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Background: People with multiple sclerosis (MS) are a vulnerable group for severe COVID-19, particularly those taking immunosuppressive disease-modifying therapies (DMTs). Objective(s): To assess characteristics of COVID-19 severity in an international sample of people with MS, including hospitalisation, ICU admission, requiring artificial ventilation, and death. Method(s): Data from 12 data-sources in 28 countries were aggregated. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes, hospitalisation, admission to ICU, requiring artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/ confirmed COVID-19 using multilevel mixed-effects logistic regression. Result(s): 657 (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19. Older age, progressive MS-phenotype, and higher disability associated with worse COVID-19 outcomes. Ocrelizumab and rituximab associated with hospitalisation (aOR=1.75,95%CI=1.29-2.38;aOR=2.76,95%CI=1.87-4.07) and ICU admission (aOR=2.55,95%CI=1.49-4.36;aOR=4.32, 95%CI=2.27-8.23) vs pooled-other-DMTs but only rituximab with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Similar associations seen compared to dimethyl fumarate and to natalizumab. No associations observed between DMTs and death. Conclusion(s): Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab and ocrelizumab with worse COVID-19, suggesting their use may be a risk factor for more severe COVID-19.
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Background: The Covid-19 pandemic has led to vast changes in working life and conditions in which we work. These changes may affect people with multiple sclerosis (MS) differently. Aim(s): To describe the work participation of people with MS during the Covid-19 pandemic and the consequences of the pandemic on their working lives. Method(s): A web-based survey was conducted in summer 2021 to investigate various aspects of life among people with MS in Sweden, including work and impacts of the pandemic. All individuals aged 20-50 listed in the Swedish MS registry were invited. Individual-level sociodemographic and clinical data were linked from nationwide registers. Differences in the responses by sex, education level (university, yes or no), and type of work (office or manual) were tested with chi2-tests. Result(s): Over 8500 adults with MS were invited and 4412 (52%) responded. The 4164 without full-time disability pension were included, with a mean age of 40.3 and 9.2 years since diagnosis. Overall, 2731 reported no impact on their work situation by the pandemic. Among the 3571 employed or self-employed, 3.2% reported less to do and 9.5% more to do due to the pandemic. Similar proportions reported no impact on work by sex (65.8% v 65.2%, p-value 0.690), but women more frequently stated they had more to do (8.7% v 6.9%, p-value: 0.058). No impact on work was more often reported among those with university education (68.2% v 61.3%, p-value <0.001) and fewer reported more to do than those without university education (6.3% v 9.4%, p-value <0.001). Fewer with university education were furloughed (Currently: 0.5% v 1.6%, p-value 0.001. Earlier: 5.6% v 6.7%, p-value 0.028). They also pursued further studies to a higher extent (2.3% v 1.4%, p-value 0.028). Office workers reported no impact on work to a higher extent than manual workers (72.4% v 63.6%, p-value <0.001), despite more stating they had more to do to (9.4% v 7.1%, p-value 0.023). Current furlough was less common among office workers (0.6% v 1.4%, p-value 0.026), with no differences earlier (6.2% v 6.0%, p-value 0.779). Fewer office workers pursued studies (0.8% v 2.9%, p-value <0.001). Conclusion(s): Many people with MS reported that the pandemic did not affect their work situation. However, the consequences reported differed among them. Further knowledge of which factors promoted or hindered their work lives during the pandemic is needed to support long-term work participation.
