In the ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), patients with coexisting medical conditions have been noted to be at a higher risk of progressive and severe disease. Patients with multiple sclerosis (MS), who are often on immunosuppressive therapy, may be among these high-risk groups.
A new study, released on the medRxiv* preprint server, examines the associations between immunosuppressive disease-modifying therapies (DMTs) used in MS with adverse outcomes in an international cohort of patients with MS COVID-19.
The study included over 2,300 subjects from 28 countries all over the world. Over 70% had confirmed, and the rest were suspected to have, SARS-CoV-2 infection. All patients were 18 years or more.
MS phenotypes were classified as either relapsing/remitting MS (RRMS) or progressive MS (SPMS, PPMS). Other comorbidities were adjusted for, as well as smoker status.
There were more men in the untreated group, and among patients on interferon or ocrelizumab. The untreated group also contained more people above 50 years, as did groups on ocrelizumab, teriflunomide, or Other DMTs.
Of those with higher disability, and among SPMS subjects, more patients were in the untreated group, or those on ocrelizumab or Other DMTs.
Non-DMT factors and adverse outcomes
Females appeared to have a lower risk of hospitalization or death following SARS-CoV-2 infection, while older people were at higher risk. SPMS was associated with a higher risk of hospitalization. All adverse outcomes were associated with higher scores on the Expanded Disability Status Scale (EDSS).
Where outcome data was available, the presence of other underlying conditions was linked to a higher risk of death. Obesity was associated with a greater risk of hospitalization, admission to the intensive care unit (ICU), and ventilation.
DMTs and adverse outcomes
Currently used DMTs were included in the analysis, including rituximab, dimethyl fumarate, beta interferons, ocrelizumab, and fingolimod. A pooled group of Other DMTs was also included. Individual DMTs were first compared for associations with adverse outcomes against dimethyl fumarate.
Dimethyl fumarate is the reference drug because it has not been shown, so far, to promote infection. Moreover, its mechanism of action does not weaken the host immune response to this infection.
The anti-CD 20 DMTs such as rituximab and ocrelizumab are known to act by their selective reduction of B cells in circulation. They, along with other DMTs, do reduce MS activity, but at the cost of a higher risk of infection.
Further comparisons were made between ocrelizumab, rituximab, and no treatment, with Other DMTs. The final assessment was between ocrelizumab and rituximab vs. natalizumab, to adjust for ascertainment bias.
Anti-CD 20 DMTs and COVID-19 severity
When compared with dimethyl fumarate, rituximab was associated with an almost 2.5-fold odds of hospitalization. These patients were at a fourfold odds of ICU admission and of requiring mechanical ventilation.
Ocrelizumab was associated with a 1.6-fold increase in the odds of hospitalization and 2.3-fold higher ICU admission odds. However, the use of DMTs was not associated with death.
Patients who were not on any treatment had a 1.8-fold increase in the odds of hospitalization.
Anti-CD 20 DMTs vs. Other DMTs
When compared with the Other DMTs group, rituximab users were at almost threefold higher odds of hospitalization, had four times the odds of ICU admission, and somewhat higher odds of mechanical ventilation. Ocrelizumab tended to show the same pattern of association with hospitalization and ICU admission, at 75% and 300% higher odds compared to all other DMTs.
Neither of these CD20 antagonists increased the mortality risk, however.
Untreated patients had twofold higher odds of death and of mechanical ventilation, and 2.5 times higher odds of death.
Anti-CD 20 DMTs vs natalizumab
When compared to natalizumab, which is administered every month or two vs. twice a year for the anti-CD20 DMTs, the researchers found that rituximab was associated with three-fold higher odds of hospitalization and ICU admission. The risk of mechanical ventilation was 5.5 times higher.
Ocrelizumab tended to show the same direction of association but showed significance only for hospitalization. Mortality risk was not increased for either of these molecules. This comparison rules out ascertainment bias, making it an important finding.
These associations among all groups were found to be independent of age, MS phenotype, and disability scores. This indicates that the risk is actually associated with the DMTs themselves.
Pooled DMTs that cause increased infection risk are associated with a fourfold increase in COVID-19 severity, relative to those which do not, according to the French COVISEP study7 of 347 MS patients. This grouping does not bring out the significantly different modes of activity, which are relevant to COVID-19 severity since they affect the immune response.
Conversely, the Italian MuSC-19 national registry study of almost 700 COVID-19 patients (suspected and confirmed) showed that the use of anti-CD 20 DMTs increased the risk of severe COVID-19 by more than 2.5-fold, compared to dimethyl fumarate, even after adjusting for other variables.
What are the implications?
The study reports the findings of the largest MS-COVID-19 cohort so far. The findings show that the use of the anti-CD 20 monoclonal antibody rituximab is associated with increased severity of COVID-19 disease. So is ocrelizumab, though to a smaller extent.
Among untreated patients, the increase in severity of COVID-19 is likely to be due to the presence of other risk factors such as progressive MS and higher disability status.
Compared to pooled Other DMTs, and dimethyl fumarate, these drugs were shown to be associated with higher hospitalization and ICU admission odds. Rituximab was also associated with a higher risk of mechanical ventilation.
The consistent association of rituximab with adverse outcomes, as well as the increased magnitude of risk, is noteworthy, especially as it, along with other DMTs, is independent of other factors like age, higher disability status, and progressive MS, which also increase the risk of adverse outcomes.
The difference in magnitude of associations with various poor outcomes between ocrelizumab and rituximab may reflect the difference in binding affinity with CD20, the difference in the antibody type, or the mode of B cell elimination.
This difference is in agreement with earlier studies. However, the potential for confounding factors must be eliminated.
The lack of association of anti-CD 20 DMTs with an increased mortality is discordant with other studies, as well as with other outcomes in the current study. This may indicate the low proportion of older patients, with the over-60 group forming less than a tenth of the sample. Further study is required to elucidate this aspect.
The increase in risk of more severe COVID-19 with anti-CD 20 DMTs rituximab and ocrelizumab suggests “that the risk-vs-benefit of continued or new exposure to CD20-depleting treatment strategies compared to other DMTs needs to be considered in the context of the ongoing COVID-19 pandemic.”
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.