#MSVirtual2020 – Rituximab, Ocrevus Linked to Higher Risk of Worse COVID-19 Outcomes

#MSVirtual2020 – Rituximab, Ocrevus Linked to Higher Risk of Worse COVID-19 Outcomes
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The use of certain disease-modifying therapies (DMTs) such as rituximab and Ocrevus (ocrelizumab), which lower the number of a patient’s immune B-cells, may increase the odds of developing a more severe COVID-19 disease course for people with multiple sclerosis (MS), a study suggests.

The study, which includes data from the largest group of patients with MS and COVID-19 currently available worldwide, found that the use of these two DMTs was associated with a higher rate of hospitalizations, intensive care unit admissions, and ventilatory support.

Study findings were presented at MSVirtual2020 by Steve Simpson-Yap, PhD, from the University of Melbourne, in Australia, in a late-breaking presentation on Sept. 26, titled “First results of the COVID-19 in MS Global Data Sharing Initiative suggest anti-CD20 DMTs are associated with worse COVID-19 outcomes.”

People with multiple sclerosis are thought to be particularly vulnerable to COVID-19, mainly due to the extensive and prolonged use of DMTs, which comprise a group of medications that suppress the activity of the immune system to reduce inflammation and the severity of MS symptoms.

Previous studies have suggested that those who are older, have higher disability, and progressive MS are more likely to develop a severe form of COVID-19. However, the impact of DMTs on the course of the disease is still unclear.

At MSVirtual2020, Simpson-Yap presented the first data from the COVID-19 and MS Global Data Sharing Initiative, an international collaboration that aims to gather information on the impact of COVID-19 on MS patients, with a goal of improving their healthcare during the pandemic. This initiative is being led by the MS International Federation and the MS Data Alliance, along with their partners.

This first analysis, which was focused on assessing the impact different DMTs might have on the severity of COVID-19 in MS patients, was based on clinician-reported data from 1,540 individuals with MS that were obtained from 21 countries worldwide.

Statistical analyses were used to evaluate possible relationships between patient characteristics, including the use of certain types of DMTs, and the rate of hospital and intensive care unit (ICU) admissions, the need for ventilator support, and death.

Among the MS patients identified, 776 (50.4%) had a confirmed diagnosis of COVID-19 and 476 (30.9%) were suspected of having the disease.

Most patients included in the analyses were women (72.4%) and three quarters had relapsing-remitting MS (RRMS; 75.1%). Scores on the Expanded Disability Status Scale (EDSS), which quantifies disability, ranged from 0-6 for 77.1% of the patients; that corresponds to a level of disability that at its worst requires patients to use a crutch or cane to walk.

Regarding DMT use, most patients were being treated with Ocrevus (marketed by Genentech; 19.0%), followed by rituximab (used off-label in MS; 13.2%), and Tecfidera (dimethyl fumarate, marketed by Biogen; 11.8%).

In total, 313 patients were hospitalized, 76 were admitted to the ICU, 54 required ventilation, and 48 died, according to Simpson-Yap.

As in the previous studies, statistical analyses found that being older, having progressive MS, and higher EDSS scores — indicative of higher disability — were all associated with a higher frequency of worse COVID-19 outcomes, namely in terms of hospital admission.

Progressive disease and greater disability also were found to be associated with ICU admission.

Regarding the need for ventilation, “positive trends for progressive MS type and higher disability” were seen but “none reached statistical significance,” Simpson-Yap said.

Finally, concerning death, women were found to be significantly less likely to die, while those with older age, progressive MS, and greater disability were more likely to die.

Analyses also found that the use of certain DMTs that lower the number of CD20-positive B-cells — immune cells that are thought to be one of the key drivers of inflammation in MS — were associated with worse clinical outcomes.

These included rituximab and Ocrevus, two antibody-based therapies specifically designed to target and destroy immune B-cells containing the CD20 protein on their surface.

More specifically, the findings demonstrated that, compared with Tecfidera, rituximab and Ocrevus were both linked to a more severe disease course. The risk of hospitalizations was 1.58 times higher with rituximab and 1.19-times higher with Ocrevus, compared to Tecfidera, while the risk of ICU admissions was 4.12 times higher with rituximab and 3.53 times higher with Ocrevus than Tecfidera. The need for ventilatory support was found to be 7.27 times higher for patients given rituximab and 3.17 times higher for those given Ocrevus compared with those administered Tecfidera.

After restricting these analyses to patients who had a confirmed diagnosis of COVID-19, the investigators found that all of the associations persisted or became stronger.

However, regarding death, “in contrast to these other three outcomes [hospitalization, ICU admission and ventilation], … we see absolutely no association for any of the DMTs with death due to COVID-19,” Simpson-Yap said during the presentation.

A pooled analysis in which investigators compared the outcomes of patients treated with either Ocrevus or rituximab (343 patients in total) with all other types of DMTs (492 patients) confirmed that these CD20-depleting DMTs were associated with a higher risk of hospitalization (1.49 times higher risk), ICU admittance (2.55 times), and need for artificial ventilation (3.05 times). No significant difference was found in terms of death.

Similar findings were obtained when the team assessed the risk of the three outcomes — hospitalization, ICU admission, and ventilation —  in patients treated with either Ocrevus or rituximab compared with those who were receiving Tysabri (natalizumab; 90 patients in total). Tysabri is another antibody-based DMT that has a different mechanism of action.

Based on the results, Simpson-Yap concluded that “rituximab is positively associated with hospital, ICU admission, and ventilation,” and that “Ocrelizumab also shows a positive trend for all those outcomes as well, although of weaker magnitude.”

When compared with other DMTs, patients on “anti-CD20 DMTs have higher frequencies of hospital admission, ICU admission and artificial ventilation, but not death,” the researcher added.

Compared with Ocrevus, rituximab seems to have a stronger effect on COVID-19 outcomes.

“We think the most simple and appropriate explanation is the fact that even though they both [Ocrevus and rituximab] bind the exact same epitope… of the CD20 molecule, rituximab binds much more strongly. Potentially this stronger binding to the CD20 molecule could result in a stronger depletion of B-lymphocytes, which could potentially lead to greater COVID-19 severity,” Simpson-Yap suggested.

Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Joana holds a BSc in Biology, a MSc in Evolutionary and Developmental Biology and a PhD in Biomedical Sciences from Universidade de Lisboa, Portugal. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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