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Introduction: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with blunted humoral vaccination responses, but relevance for SARS-CoV-2 infection is unclear. Objective(s): To determine SARS-CoV-2 exposure rates and formation of antibody memory among participants of the COMparison Between All immunoTherapies for MS (COMBAT-MS;NCT03193866) and the Immunomodulation and MS Epidemiology (IMSE) studies. Aim(s): To determine SARS-CoV2 serological response of people living with MS (pwMS). Method(s): Using a multiplex bead-based assay we determined SARS-CoV-2 spike and nucleocapsid antibody levels in 3,723 pwMS in paired serum samples (n=7,157) donated prior (<January 31st 2020) and during the pandemic (July-October 2020);16.6% had natalizumab, 6.4% fingolimod, 9.7% dimethyl fumarate, 1.9% interferon beta, 50.4% rituximab, 1.4% cladribine, 7.6% other DMTs, and 6.1% were untreated. Median fluorescent intensity (MFI) and bead-count were determined for spike and nucleocapsid antibodies, and samples were regarded as positive only when reactive to both viral antigens. Hazard ratios, from multivariable Cox regression models, were derived to assess association between antibody levels above cut-off for each antigen, comparing exposure to rituximab or fingolimod at time of sampling vs. other reference DMTs. All models were adjusted for age, sex, treatment center, time since reported infection, MS severity, disease duration, and number of previous DMTs. Result(s): Specificity and sensitivity of the assay for SARS-CoV-2 was 100% and 99.7%, respectively. The proportion of positive samples for SARS-CoV-2 differed moderately across DMTs with the highest values among cladribine-treated (7.4%) and the lowest number among rituximab-treated pwMS (3.9%). Similarly, the proportion of positive cases not reported in the Swedish MS registry varied from 100% for cladribine to 33.3% among untreated pwMS. Comparing levels of antibodies titers showed that levels were lower among those treated with rituximab or fingolimod vs interferon treated pwMS. Point estimates indicated a similar trend comparing rituximab or fingolimod vs untreated pwMS. Conclusion(s): Overall rates of SARS-CoV-2 antibody positivity after the first COVID-19 wave differed only moderately across DMTs, while antibody levels were lower with rituximab or fingolimod compared to interferon-treated pwMS. This indicates quantitative rather than qualitative differences in the humoral response to infection.
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Background: As the COVID-19 pandemic continues, evidencebased clinical guidance for managing the care of people with multiple sclerosis (MS) is an ongoing concern. In recent months, data from cohorts of people with MS has indicated that certain demographic and clinical characteristics, including use of some disease- modifying therapies (DMTs), leads to worse outcomes from SARS-CoV-2 infection. The COVID-19 in MS global data sharing initiative, which now includes over 4,500 confirmed COVID- 19 cases in people with MS, gives the opportunity to corroborate previous findings with greater certainty. Methods: Clinician-reported data from 32 countries were aggregated into a dataset of 5,543 patients who had suspected or confirmed COVID-19. Demographic and clinical covariates were queried, alongside COVID-19 clinical severity outcomes. These outcomes (hospitalisation, admission to ICU, requiring artificial ventilation, and death) were assessed in patients with suspected/ confirmed COVID-19 using multilevel mixed-effects logistic regression. All models were corrected for age, sex, EDSS, and MS type. DMTs were individually compared to glatiramer acetate (GA), as well as to pooled other DMTs and natalizumab. Results: Of 5,543 patients in the clinician-reported dataset, 909 with suspected and 4,634 with confirmed COVID-19 were included in the analysis. Previous demographic findings were confirmed: male sex, older age, progressive MS, and higher disability were associated with worse outcomes from SARS-CoV-2 infection. Use of anti-CD20 DMTs (ocrelizumab and rituximab) was associated with worse COVID-19 outcomes. Compared to GA, ocrelizumab and rituximab were associated with increased risk of hospitalisation (aOR=1.61(95%CI=1.06-2.43);aOR=2.42(95%CI=1.54-3.81) and ICU admission (aOR=3.13(95%CI=1.22-8.00);aOR=4.46 (95%CI=1.64-12.09)). Rituximab was associated with increased risk of artificial ventilation (aOR=3.57(95%CI=1.38-9.20));ocrelizumab showed a positive trend (aOR=1.86(95%CI=0.76-4.55). Rituximab showed a positive trend with increased risk of death (aOR=2.74(95%CI=0.68-11.09). Associations persisted on restriction to confirmed COVID-19 cases. Conclusions: Analysing the largest international real world dataset of people with MS who have suspected or confirmed COVID- 19 confirms previous findings that male sex, older age, progressive MS, higher disability, the use of anti-CD20 medication (ocrelizumab and rituximab) are associated with worse COVID-19 outcomes.
