Associations of Disease-Modifying Therapies With COVID-19 Severity in Multiple Sclerosis

Abstract

Background and Objectives People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. Methods Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1–12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. Results Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01–2.41; aOR 2.43, 95% CI 1.48–4.02) and ICU admission (aOR 2.30, 95% CI 0.98–5.39; aOR 3.93, 95% CI 1.56–9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54–10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (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), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09–12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13–3.07; aOR 2.88, 95% CI 1.68–4.92) and ICU admission (aOR 2.13, 95% CI 0.85–5.35; aOR 3.23, 95% CI 1.17–8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71–17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. Discussion Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.

Background and Objectives People with multiple sclerosis (MS) are a vulnerable group for severe coronavirus disease 2019 (COVID-19), particularly those taking immunosuppressive disease-modifying therapies (DMTs). We examined the characteristics of COVID-19 severity in an international sample of people with MS. Methods Data from 12 data sources in 28 countries were aggregated (sources could include patients from 1–12 countries). Demographic (age, sex), clinical (MS phenotype, disability), and DMT (untreated, alemtuzumab, cladribine, dimethyl fumarate, glatiramer acetate, interferon, natalizumab, ocrelizumab, rituximab, siponimod, other DMTs) covariates were queried, along with COVID-19 severity outcomes, hospitalization, intensive care unit (ICU) admission, need for artificial ventilation, and death. Characteristics of outcomes were assessed in patients with suspected/confirmed COVID-19 using multilevel mixed-effects logistic regression adjusted for age, sex, MS phenotype, and Expanded Disability Status Scale (EDSS) score. Results Six hundred fifty-seven (28.1%) with suspected and 1,683 (61.9%) with confirmed COVID-19 were analyzed. Among suspected plus confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalized, 5.4% and 7.2% were admitted to ICU, 4.1% and 5.4% required artificial ventilation, and 3.2% and 3.9% died. Older age, progressive MS phenotype, and higher disability were associated with worse COVID-19 outcomes. Compared to dimethyl fumarate, ocrelizumab and rituximab were associated with hospitalization (adjusted odds ratio [aOR] 1.56, 95% confidence interval [CI] 1.01–2.41; aOR 2.43, 95% CI 1.48–4.02) and ICU admission (aOR 2.30, 95% CI 0.98–5.39; aOR 3.93, 95% CI 1.56–9.89), although only rituximab was associated with higher risk of artificial ventilation (aOR 4.00, 95% CI 1.54–10.39). Compared to pooled other DMTs, ocrelizumab and rituximab were associated with hospitalization (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), but only rituximab was associated with artificial ventilation (aOR 6.15, 95% CI 3.09–12.27). Compared to natalizumab, ocrelizumab and rituximab were associated with hospitalization (aOR 1.86, 95% CI 1.13–3.07; aOR 2.88, 95% CI 1.68–4.92) and ICU admission (aOR 2.13, 95% CI 0.85–5.35; aOR 3.23, 95% CI 1.17–8.91), but only rituximab was associated with ventilation (aOR 5.52, 95% CI 1.71–17.84). Associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS phenotype, and EDSS score found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity. Discussion Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalization, ICU admission, and need for artificial ventilation and of ocrelizumab with hospitalization and ICU admission. Despite the cross-sectional design of the study, the internal and external consistency of these results with prior studies suggests that rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.