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

Abstract

Background:People with multiple sclerosis (MS) are a vulnerable group for severe 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, alongside COVID-19 severity outcomes, hospitalisation, ICU admission, requiring 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 EDSS.Results:657(28.1%) with suspected and 1,683(61.9%) with confirmed COVID-19 were analysed. Among suspected+confirmed and confirmed-only COVID-19, 20.9% and 26.9% were hospitalised, 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 hospitalisation (aOR=1.56,95%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), though 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 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) but only rituximab with artificial ventilation (aOR=6.15,95%CI=3.09-12.27). Compared to natalizumab, ocrelizumab and rituximab wereassociated with hospitalisation (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 with ventilation (aOR=5.52,95%CI=1.71-17.84). Importantly, associations persisted on restriction to confirmed COVID-19 cases. No associations were observed between DMTs and death. Stratification by age, MS-phenotype, and EDSS found no indications that DMT associations with COVID-19 severity reflected differential DMT allocation by underlying COVID-19 severity.Conclusions:Using the largest cohort of people with MS and COVID-19 available, we demonstrated consistent associations of rituximab with increased risk of hospitalisation, ICU admission, and requiring artificial ventilation, and ocrelizumab with hospitalisation and ICU admission. Despite the study’s cross-sectional design, the internal and external consistency of these results with prior studies suggests rituximab/ocrelizumab use may be a risk factor for more severe COVID-19.

Preserved T-cell Response in anti-CD20 Treated Multiple Sclerosis Patients Following SARS-CoV-2 Vaccination

“…During the last 20 years, scienti c progress led to the development of nearly 20 medications for MS therapy, including monoclonal antibodies targeting B cells via anti-CD20 (aCD20) such as rituximab or ocrelizumab 1 . aCD20 treated patients are at higher risk for hospitalization and a more severe course of COVID19 2 . Since the end of 2020, the rst vaccine candidates received emergency use authorization, showing high e cacy against SARS-CoV-2 infection 3 .…”

Keep your eyes on the prize: Tackling breakthrough COVID-19 in MS patients

“… 1 – 3 An international cohort encompassing 1,683 confirmed COVID-19 cases in MS patients found that older age, progressive MS-phenotype, higher disability, comorbidities and anti-CD20 therapies were risk factors for a more severe course of COVID-19. 4 Other disease modifying therapies do not seem to carry an increased risk of a worse outcome of COVID-19 in MS patients. 1 – 4 Still, for all patients with MS, reaching protective immunity against SARS-CoV-2 is of utmost importance.…”

“… 4 Other disease modifying therapies do not seem to carry an increased risk of a worse outcome of COVID-19 in MS patients. 1 – 4 Still, for all patients with MS, reaching protective immunity against SARS-CoV-2 is of utmost importance.…”

Rituximab during the COVID-19 pandemic: time to discuss treatment options with patients

“…Accumulating data suggest that treatment with anti-CD20 therapy, such as rituximab and ocrelizumab, puts patients at considerably increased risk of developing severe outcomes from COVID-19 (risk ratios ranging from 1·7 to 5·5 have been reported). 1 , 2 This reported risk emphasises how important it is that these patients develop protective immunity via COVID-19 vaccinations, but, unfortunately, studies have shown that humoral immune responses after COVID-19 vaccination are poor in patients with rheumatic diseases or multiple sclerosis who are taking anti-CD20 agents, even after two doses. 3 , 4 T-cell immunity after COVID-19 vaccination might be relatively unaffected by rituximab, but results from studies have varied, 5 , 6 and whether cellular immunity in the absence of humoral immunity provides sufficient protection against severe COVID-19 remains uncertain.…”