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Introduction: This study group has previously demonstrated a significantly increased risk of hospitalisation for COVID-19 amongst rituximab-treated patients in Sweden. Objective: The primary objective of this study was to analyse the association between multiple sclerosis (MS) disease modifying therapy (DMT) exposure and hospitalisation in patients infected with COVID-19. Methods: Nationwide registry-based cohort study. Associations between MS DMT exposure and COVID-19 hospitalisation were analysed using univariable and multivariable clustered propensity score weighted logistic regression, where the models were clustered on the individual patients to control for patients contributing multiple COVID-19 episodes. Results: As of 4th June 2021, a total of 950 reported COVID-19 cases had been recorded in MS patients in the Swedish MS registry. Of these, 697 (73.4%) had confirmed COVID-19. The mean (SD) age at infection was 44.4 years (11.2). Of the 697 confirmed infections 117 (16.8%) required hospitalisation. A total of 73 of the 308 confirmed COVID-19 patients on rituximab at baseline (23.7%) required hospitalisation, compared to a rate of 11.3% for all other DMTs combined. Rituximab in confirmed COVID-19 patients was associated with 3.10 times the odds of hospitalisation relative to any other DMT combined (adjusted Odds Ratio 3.10;95% CI 1.68-5.74), controlling for age, sex, EDSS and MS course and duration of treatment at baseline. There was no difference in the rate of hospitalisation between any of the non-rituximab DMTs when compared to one another. Amongst rituximab treated patients only, the duration of rituximab at baseline was not associated with a changed risk of hospitalisation. Conclusions: Rituximab treatment, known to increase the risk of severe infections in general, also confers such a risk for MS patients with COVID-19, in comparison with other MS DMTs.
ABSTRACT
Introduction: Mounting evidence suggests that B-cell depleting disease-modifying therapies (DMTs) may be associated with an increased risk of a moderate to severe COVID-19. Use of rituximab (RTX) is frequent in Sweden, a country that suffered high COVID-19 rates. Objective: To explore the association between timing and dose of RTX and risk of hospitalization for COVID-19 in a well-characterized cohort of MS patients. Methods: We included participants in COMBAT-MS, (NCT03193866) with ongoing treatment with RTX. Data include detailed demographic and clinical information, DMT exposure (date and dose of all RTX infusions), COVID-19 information (dates of infection and hospitalization as reported by the patient), as well as patient-reported outcomes. Among all persons who developed COVID-19, we measured the odds of hospitalization for COVID-19 as they related to 1) the time between most recent RTX infusion and COVID-19 onset date (measured in months), and 2) the total lifetime cumulative dose of RTX received (measured in grams), using logistic regression. The reference cohort included all persons with 'mild' COVID-19, not requiring hospitalization. Models were adjusted for age and sex with results reported as odds ratios (OR) and 95% confidence intervals (CI). Results: Of 3391 persons actively enrolled in the COMBAT-MS cohort, 326 (9.6%) developed COVID-19 between March 1, 2020 and April 30, 2021. Amongst these patients, 172 (52.8%) were exposed to RTX prior to their COVID-19 onset, and 26 (15.1%) required hospitalization. No deaths occurred. Median time between last RTX infusion and COVID-19 onset was 6.1 months [interquartile range (IQR): 3.9, 11.0] among mild cases, and 4.6 months [IQR: 3.6, 5.6] among those hospitalized for COVID-19 (difference not significant, Mann-Whitney U-test p=0.16). Persons with mild COVID-19 had a median cumulative lifetime RTX dose of 3.5g [IQR: 2.5, 4.5], compared to 3.3g [IQR:2.6, 4.5] for hospitalized cases. The time between most recent DMT infusion and COVID-19 onset was not associated with altered odds of requiring hospitalization (age-and sexadjusted OR: 0.97 (95%CI: 0.90-1.03), nor was lifetime cumulative dose of RTX (age and sex-adjusted OR: 1.05 (95%CI: 0.83-1.31). Conclusions: Among COMBAT-MS participants who contracted COVID-19, there was no significant association between timing of RTX infusion nor cumulative lifetime RTX dose and the odds of hospitalization for COVID-19.