found higher age and ambulation impairment were significant predictors of hospitalization due to COVID-19.

DMTs and COVID-19 Risks and Outcomes

Significant concern continues regarding the effects of certain DMTs for MS on susceptibility to and outcomes of COVID-19. The EHR database study already analyzed 30,478 people with MS using DMTs and found hospitalization risk of 21.5% (74/344) due to COVID-19. Deaths due to COVID-19 were 4.2% (32/761) in the overall population with MS in this study and 3.5% (12/344) in those using DMTs. With adjustments for age, sex, body mass index (BMI), the social construct of race, and comorbidities, the odds of developing COVID-19 were higher for those taking antiCD20 therapies vs fumarates (odds ratio[OR], 3.25; 95% CI 2.31-4.64; P<.0001) and when compared to the aggregate of all individuals on other DMTs (P<.0001). Interestingly, the COVID-19 incidence in those with prescriptions for interferon Β or glatiramer acetate was less than for all other DMTs (0.61% vs 1.27% and 0.51% vs 1.31%, respectively, P<.0001 for each).

COViMS North American registry data have also provided insights into effects of specific DMTs, with approximately 85% of entries reporting DMT use. Approximately 30% were taking ocrelizumab, whereas use of sphingosine-1-phosphate receptor (S1PR) modulators, natalizumab, fumarates, or rituximab (off-label) comprised about 9.5%, 10.6%, 11.3%, and 4.7%, respectively. In earlier published analyses of these data, those using rituximab had a 4.5-times increase in the odds of hospitalization compared with those using no DMT. Those using ocrelizumab had 1.63-times increase in the odds of hospitalization for COVID-19. Findings from COViMS were in accord with data from other international registries, including early results from an Italian MS registry and a later analysis of combined Italian and French registry data. Each analysis found worse clinical outcomes with the use of antiCD20 agents and with longer duration of antiCD20 exposure. In the early Italian cohort, recent use of methylprednisolone was also associated with worse outcomes (OR 5.2, P=.001), a finding that was reproduced by the later analyses of the combined Italian and French registries (OR = 2.7, P<.001).8,9 In COViMS, glucocorticoid use in the prior 2 months was associated with twofold increased risk of hospitalization and fourfold increased risk of death.

Notably, in the North American, Italian, and French registries, interferon Β and glatiramer acetate treatments were consistently associated with a lower incidence of developing severe COVID-19 in comparison to other DMTs, suggesting a potential protective effect. This association persisted after adjustment for age, sex, race, BMI, and other comorbidities.9 A large cohort study of clinician-submitted data from over 30 countries in Europe, North America, and South America reporting on 2,340 people with MS with 1,683 confirmed COVID-19 cases also found the same associations that remained after adjustment for age, sex, MS phenotype and Expanded Disability Status Scale (EDSS) scores.10 As shown in the Figure, compared with dimethyl fumarate, rituximab use had 2.43 increased adjusted odds of hospitalization, 3.93 times increased adjusted odds of ICU admission, and 4 times increased odds of requiring ventilation support. Use of ocrelizumab showed 1.56 increased adjusted odds of hospitalization and 2.30 times increased in the odds of ICU admission, but no increase for artificial ventilation was observed. Characteristics of these individuals were assessed in an effort to determine if these associations were due to disease characteristics of those using these treatments vs use of other DMTs. Worse clinical outcomes associated with rituximab and ocrelizumab were attributable to the DMTs and not a function of other known risk factors of those taking these DMTs.

All registry data discussed are subject to several limitations of voluntary registry data, including lack of denominators, ascertainment bias, and a likely lag in time from COVID-19 occurrence until data entry. Moreover, the behaviors of the participant populations cannot be controlled for and may change over time. Improvements in COVID-19 treatment and introduction of vaccines have likely changed outcomes. Virus variants have also appeared over time and in different geographies.

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